Biochemistry Flashcards

Question

Hypoxanthine

Answer 1

It can be salvaged by hypoxanthine guanine phosphoribosyltransferare (HGPRT), which converts hypoxanthine into IMP. Or it can be further degraded into xanthine, then uric acid by xanthine oxidase (XO). XO is inhibited by allopurinol or febuxostat. Uric acid is then converted into urine, which is induced by probencid.

Answer 2

ADA converts adenosine into inosine within the purine salvage pathway. A deficiency leads to an excess of ATP and dATP, which causes an imbalance in nucleotide pool. Excess dATP inhibits ribonucleotide reductase, thereby preventing DNA synthesis and thus decreasing lymphocyte count. It is one of the major causes of autosomal recessive SCID.

Answer 3

Lesch-Nyhan syndrome results from a deficiency in hypoxanthine-guanine phosphoribosyl transferase (HGPRT), causing an excessive buildup of uric acid and de novo purine synthesis due to buildup of PRPP. Lesch-Nyhan syndrome is a X-linked recessive disorder. HGPRT normally converts hypoxanthine to IMP and guanine to GMP. Lesch-Nyhan syndrome clinical presents with: Mental retardation, Self-mutilation, Gout from hyperuricemia, Dystonia. Lesch-Nyhan syndrome is treated with allopurinol or febuxostat as a second line medication. HGPRT: Hyperuricemia, Gout, Pissed off (aggression and self mutilation), Retardation, dysTonia.

Answer 4

It is unambiguous; each codon specifies only 1 amino acid. It is degenerate/redundant; most amino acids are coded by multiple codons. Exceptions include methionine and tryptophan, which are encoded by only 1 codon (AUG and UGG, respectively). It is commaless and nonoverlapping; it is read from a fixed starting point as a continuous sequence of bases (exceptions are some viruses). It is universal; genetic code is conserved throughout evolution.

Answer 5

Prokaryotic replication uses only 1 ORI (origin of replication). Eukaryotic replication uses multiple ORI’s. DNA replication is semiconservative, in that each resulting dsDNA has 1 strand from the parent DNA and 1 new strand. Regardless of which strand is being replicated, DNA replication proceeds in the 5' to 3' direction.

Answer 6

The leading strand of parent DNA is the one whose sequence is complementary to the natural 5' to 3' direction of synthesis (i.e. 3' to 5'), allowing for continuous synthesis.

Answer 7

The lagging strand must be synthesized in discontinuous Okazaki fragments, because the parent DNA sequence is 5' to 3' but DNA replication must still proceed in a 5' to 3' direction. These fragments are synthesized in the 5' to 3' direction (which is away from the replication fork), then polymerase jumps "behind" the newly made segment (in normal direction of the replication fork), and makes a new fragment until the previous fragment is bumped into.

Answer 8

It unwinds DNA at the replication fork.

Answer 9

SSBPs (single-strand binding proteins) prevent DNA from reverting to duplex form (re-annealing). The strong hydrogen bonds between nucleotide bases attract one another.

Answer 10

Gyrase (a topoisomerase type II enzyme) introduces negative supercoils, thereby relaxing positive supercoils that form during helicase unwinding.

Answer 11

DNA Primase synthesizes a short RNA segment on the ssDNA template. No DNA polymerase can start synthesis without a DNA or RNA primer.

Answer 12

DNA Polymerase III (the main prokaryotic polymerase) adds DNA nucleotides to the hydroxyl group on the 3’ end of the new strand (synthesis is therefore 5’ to 3’). DNA Pol III also has a 3’ to 5’ proofreading ability w/ exonuclease function to correct mistakes.

Answer 13

DNA polymerase I (a prokaryotic polymerase) degrades the RNA primer that blocks cohesiveness between Okazaki fragments. Because Okazaki fragments are synthesized in the 5' to 3' direction just like leading strand synthesis, DNA polymerase therefore has 5' to 3' exonuclease activity. It is the only polymerase with this unique activity.

Answer 14

Eukaryotic DNA replication is similar to prokaryotic replication, with analagous enzymes that have different names. DNA Pol α acts in a complex with RNA primase in the following manner: RNA primase lays down a short series of RNA molecules (as DNA primase does in prokaryotes)

Answer 15

DNA Pol α (eukaryotic polymerase) elongates the RNA primer with ~20 DNA nucleotides. Once this short strand of nucleotides is finished, the DNA Pol α/RNA primase dissociates and DNA Pol δ takes over.

Answer 16

The main eukaryotic DNA polymerase. It has 3’ to 5’ exonuclease proofreading and is analogous to prokaryotic DNA Pol III.

Answer 17

Telomerase is a reverse transcriptase enzyme with an intrinsic RNA template that adds DNA to the end of the parent strand of a replicating chromosome to avoid chromosome shortening with each round of replication. Stem cells and cancer cells upregulate telomerase activity to enhance replicative ability.

Answer 18

Catalyzes the formation of a phosphodiester bond within a strand of double stranded DNA.

Answer 19

In a transition, a purine is substituted for a purine or a pyrimidine is substituted for a pyrimidine (adenine for guanine).

Answer 20

In a transversion, purine get converted into pyrimidine or pyrimidine get converted into purine (adenine for thymine).

Answer 21

Order of increasing severity: silent, missense, nonsense, frameshift.

Answer 22

mutation that yields the same amino acid (often a base change in the 3rd position of a codon yields the same amino acid due to tRNA wobble) Amino acid mutations in other positions can also lead to silent mutations because the genetic code is degenerate. This means that amino acids can be coded for by more than one codon. (the exceptions are methionine, which is only encoded by AUG, and tryptophan encoded by UGG).

Answer 23

mutation that creates a change in the amino acid

Answer 24

a type of missense mutation that yields a new amino acid with a similar chemical property as the original amino acid (e.g. hydrophobic)

Answer 25

mutation that creates an early stop codon, making the protein truncated. (It’s early, stop the nonsense!)

Answer 26

deletion or addition of any number of nucleotides not divisible by 3, that causes all downstream codons to change. Occurs because the genetic code is commaless & non-overlapping (read from a single starting point in a continuous string)

Answer 27

This is a classic example of a genetic response to an environmental change. Glucose is the preferred metabolic substrate in E. cole, but when glucose is absent and lactose is available, the lac operon is activated to switch to lactose metabolism. Low glucose triggers an increase adenylyl cyclase activity, which generates cAMP from ATP. This activates catabolite activator protein (CAP), increasing transcription. High lactose unbinds repressor protein from repressor/operate site, increasing transcription.

Answer 28

Special structure-specific endonucleases recognize bulky distortions alter the shape of the DNA double helix. A small region of DNA on either side of the damaged base (about 20 base pairs total) is removed from the DNA helix. Sequential action of DNA polymerase and DNA ligase fills in the gap left by the NER enzymes. UV light-induced damage is primarily managed through nucleotide excision repair. The characteristic DNA lesion produced by UV light is the pyrimidine dimer (e.g. thymine dimer). The electrochemical ramifications of this dimer cause the bulky distortion recognized by NER enzymes. Defects in nucleotide excision repair enzymes cause xeroderma pigmentosum. Patients with xeroderma pigmentosum have a greatly increased risk of developing skin cancer, often during childhood. Xeroderma pigmentosum is an autosomal recessive disorder. Nucleotide excision repair occurs in the G1 phase of the cell cycle.

Answer 29

Base excision repair is another method of repairing single-strand DNA damage. It is characterized by the following steps: 1. Glycosylase enzymes recognize and remove incorrectly paired and chemically altered bases without interrupting the phosphodiester backbone. 2. AP-endonuclease (AP can stand for both apyrimidinic and apurinic) enzymes detect that a base is missing and begin the process of excision by making an endonucleolytic cut on the 5′-side of the AP location. 3. Lyase cuts at the 3'-end to remove the baseless sugar-phosphate molecule. 4. DNA Pol I (prokaryotic) or DNA Pol β (human) then replaces the damaged base and DNA ligase seals the new DNA strand. Base excision repair is the DNA repair modality used to repair spontaneous deamination of cytosine to uracil, which occurs randomly and consistently throughout the body's cells. Base excision repair occurs in all phases of the cell cycle.

Answer 30

Mismatch repair is a third single-strand DNA repair modality, which recognizes and fixes mispaired bases (G-T or A-C pairs). Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition in which a defective mismatch repair gene causes a microsatellite repeat replication error to go unfixed. Mismatch repair enzymes are most active in the G2 phase of the cell cycle.

Answer 31

There are two methods of correcting double strand DNA breaks: homologous recombination (HR) and non-homologous end joining (NHEJ). HR results in accurate repair while NHEJ can cause significant errors because homology is not checked for when DNA fragments are joined. NHEJ is the predominant method of double-stranded break repair in mammals. Mutations genes that participate in non-homologous end joining lead to ataxia-telangiectasia and Fanconi anemia.

Answer 32

Brings together two ends of DNA fragments to repair double stranded breaks. No requirement for homology. Some DNA may be lost. Mutated in ataxia telangiectasia and Fanconi anemia

Answer 33

DNA and RNA are both synthesized from 5' to 3'. The 5' end of the incoming nucleotide bears the triphospate (energy source for bond). Protein synthesis is N-terminus to C-terminus. mRNA is read 5' to 3'. The triphosphate bond is the target of the 3' hydroxyl attack. Drugs blocking DNA replication often have modified 3' OH, preventing addition of the next nucleotide (chain termination).

Answer 34

AUG (or rarely GUG). AUG inAUGurates protein synthesis. In eukaryotes, it codes for methionine, which may be removed before translation is completed. In prokaryotes, it codes for N-formylmethionine (fMet). fMet stimulates neutrophil chemotaxis.

Answer 35

UGA, UAA, UAG. U Go Away, U Are Away, U Are Gone.

Answer 36

Promoters are where RNA polymerase and transcription factors (TFs) bind to initiate transcription (often located 25 to 50 bases upstream of the gene, and often contains A-T rich sequences of TATA or CAAT boxes)

Answer 37

Enhancers also bind transcription factors, and can significantly ↑ the rate of transcription (can be located upstream, downstream, or a distance from the gene)

Answer 38

Silencers repress transcription when repressors, a subset of transcription factors, bind to them (known as operators in prokaryotes)

Answer 39

Response elements bind specific transcription factors (e.g. heat shock response element, estrogen response element) and modulate transcription

Answer 40

RNAP I transcribes rRNA (most abundant). "Rampant, Massive, Tiny": RNAP I transcribes the most abundant type rRNA, RNAP II transcribes the longest type mRNA, RNAP III transcribes the shortest type tRNA

Answer 41

RNAP II transcribes mRNA

Answer 42

RNAP III transcribes tRNA (shortest RNA)

Answer 43

α-amanitin (deadly toxin found in certain mushrooms) inhibits RNAP II causing liver damage when ingested

Answer 44

In contrast to eukaryotes (which use three different RNA polymerases), prokaryotic RNA Polymerase RNAP can synthesize all the three kinds of RNA (mRNA, rRNA, tRNA). RNA polymerases do not require primers. Prokaryotic RNAP binds directly to promoters

Answer 45

Eukaryotic RNAP’s require transcription factors (pre-initiation complex) to direct transcription. Examples of transcription factors include TATA Binding Protein (TBP), which binds the TATA box in the promoter region, and Transcription Factors (TF) such as TFIIA.

Answer 46

The 3 primary modifications that occur in post-transcriptional processing include: 5’ capping, 3’ poly-adenylation, Splicing

Answer 47

5’ capping adds a 7-methylguanosine to the 5’ end of the transcript. The cap protects the transcript from ribonucleases and is involved in initiating translation of mRNA.

Answer 48

Poly (A) polymerase adds the 3’ poly-A tail, as many as 200 adenines (does not require a template). The poly-A tail facilitates the mRNA’s exit from the nucleus and is also thought to protect the transcript from 3’ to 5’ exonuclease activity.

Answer 49

Splicing removes introns (non-coding segments); the remaining exons are re-joined to form a single transcript. INtrons are INtervening segments and are removed; EXons are EXpressed. Splicing is catalyzed by the spliceosome and snRNPs (small nuclear ribonucleoproteins). Splicing occurs in the nucleus. Small nuclear ribonucleoproteins (snRNPs) include: U1, U2, U4, and U6. Antibodies directed against U1 RNP (ribonucleoprotein) are associated with mixed connective tissue disease (MCTD).

Answer 50

Alternative splicing allows multiple proteins to be translated from a single transcript (e.g. antibodies); though exons are usually expressed, in alternative splicing some exons may be discarded in a controlled fashion.

Answer 51

Transfer RNA (tRNA) is composed of 75-90 nucleotides. The secondary structure is "cloverleaf,"while the tertiary structure is "L-shaped". The "bottom" of the cloverleaf houses the anti-codon, which pairs with mRNA codons when brought together in a ribosome. The 3’ end of tRNA has a CCA sequence that accepts the amino acid to be matched with it. Mnemonic: CCA "Can Carry Amino Acids". The T-arm of tRNA facilitates binding of the tRNA to the ribosome for protein synthesis. The T-arm of tRNA contains the sequence TΨC, which stands for: Ribothymidine, Pseudouridine, Cytidine. The D-arm of tRNA contains dihydrouridine residues that act as a recognition site for for the corresponding aminoacyl-tRNA synthetase.

Answer 52

Aminoacylation (aka "charging") covalently bonds an amino acid to the 3’ end of the tRNA. There is one aminoacyl-tRNA synthetase per amino acid. Because the genetic code is degenerate, some amino acids use multiple different tRNAs that recognize different codons that code for the same amino acid. Thus, each aminoacyl-tRNA synthetase may recognize multiple tRNAs but only one amino acid. Aminoacylation (aka "charging") uses ATP. It gives a phosphate group (hence "charged") that later provides energy for peptide bond formation; aminoacylation converts ATP to AMP (2 phosphate bonds).

Answer 53

Aminoacyl-tRNA synthetases proofread both before and after charging a tRNA with an amino acid. If the wrong amino acid is on the tRNA, the covalent bond is hydrolyzed. In the event that an error in proofreading occurs, a mischarged tRNA is formed. Mischarged tRNAs insert the incorrect amino acid into a growing polypeptide chain because they retain the ability to read the codon corresponding to the amino acid they should have been matched to.

Answer 54

The 3rd position of the mRNA codon isn’t as critical to pairing and is allowed some "wobble" with respect to nucleotide base pairing with the tRNA. tRNAs that code for the same amino acid often differ in this "wobble" position.

Answer 55

The process of converting the mRNA message into protein is called translation. Translation has three steps: Initiation, Elongation, Termination. The "A" of A-site stands for "aminoacyl"; it’s where the aminoacyl-tRNA complexes (except initiation tRNA) enter. The "P" of P-site stands for "polypeptide"; it’s where the polypeptide chain sits. The "E" of E-site stands for "exit" and holds the empty tRNA as it is exiting the ribosome.

Answer 56

Initiation: Using GTP, the small ribosomal subunit binds upstream on the 5’ end, then proceeds downstream (5' to 3') until AUG (start codon) is encountered. Prokaryotic small subunit: 30S. Eukaryotic small subunit: 40S. Mnemonic:"prOkaryotic=Odd=30S (small), 50S (large), 70S (whole ribosome complex), Eukaryotic=Even=40S (small), 60S (large), 80S (whole ribosome complex)". The small ribosomal subunit is joint by the large subunit, initiation factors, and the initiator tRNA. The initiator tRNA (Met or fMet) enters the P-site. The initiation factors dissociate from the ribosome-mRNA complex once initiation is complete. Prokaryotic large subunit: 50S. Eukaryotic large subunit: 60S. Mnemonic:"prOkaryotic=Odd=30S (small), 50S (large), 70S (whole ribosome complex), Eukaryotic=Even=40S (small), 60S (large), 80S (whole ribosome complex)". Initiator tRNA is the only tRNA that can bind to the P-site; all others bind to A-site.

Answer 57

Elongation begins when a tRNA enters the A-site. Binding of the aminoacyl tRNA to the A-site requires GTP hydrolysis (think "G" for Gripping, i.e. binding) and elongation factors (EFs). Ribosomal peptidyl transferase catalyzes formation of a peptide bond between the amino acids in the A and P sites. The prior tRNA is released from the P-site. As peptidyl transferase catalyzes the new peptide bond, the ribosome translocates one codon downstream, moving the latest tRNA and the newly elongated polypeptide chain into the P-site and emptying the A-site. Translocation consumes 1 GTP (think "G" for Going places, i.e. translocation). So, two GTP are used per cycle, one for binding ("Gripping") of the aminoacyl tRNA and one for translocation ("Going places") of the ribosome along the mRNA.

Answer 58

Stop codons are recognized by protein release factors, which release the polypeptide from the ribosome and cause the ribosomal subunits to dissociate. In all, translation uses 4 high-energy phosphate bonds per amino acid: 2 during aminoacylation (tRNA charging): ATP to AMP (A for Activation). 1 during tRNA "loading" into the A-site: GTP to GDP (G for Gripping). 1 during translocation: GTP → GDP (G for Going places)

Answer 59

Removal of N or C-termininal propeptides from zymogen to generate mature protein (eg trypsinogen to trypsin).

Answer 60

Phosyphorylation, glycosylation, hydroxylation, methylation, acetylation, and ubiquitnation

Answer 61

Intracellular protein involved in facilitating and/ or maintaining protein folding. For example, in yeast, heat shock proteins (eg Hsp60) are expressed at high temperatures to prevent protein denaturing/ misfolding.

Answer 62

Checkpoints control transitions between phases of cell cycle. This process is regulated by cyclins. This process is regulated by cyclins, cyclin dependent kinases (CDKs), and tumor suppressors. M phase (the shortest phase of cell cycle) includes mitosis (prophase, prometaphase, metaphase, anaphase, telophase) and cytokinesis (cytoplasm splits in two). G1 and G0 are of variable duration.

Answer 63

Constitutive and inactive.

Answer 64

Regulatory proteins that control cell cycle events. It is phase specific. It activates CDKs.

Answer 65

Phosphorylate other proteins to coordinate cell cycle progression. It must be activated and inactivated at appropriate times for cell cycle to progress.

Answer 66

p53 and hypophosphorylated Rb normally inhibits G1 to S progression. Mutations in these genes result in unrestrained cell division (eg Li- Fraumeni syndrome).

Answer 67

Remain in G0, regenerate from stem cells. For example, neurons, skeletal and cardiac muscle, RBCs.

Answer 68

Enter G1 from G0 when stimulated. For example, hepatocytes and lymphocytes.

Answer 69

It never goes to G0, divide rapidly with a short G1. They are the most affected by chemotherapy. For example, bone marrow, gut epithelium, skin, hair follicles, and germ cells.

Answer 70

It is the site of synthesis of secretory (exported) proteins and of N-linked oligosaccharide addition to many proteins.

Answer 71

Nissl bodies (RER in neurons) and synthesize peptide neurotransmitters for secretion.

Answer 72

They are unattached to any membrane and is the site of synthesis of cytosolic and organellar proteins. Mucus secreting goblet cells of the small intestine and antibody secreting plasma cells are rich in RER.

Answer 73

I is the site of steroid synthesis and detoxification of drugs and poisons. Lacks surface ribosomes. Liver hepatocytes and steroid hormone-producing cells of the adrenal cortex and gonads are rich in SER.

Answer 74

The golgi is the distribution center for proteins and lipids from the ER to the vesicles and plasma membrane. It modifies N-oligosacharides on asparagine and adds O-oligosaccharides on serine and threonine. It adds mannose-6-phosphate to proteins for trafficking lysosomes.

Answer 75

Endosomes are sorting centers for material from outside the cell or from the Golgi, sending it to lysosomes for destruction or back to the membrane/Golgi for further use.

Answer 76

Also called inclusion cell disease. It is an inherited lysosomal storage disorder with a defect in N-acetylglucosaminyl-phosphotransferase, which causes there to be a failure of the Golgi to phosphorylate mannose residues (ie a decrease in mannose-6-phosphate) on glycoproteins, which causes proteins to be secreted extracellularly rather than delivered to lysosomes. It results in coarse facial features, clouded corneas, restricted joint movement, and high plasma levels of lysosomal enzymes. It is often fatal in childhood.

Answer 77

Abundant, cytosolic ribonucleoprotein that traffics proteins from the ribosome to the RER. If it is absent or dysfunctional, than proteins accumulate in the cytosol.

Answer 78

A vesicular trafficking proteins. Transports vesicles retrograde in the Golgi, to cis Golgi, to ER.

Answer 79

A vesicular trafficking proteins. Transport vesicles anterograde from ER to cis-ER.

Answer 80

A vesicular trafficking proteins. Transports vesicles from trans-golgi to lysosomes and plasma membrane to endosomes (receptor mediated endocytosis [eg LDL receptor activity]).

Answer 81

Membrane enclosed organelle involved in catabolism of very-long chain fatty acids, branched chain fatty acids, and amino acids.

Answer 82

Barrel shaped protein complex that degrades damaged or ubiquitin-tagged proteins. Defects in the ubiquitin- proteasome system have been implicated in some cases of Parkinson disease.

Answer 83

A network of protein fibers within the cytoplasm that supports cell structure, cell and organelle movement, and cell division. Includes microfilaments, intermediate filaments, and microtubules.

Answer 84

Involved in muscle contraction and cytokinesis. An example is actin.

Answer 85

Involved in maintaining cell structure. Examples include vimentin, desmin, cytokeratin, lamins, glial fibrillary acid proteins (GFAP), neurofilaments.

Answer 86

Involved in movement and cell division. Examples include cilia, flagella, mitotic spindle, axonal trafficking centrioles. They are of cylindrical structure composed of a helical array of polymerized heterodimers of alpha and beta tubulin, which create protofilaments, which combine to create microtubule. Each dimer has two GTP bound. Incorporated into flagella, cilia, mitotic spindles. They grow slowly, collapses quickly. It is also involved in slow axoplasmic transport in neurons.

Answer 87

located within connective tissue.

Answer 88

Located within muscle (Muscle=desMin).

Answer 89

Located within epithelial cells

Answer 90

Located within neuroGlia

Answer 91

Located within neurons

Answer 92

Dynein acts retrograde to microtubule (from positive to negative). They transport cellular cargo toward opposite ends of microtubule tracks.

Answer 93

Acts anterograde to microtubule (from negative to positive)

Answer 94

Mebendazole (antihelminthic), Griseofluvin (antifungal), Colchicine (antigout), Vincristine/Vinblastine (anticancer), Paclitaxel (anticancer). Microtubules Get Constructed Very Poorly.

Answer 95

9+2 arrangement of microtubule doublets.

Answer 96

ATPase that links peripheral 9 doublets and causes bending of celium by differential sliding of doublets.

Answer 97

Also called primary ciliary dyskinesia. It causes there to be immotile cilia due to a dynein arm defect. It results in male and female infertility due to immotile sperm and dysfunctional fallopian cube cilia, respectively. It increases the risk of ectopic pregnancy. It can cause bronchiectasis, recurrent sinusitis, and situs inversus (eg dextrocardia on CXR).

Answer 98

Asymmetric lipid bilayer. It contains cholesterol, phospholipids, sphingolipids, glycolipids, and proteins. Fungal membranes contain ergosterol.

Answer 99

Na-K ATPase is located in the plasma membrane ATP site on cytosolic side. For each ATP consumed, 3 Na go out of the cell (pump phosphorylated) and 2 K come into the cell (pump dephosphorylated). Ouabain inhibits the pump by binding to K site. Cardiac glcosides (digoxin and digitoxin) directly inhibit the Na-K ATPase, which leads to indirect inhibition of Na/Ca exchange, causing there to be a higher intracellular [Ca], increasing cardiac contractility.

Answer 100

It is the most abundant protein in the human body. It is extensively modified by posttranslational modification. It organizes and strengthens extracellular matrix. Be (So Totally) [type I] Cool [type II] Read [type III] Books [type IV]. Bone (Skin, Tendon), Cartilage, Reticulin, and Basement membrane.

Answer 101

It is the most common (90%). Located within bone (made by osteoblasts), skin, tendon, dentin, fascia, cornea, late wound repair. There is decrease production in osteogenesis imperfecta type I. (Type I= bONE).

Answer 102

Located within cartilage (including hyaline), vitreous body, nucleus pulposus. (Type II= carTWOlage)

Answer 103

Located with reticulin, including skin, blood vessels, uterus, fetal tissue, and granulation tissue. This is deficiency in the uncommon, vascular type of Ehlers-Danlos syndrome.

Answer 104

Located within basement membrane, basal lamina, and lens. It is defective in Alport syndrome and is the target of autoantibodies in Goodpasture syndrome. (Type IV, under the floor).

Answer 105

Occurs within the RER of fibroblasts. Translation of collagen alpha chains (preprocollagen), usually Gly-X-Y (X and Y are proline or lysine). Glycine content best reflects collagen synthesis (collagen is 1/3 glycine).

Answer 106

Occurs within the RER of fibroblasts. Hydroxylation of specific proline and lysine residues, which requires vitamin C (deficiency causes scurvy).

Answer 107

Occurs within the RER of fibroblasts. Glycosylation of pro-alpha-chain hydroxylysine residues and formation of procollagen via hydrogen and disulfide bonds (triple helix of 3 collagen alpha chains). Problems forming triple helix causes osteogenesis imperfecta.

Answer 108

Exocytosis of procollagen from fibroblasts into extracellular space.

Answer 109

Cleavage of disulfide-rich terminal regions of procollagen, transforming it into insoluble tropocollagen. Occurs outside of the fibroblasts.

Answer 110

Reinforcement of many staggered tropocollagen molecules by covalent lysine-hydroxylysine cross-linkage (by copper-containing lysyl oxidase) to make collagen fibrils. Problems with cross-linking causes Ehlers Danlos syndrome, Menkes disease.

Answer 111

A genetic bone disorder (brittle bone disease) caused by a variety of gene defects. The most common form in autosomal dominant with a decrease production of otherwise normal type I collagen. Manifestations can include multiple fractures with minimal trauma (may occur during the birth process), blue sclera due to the translucency of the connective tissue over the choroidal veins, hearing loss (abnormal ossicles), dental imperfections due to a lack of dentin.

Answer 112

Polymerase chain reaction (PCR) is a laboratory technique that can be used to amplify a specific DNA segment. One cycle of the polymerase chain reaction (PCR) is as follows. In a PCR tube, the following are placed: DNA sample of interest. Two different known primers (one for each strand of the double-stranded DNA). Taq polymerase. Nucleotides. DNA is heated (95ºC) to denature and separate the strands. The sample is cooled (50ºC) to anneal the primer to the sample. The primer sequence must be known, usually ~20 nucleotides long. DNA primers are in molar excess so that upon cooling it is the primer that anneals to the strand. The sample is heated to 72ºC and Taq DNA polymerase (or another heat stable DNAP) elongates the primer, generating a new copy of the desired DNA fragment. The process is repeated; every cycle doubles the number of copies (8 cycles = 2^8 copies = 256 copies).

Answer 113

Faulty collagen synthesis causing hyperextensible skin, tendency to bleed (easy bruising), and hypermobile joints. There are multiple types. Inheritance and severity vary. It can be autosomal dominant or recessive. It may be associated with joint dislocation, berry and aortic aneurysms, and organ rupture. Hypermobility type (joint instability) is the most common type. The classical type (joint and skin symptoms) is caused by a mutation in type V collage. Vascular type (vascular and organ rupture) is caused by a deficiency in type III collagen.

Answer 114

X-linked recessive connective tissue disease caused by impaired copper absorption and transport due to defective Menkes protein (ATP7A). This leads to a decrease in activity of lysyl oxidase (copper is a necessary cofactor). this results in brittle, kinky hair, growth retardation, and hypotonia.

Answer 115

It is the stretchy protein within skin, lungs, large arteries, elastic ligaments, vocal cords, ligamenta flava (connect vertebrae in either relaxed or stretched conformations). It is rich in nonhydroxylated proline, glycine, and lysine residues. Synthesis of elastin involves cross-linking multiple tropoelastin molecules on a fibrillin (encoded by the FBN1 gene) framework. Cross-linking takes place extracellularly and gives elastin its elastic properties. It is broken down by elastase, which is produced by neutrophils and some other cell types such as macrophages. Elastin is normally inhibited by alpha 1-antitrypsin.

Answer 116

It is caused by a defect in fibrillin, a glycoprotein that forms a sheath around elastin.

Answer 117

α1-antitrypsin is a protein that inhibits excess elastase (thereby protecting elastin proteins). A deficiency in α1-antitrypsin causes emphysema as elastase destroys pulmonary elastin. α1-antitrypsin deficiency also causes cirrhosis due to accumulation of misfolded α1-antitrypsin proteins in the liver. These accumulations can be seen by PAS stain on histological section. Wrinkles of aging are due to a decrease in collagen and elastin production.

Answer 118

Blotting is a molecular biology technique that checks for the presence of a specific sequence of nucleotides or protein in a sample (usually encased in a gel). SNoW DRoP: Southern=DNA, Northern=RNA, Western=Protein.

Answer 119

Southern blot detects DNA. The process involves the following steps: 1. DNA samples are separated (via electrophoresis) on a gel. 2. Separated DNA is transferred to a filter. 3. DNA is exposed to a labeled DNA probe that anneals to its complement. 4. Labeled probe is visualized, locating the DNA sample of interest

Answer 120

Northern blot detects RNA. The process is the same as Southern blot, except the sample is RNA, not DNA. Note that the probe remains DNA.

Answer 121

Western blots detect protein. The process involves: 1. Proteins are electrophoretically separated and transferred to a filter. 2. A primary antibody (specific to the protein of interest) is applied. 3. Excess primary antibody is washed off, and secondary antibody (enzyme-linked, e.g. horseradish peroxidase) is applied. Secondary antibody recognizes and binds to the primary antibody. 4. An appropriate substrate is added to visualize the bands of interest. The western blot is the confirmatory test in a presumed HIV infection. (ELISA is the screening test).

Answer 122

Southwestern blot detects interactions between DNA and proteins. Southwestern blots are used to study the interaction of DNA with DNA-binding proteins, such as proteins that regulate transcription. The steps of a southwestern blot are as follows: 1. Proteins are separated (via electrophoresis) on a gel. 2. Proteins are transferred to a filter. 3. Proteins are exposed to radiolabeled known DNA sequences. 4. Proteins that bind that sequence will bind the DNA, which can then be visualized on a film

Answer 123

DNA microarray is a glass chip that contains an arrangement of thousands of sample genes. They are used to measure gene expression in any given cell by taking advantage of the fact that mRNA (and cDNA) binds to its parent DNA. DNA oligonucleotides with known sequences are synthesized by machines and immobilized on the grid. mRNA from the cell of interest is isolated and used to construct a cDNA library, which contains fluorescent tags. This forms the “mobile probe”. The “mobile probe” can consist of cDNA, mRNA or DNA. The fluorescent probe is then incubated on the immobilized sequences and allowed to hybridize. The more sample that binds, the greater the degree of fluorescence, which represents higher gene expression. Used to simultaneously profile gene expression of different tissues and diseases.

Answer 124

Enzyme linked immuno-sorbent assay (ELISA) is a biochemical technique used to detect the presence of antigens or antibodies in blood. Direct ELISA detects antigen presence in a patient sample by applying an antibody conjugated to a color generating or fluorescent enzyme. If the antigen is present, the antibody will bind it and the enzyme will change color or fluoresce. Indirect ELISA can detect antigens or antibodies. The steps are: 1. A test antigen is applied to detect an antibody in a patient sample, or an antibody is applied to detect an antigen in a patient sample. 2. A second antibody conjugated to a color generating or fluorescent enzyme is then applied. 3. The second antibody binds the antigen-antibody complex and changes color or fluoresces. ELISA has both high sensitivity and high specificity.

Answer 125

A process in which metaphase chromosomes are stained, ordered, and numbered according to morphology, size, arm-length ratio, and banding pattern. It can be performed on a sample of blood, bone marrow, amniotic fluid, or placental tissue. It is used to diagnose chromosomal imbalances (eg autosomal trisomies and sex chromosome disorders).

Answer 126

Fluorescent in situ hybridization (FISH) is a cytogenetic technique that allows scientists to detect the presence and location of a specific sequence of DNA or RNA. The process for performing a basic FISH are as follows: The DNA double helix is separated by heating or chemicals. A fluorescent DNA probe hybridizes to its complementary DNA. The sample is washed to remove excess probe and visualized under a microscope. Though the steps for a DNA FISH are described above, this process can be used to probe for both specific DNA and RNA sequences. FISH can be used to detect deletions, translocations, and duplications that are too small to be detected by karyotype. Another advantage of FISH over karyotype is that FISH can be used on non-mitotic cells (i.e. FISH can be used on cells in interphase).

Answer 127

Cloning is a recombinant DNA technique in which specific cDNA is incorporated into a cloning vector, which then is inserted into cultured host cells. The cDNA can then be expressed in large amounts. The steps for using a plasmid as a vector for cloning are as follows: 1. Eukaryotic mRNA is isolated and reverse transcriptase is used to generate cDNA without intron and exon regions (this is necessary because prokaryotes don't have the necessary machinery to process the introns and exons of eukaryotic genes). 2. Restriction enzymes are used to insert the cDNA into the plasmid which also contains antibiotic resistance. 3. Competent cells (e.g. E. coli) are then used to take up the plasmid. This process is known as transformation. The bacteria are then grown in antibiotic medium and only the cells containing the plasmid (and thus gene of interest and antibiotic resistance) will proliferate.

Answer 128

Carrier for the recombinant DNA of interest. Commonly used vectors includes plasmids, BAC (bacterial artificial chromosomes), and viruses (e.g. λ phage).

Answer 129

Strategies for the modulation of gene expression include: Knock-down, which is the inactivation or removal of mRNA encoding a particular gene. Knock-out, which is the inactivation or removal of DNA encoding a particular gene. Knock-in, which is the addition of DNA encoding a particular gene. Transgenic mice can be generated by both nonhomologous (random) or homologous (targeted) recombination in mouse embryonic stem cells.

Answer 130

The Cre-lox system is used to inducibly delete a gene at particular developmental timepoint or in a particular tissue. This is a particularly useful strategy for studying genes whose deletion is embryonic lethal or for studying the tissue-specific role of a gene.

Answer 131

RNA interference is commonly used to knock-down a gene of interest. RNA interference uses synthetic dsRNA that is complementary to the targeted mRNA sequence. After transfection, the synthetic dsRNA is: Separated into ssRNA; The complementary ssRNA sequence binds the targeted mRNA sequence; The newly-formed dsRNA complex is degraded, knocking-down gene expression

Answer 132

Allelic heterogeneity is exhibited when different mutations in the same gene (at the same locus) cause similar phenotype. Example: Duchenne and Becker muscular dystrophy have a similar phenotype and both are caused by dystrophin mutations. However, Duchenne muscular dystrophy is a frameshift mutation resulting in nonfunctional protein, while Becker muscular dystrophy is another mutation (usually a point mutation) that retains some dystrophin function.

Answer 133

Anticipation is the phenomenon in which a disease exhibits increased severity or an earlier age of onset with each succeeding generation. Example: Trinucleotide repeat diseases such as Huntington disease or myotonic dystrophy classically exhibit anticipation.

Answer 134

Codominance describes genes whose alleles are both expressed simultaneously (i.e. dominance is shared). Example: The ABO blood group exhibit codominance, such that both the A and B antigen alleles may be expressed individually or simultaneously (type AB blood).

Answer 135

Dominant negative mutations occur when the product of the mutant allele actually inactivates the product of the normal gene. Thus, the mutation exerts a dominant effect. Example: Mutant forms of fibrillin-1 in Marfan syndrome interfere with the utilization of the normal protein from the normal allele.

Answer 136

Heteroplasmy is a condition in which there is a mixture of normal and mutant mitochondrial DNA within a cell or individual. As such, there is inconsistent expression (variable expressivity) of the disease among patients. Example: Heteroplasmy is classically tested as the genetic mechanism observed in mitochrondrial myopathies (recall the "ragged red fiber" appearance of these myopathies on muscle biopsy).

Answer 137

Imprinting is an allele inactivation process (via methylation) that results in the presence of only one active allele at some gene loci. While this occurs physiologically in some genes without consequence, it produces pathology when the active allele is mutated. Example: Classically, Prader-Willi and Angelman syndromes are two disorders that may result from mutation of an active allele when the other allele is imprinted. In Prader-Willi syndrome, a paternal gene is deleted at a loci where the maternal allele is imprinted. In Angelman syndrome, a maternal gene is deleted at a loci where the paternal allele is imprinted.

Answer 138

Incomplete penetrance refers to a mutant phenotype that is not expressed in all individuals containing the mutation. Example: Familial cancer syndromes such as hereditary nonpolyposis colorectal cancer. While multiple members of a family may have the mutant gene, not all will develop cancer.

Answer 139

Linkage refers to the possibility of two different genes on the same chromosome segregating together during recombination. This produces a disequilibrium in gene occurrence, such that certain linked alleles may occur more often than chance would dictate. Example: HLA alleles HLA-A1 and HLA-B8 occur together more frequently in European populations than random chance would suggest.

Answer 140

Locus heterogeneity describes the phenomenon in which mutations at different loci can produce a similar phenotype. Example: Severe combined immunodeficiency (SCID) exhibits locus heterogeneity because it can be caused by an adenosine deaminase mutation, interleukin receptor mutations, as well as mutations at other loci.

Answer 141

Loss of heterozygosity (LOH) is a term used to describe a mutation in the single normal allele at a locus where there is only one functioning allele (the other allele is most commonly inherited as non-functional). Example: Classically, tumor suppressor genes such as retinoblastoma-1 (RB1) are said to exhibit loss of heterozygosity when the second allele becomes mutated, after the individual inherited the first defective RB1 allele. This references the Knudson "two-hit hypothesis of tumorigenesis."

Answer 142

Mosaicism refers to mutations that are not reflected throughout the entire patient's cell line (typically due to a mutation early in embryogenesis). This may allow for less severe phenotypes of mutations, or allow for the sparing of a patient with an otherwise fatal mutation. Example: Patients with Turner syndrome may have a less severe phenotype if their 45, XO mutation is mosaic. Germline mosaicism is the presence of two or more genetically distinct cell lines limited to the egg and sperm cells. It should be considered when there is a mutation present in the offspring that is not present in the parents.

Answer 143

Pleiotropy refers to a single gene causing several, sometimes seemingly unrelated phenotypic effects. Example: The CFTR gene mutation in cystic fibrosis contributes to pancreatic, pulmonary, and other systemic manifestations.

Answer 144

Uniparental disomy is a genetic error in which a child receives 2 copies of a chromosome from one parent and none from the other. Note that uniparental disomy results in a euploid child, unlike most cases of nondisjunction. Example: Uniparental disomy is a cause of Prader-Willi and Angelman syndromes, in which one parent donates two copies of normally imprinted (inactivated) genes.

Answer 145

Variable expressivity describes a disease that can have different manifestations in people with the same genetic condition. Example: Two people with Marfan syndrome (same mutation in the fibrillin-1 gene) may have a different spectrum of disease manifestations; both may have physical manifestations, but only one may develop an acute aortic dissection.

Answer 146

Occurs due to mutation affecting G-protein signaling. It presents with unilateral cafe-au-lait spots, polysototic fibrous dysplasia (the replacement of multiple areas of bone by fibrous tissue, which may cause fractures and deformity), precocious puberty, multiple endocrine abnormalities. It is lethal if mutation occurs before fertilization (affecting all cells), but survivable in patients with mosaicism.

Answer 147

Both allele and genotype frequencies in a population remain constant if 5 conditions are met: No mutations. No natural selection. The population is large. Random mating. No migration

Answer 148

Allele prevalence: p+q=1. p is the frequency for allele A. q is the frequency for allele B. Genotype prevalence: p2 + 2pq + q2 = 1. p2 = frequency of AA genotype (homozygote). 2pq = frequency of AB genotype (heterozygote). q2 = frequency of BB genotype (homozygote). If allele A is X-linked recessive: If males inherit one A allele, they have the A phenotype. The frequency of A = p. Females must inherit two A alleles in order to have the A phenotype since the disease is X linked recessive. If the frequency of A = p, then the odds of having two A alleles can be calculated by multiplying p by p, which is equal to p2.

Answer 149

Maternal imprinting on this region of chromosome 15 makes gene from mom silent and Paternal gene is deleted/ mutated. It results in hyperphagia, obesity, intellectual disability, hypogonadism, and hypotonia. 25% of cases occurs due to maternal uniparental disomy (two maternally imprinted genes are received), no paternal gene received.

Answer 150

Paternal imprinting on this region of chromosome 15 makes gene from dad is normally silent and Maternal gene is deleted/mutated. This results in inappropriate laughter (happy puppet), seizures, ataxia, and severe intellectual disability. 5% of cases occurs due to paternal uniparental disomy (two paternally imprinted genes are received; no maternal gene received).

Answer 151

Autosomal dominant disorders result from mutations of genes on autosomal chromosomes. Development of an autosomal dominant disorder requires inheritance of one mutation to develop the disease. The mutation often affects structural genes. Homozygous dominant phenotypes are typically lethal, while heterozygous phenotypes are typically less severe than autosomal recessive diseases. Phenotypes are often pleiotropic. Men and women are affected equally, and have an equal likelihood of passing the gene to offspring, since the mutations occur on autosomal chromosomes. When analyzing a pedigree, look for affected people in each generation.

Answer 152

Two alleles (homozygote) are required for expression of the phenotype. A common feature of an autosomal recessive pedigree is that the phenotype skips generations. Males and and females are equally affected.

Answer 153

No father-to-son transmission; sons of heterozygous mothers have a 50% chance of being affected. In women, X chromosomes are randomly inactivated in each cell (this takes place early in embryogenesis). Female carriers are rarely symptomatic, however they can be. This would be due to inactivation of the normal allele. X-linked recessive traits are much more common in males.

Answer 154

All daughters of an affected father (only one X chromosome) are affected. No father-to-son transmission.

Answer 155

It is only transmitted via mother. No children of an affected father will inherit a mitochondrial disease (assuming a normal mother). Mitochondrial inheritance affects male and female offspring of an affected mother equally.

Answer 156

It is formely known as vitamin D resistant rickets. It is inherited disorder resulting in an increase in phosphate wasting at the proximal tubules. It is X-linked dominant. It results in a rickets like presentation.

Answer 157

A group of mitochondrial inherited rare disorders that often present with myopathy, lactic acidosis and CNS disease. It occurs secondarily to failure in oxidative phosphorylation. Muscle biopsy often shows ragged red fibber.

Answer 158

Bilateral, massive enlargement of kidneys due to multiple large cysts. 85% of cases are due to mutation in PKD1 (chromosome 16; 16 letters in polycystic kidney); remainder are due to mutation in PKD2 (chromosome 4).

Answer 159

Autosomal dominant. Colon becomes covered with adenomatous polyps after puberty. Progresses to colon cancer unless colon is resected. Mutations on chromosome 5q (APC gene); 5 letters in polyp.

Answer 160

Autosomal dominant. Elevated LDL due to defective or absent LDL receptor. It leads to severe atherosclerotic disease early in life, corneal arcus, tendon xanthomas (classically seen in the Achilles tendon).

Answer 161

Autosomal dominant. Inherited disorder of blood vessels. Findings include branching skin lesions (telangiectasia), recurrent epistaxis, skin discoloration, arteriovenous malformations (AVMs), GI bleeding, hematuria. It is also known as Osler-Weber-Rendu syndrome.

Answer 162

Autosomal dominant. Spheroid erythrocytes due to spectrin or ankyrin defect. It causes hemolytic anemia, an increase in mean corpuscular hemoglobin concentration (MCHC), an increase in RDW. Treatment is splenectomy.

Answer 163

Autosomal dominant. Findings include depression, progressive dementia, choreiform movements, and caudate atrophy. There is an increase in dopamine, a decrease in GABA, a decrease in ACh in the brain. Gene is on chromosome 4; a trinucleotide repeat disorder (CAG)n. Demonstrates anticipation: an increase in repeats leads to an earlier age of onset. Hunting 4 food.

Answer 164

Autosomal dominant. Abnormalities in TP53 leads to multiple malignancies at an early age. It is also known as SBLA cancer syndrome (sarcoma, breast, leukemia, and adrenal gland).

Answer 165

Autosomal dominant. FBN1 gene mutation on chromosome 15 creates a defective fibrin (scaffold for elastin), leading to a connective tissue disorder affecting skeleton, heart, and eyes. Findings include being tall with long extremities, pectus excavatum, hypermobile joints, and long tapering fingers and toes (arachnodactyly). There is cystic medial necrosis of the aorta causes aortic incompetence and dissecting aortic aneurysms. There is also a floppy mitral valve. Subluxation of the lens is typically upward and temporally.

Answer 166

Autosomal dominant. They are several distinct syndromes (1, 2A, and 2B) characterized by familial tumors of endocrine glands, including those of the pancreas parathyroid, pituitary, thyroid, and adrenal medulla. Men 1 is associated with MEN1 gene, MEN 2A and 2B are associated with the RET gene.

Answer 167

Autosomal dominant. Neurocutaneous disorder characterized by cafe au lait spots, cutaneous neurofibromas, optic gliomas, pheochromocytomas, Lisch nodules (pigmented iris hamartomas). 100% penetrance with variable expression. It is caused by mutations in NF1 gene on chromosome 17 (17 letters in von Recklinghausen).

Answer 168

Autosomal dominant. Findings include bilateral acoustic schwannomas, juvenile cataracts, meningiomas, and ependymomas. NF2 gene on chromosome 22; type 2=22.

Answer 169

Autosomal dominant. Neurocutaneous disorder with multi-organ system involvement, characterized by numerous benign hamartomas. Incomplete penetrance and variable expression.

Answer 170

Autosomal dominant. Disorder characterized by development of numerous tumors, both benign and malignant. It is associated with deletion of VHL gene (tumor suppressor) on chromosome 3 (3p). Von Hippel-Lindau=3 words for chromosome 3.

Answer 171

Albinism, autosomal recessive polycystic kidney disease (ARPKD), cystic fibrosis, glycogen storage disease, hemochromatosis, Kartagener syndrome, mucopolysaccharidoses (except Hunter syndrome), phenylketonuria, sickle cell anemia, sphingolipidoses (except Fabry disease), thalassemia, Wilson disease.

Answer 172

Autosomal recessive; defect in CFTR gene on chromosome 7; commonly a deletion of delta508. Most common lethal genetics disease in Caucasian populations.

Answer 173

CFTR encodes an ATP gated Cl channel that secretes Cl in the lungs and GI tract, and reabsorbs Cl in sweat glands. The most common mutation is due to a misfolded protein causing protein to be retained in RER and not transported to cell membrane, causing a decrease in Cl (and H2O) secretion. An increase in intracellular Cl results in compensatory increase in Na reabsorption via epithelial Na channels causing an increase in H2O reabsorption creating abnormally thick mucus secreted into lungs and GI tract. An increase in Na reabsorption also causes a more negative transepithelial potential difference.

Answer 174

There is an increase Cl concentration (over 60 mEq/L) in sweat is diagnostic. It can present with contraction alkalosis and hypokalemia (ECF effects analogous to a patient taking a loop diuretic) because of ECF H2O/Na losses and concomitant renal K/H wasting. There is also an increase in immunoreactive trypsinogen (newborn screening).

Answer 175

Patients experience chronic bronchitis and recurrent pneumonias, which leads to bronchiectasis, most commonly Pseudomonas aeruginosa and Staphylococcus aureus. Pancreatic insufficiency from exocrine duct clogging leads to the classic symptoms of malabsorption, including steatorrhea and fat-soluble vitamin (A, D, E, and K) deficiencies. Almost all males with cystic fibrosis are infertile due to congenital absence of the vas deferens. The forming vas deferens become occluded in utero and ceases to develop. Spermatogenesis is normally intact. Meconium ileus is highly concerning for cystic fibrosis. Thickened meconium clogs the intestinal tract leading to the classic radiological finding of a microcolon distal to the obstruction. Some women may have reduced fertility due to especially thick cervical mucus and amenorrhea (which can be secondary to nutrient deficiencies).

Answer 176

N-acetylcysteine can be used to break up thickened mucus in cystic fibrosis. The mechanism of N-acetylcysteine is lysis of disulfide bonds within the mucus. Dornase alfa (DNAse) can also be used to thin mucus in cystic fibrosis through DNA degradation. Azithromycin is used in patients with cystic fibrosis to reduce lung inflammation. Hypertonic saline inhalation is used in patients with cystic fibrosis to facilitate mucus clearance. Pancreatic enzymes are used in patients with cystic fibrosis and pancreatic insufficiency.

Answer 177

Mnemonic: For X-linked recessive disorders, Be Wise, Fools’ GOLD Heeds Silly HOpe: Bruton’s Agammaglobulinemia; Wiskott-Aldrich; Fabry’s disease; G6PD deficiency; Ocular albinism (Oculocutaneous albinism is different than ocular albinism. Oculocutaneous albinism is caused by an autosomal recessive mutation of the tyrosinase enzyme.); Lesch-Nyhan; Duchenne’s (and Becker’s) muscular dystrophy; Hunter’s Syndrome; SCID (severe combined immunodeficiency). Note that there are several etiologies of SCID: The most common form is X-linked, caused by a defect in the interleukin-2 receptor. Another cause of SCID is an autosomal recessive form caused by adenosine deaminase deficiency. Hemophilia A and B; Ornithine transcarbamylase deficiency

Answer 178

Duchenne muscular dystrophy (DMD) is an X-linked disorder that is the result of a deficiency of dystrophin (subsarcolemmal cytoskeletal protein). An overwhelming majority of the genetic defects are deletions to the dystrophin gene, causing absence of the protein. DMD is the most common lethal muscular dystrophy. The onset of DMD occurs between the ages of 2 and 6. The weakness associated with Duchenne muscular dystrophy can present in the following ways: Difficulty standing up and walking; Progressive clumsiness and easy fatigability; Waddling gait; Positive Gower maneuver, which is where the child will be observed pushing on their thighs with their hands in order to stand up. The weakness associated with DMD occurs in proximal muscles before distal muscles. Pseudohypertrophy of the calf muscles due to fatty infiltration can be seen during physical examination. Dilated cardiomyopathy may also be associated with DMD due to fibrosis of the left ventricular wall. Complications associated with DMD include: Progressive cardiac issues; Scoliosis; Flexion contractures; Death by age 20 as a result of respiratory issues.

Answer 179

Becker muscular dystrophy (BMD) is also an X-linked disorder that is similar in pathogenesis to DMD, but the symptoms are much less severe and the progression of symptoms occurs more slowly. Patients with Becker muscular dystrophy have an abnormal copy of the dystrophin protein, rather than an absence.

Answer 180

Myotonic dystrophy is an autosomal dominant muscular dystrophy that can present both in childhood and early adulthood. Myotonic dystrophy is caused by trinucleotide repeats and the severity of the disease is determined by the number of repeats. While many genes are affected, skeletal muscle chloride channel dysfunction is responsible for the myotonia. Myotonia is a slowed relaxation following a normal muscle contraction and is most prominent in the early stages of the illness. It is aggravated by cold and stress, and is seen most consistently in facial, jaw, tongue, and hand intrinsic muscles. Other symptoms of myotonic dystrophy includes: Muscle weakness; Insulin resistance; Cardiac abnormalities including increased risk of cardiomyopathy, heart failure, conduction disorders, and arrhythmias; Cataracts; Testicular failure

Answer 181

Genetic testing using PCR or southern blot assay is the test of choice for patients with suspected muscular dystrophy. While muscle biopsy used to be the initial test of choice it is now used to confirm diagnosis in patients in which genetic testing is negative or inconclusive. Muscle biopsy findings associated with DMD include muscle fiber degeneration, fibrosis, increased fatty tissue, and basophilic fibers. Immunostaining muscle fiber for dystrophin is diagnostic, which will show an absence of dystrophin in DMD. BMD will show some staining as there is still protein produced (albeit abnormal). Serum creatinine kinase (CK) and aldolase levels are elevated in patients with DMD even before clinical symptoms are apparent. Electromyography findings associated with DMD include polyphasic potentials and increased muscle fiber recruitment.

Answer 182

X-linked defect affecting the methylation and expression of the FMR1 gene. The 2nd most common cause of genetic intellectual disability (after Down syndrome). Findings include post-pubertal macroorchidism (enlarge testes), long face with a large jaw, large everted ears, autism, mitral valve prolapse. Trinucleotide repeat disorder (CGC)n. Fragile X= eXtra large testes, jaws, and ears.

Answer 183

Huntington disease (CAG), myotonic dystrophy (CTG), Friedreich ataxia (GAA), fragile X syndrome (CGG). X-Girlfriend's First Aid Helped Ace My Test (first letter=first letter of disease, second letter= second letter of repeat, than repeats). May show genetic anticipation

Answer 184

Intellectual disability, flat facies, prominent epicanthal folds, single palmar crease, gap between 1st 2 toes, duodenal atresia, Hirschsprung disease, congenital heart disease (atrial septal defect [ASD], Brushfield spots. It is also associated with early onset Alzheimer disease (chromosome 21 codes for amyloid precursor protein), and an increase risk of ALL and AML.

Answer 185

95% of cases due to meiotic nondisjunction (associated with advanced maternal age; from 1:15000 in women younger than 20 to 1:25 in women over 45. 4% of cases are due to Robertsonian translocation. 1% of cases occur due to mosaicism (no maternal association; post-fertilization mitotic error). Drinking age is 21. It is the most common viable chromosomal disorder and most common cause of genetic intellectual disability.

Answer 186

On ultrasound, there is an increase nuchal translucency and hypoplastic nasal bone; serum PAPP-A is decreased, free beta-hCG is increased.

Answer 187

A quad screen shows a decrease in alpha-fetoprotein, an increase in beta-hCG, a decrease of estriol, an increase of inhibin A.

Answer 188

Trisomy 18; 1:8000. Findings include severe intellectual disability, rocker-bottom feet, micrognathia (small jaw), low-set Ears, clenched hands with overlapping fingers, prominent occiput, congenital heart disease. Death usually occurs within 1 year of birth. Election age is 18. It is the 2nd most common trisomy resulting in live birth.

Answer 189

PAPP-A and free beta-hCG are decreased

Answer 190

Quad screen shows a decrease in alpha-fetoprotein, a decrease in beta-hCG, a decrease in estriol, and a decrease or normal inhibin A.

Answer 191

Findings include severe intellectual disability, rocker-bottom feet, microphthalmia, microcephaly, cleft liP/Palate, holoProsencephaly, Polydactyly, congenital heart disease, cutis aplasia. Death usually occurs within 1 year of birth.

Answer 192

von Hippel-Lindau disease and renal cell carcinoma.

Answer 193

ADPKD with PKD2 defect and Huntington disease

Answer 194

Cri-du-chate syndrome and familial adenomatous polyposis

Answer 195

Williams syndrome and cystic fibrosis

Answer 196

Friedreich ataxia

Answer 197

Wilms tumor

Answer 198

Patau syndrome and Wilson disease

Answer 199

Prader Willi syndrome and Angelmann syndrome

Answer 200

ADPKD with PKD1 defect

Answer 201

Neurofibromatosis type 1

Answer 202

Edwards syndrome

Answer 203

Fragile X syndrome, X-linked agammaglobulinemia, Klinefelter sundrome (XXY)

Answer 204

Down syndrome

Answer 205

Neurofibromatosis type 2 and DiGeorge syndrome (22q11)

Answer 206

Chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21, and 22. One of the most common types of translocation. It occurs when the long arms of 2 acrocentric chromosomes (chromosomes with centromeres near their ends) fuse at the centromere and the 2 short arms are lost. Balanced translocations normally do not cause any abnormal phenotype. Unbalanced translocations can result in miscarriage, stillbirth, and chromosomal imbalance (eg Down syndrome and Patau syndrome).

Answer 207

Congenital microdeletion of the short arm of chromosome 5. Findings include microcephaly, moderate to severe intellectual disability, high-pitched crying/mewing, epicanthal folds, cardiac abnormalities (VSD).

Answer 208

Congenital microdeletion of the long arm of chromosome 7 (deleted region includes elastin gene). Findings include distinctive "elfin" facies, intellectual disability, hypercalcemia (an increase in sensitivity to vitamin D), well-developed verbal skills, extreme friendliness with strangers and cardiovascular problems.

Answer 209

Microdeletions at chromosome 22q11 leads to a variable presentations including Cleft palate, Abnormal facies, Thymic aplasia causes T-cell deficiency, Cardiac defects, and Hypocalcemia secondary to parathyroid aplasia. (CATCH-22). This all occurs due to aberrant development of the 3rd and 4th branchial pouches. DiGeorge syndrome will have thymic, parathyroid, and cardiac defects. Velocardiofacial syndrome will have palate, facial, and cardiac defects.

Answer 210

A, D, E, K. Absorption dependent on the gut and pancreas. Toxicity is more common than for water-soluble vitamins because fat-soluble vitamins accumulate in fat. Malabsorption syndromes with steatorrhea, such as cystic fibrosis and sprue, or mineral oil intake can cause fat-soluble vitamin deficiencies.

Answer 211

B vitamins and vitamin C. All wash out easily from body except vitamin B12 and folate (stored in liver). B-complex deficiencies often the result in dermatitis, glossitis, and diarrhea.

Answer 212

It is an antioxidant, a constituent of visual pigments (retinal), essential for normal differentiation of epithelial cells into specialized tissue (pancreatic cells and mucus-secreting cells),prevents squamous metaplasia. It is used to treat measles and AML subtype M3. Retinol is vitamin A, so think retin-A 9used topically for wrinkles and acne). Found in the liver and leafy vegetables.

Answer 213

Causes night blindness (nyctalopia), dry scaly skin (xerosis cutis), corneal degeneration (keratomalacia), Bitot spots on conjunctiva, and immunosupression

Answer 214

Acute toxicity causes nausea, vomiting, vertigo, and blurred vision. Chronic toxicity includes alopecia, dry skin (eg scaliness), hepatic toxicity and enlargement, arthralgias, and pseudotumor cerebri. Teratogenic (causes cleft palate, cardiac abnormalities), therefore a negative pregnancy test is required before isotretinoin (vit A derivative) is prescribed for severe acne.

Answer 215

B vitamins are water soluble; therefore, body stores of B vitamins are quickly depleted (except folate and B12 cobalamin, which are stored in the liver). Each B vitamin is used in a unique type of biochemical reaction. By understanding the biochemical roles of each B vitamin, one can deduce B vitamin cofactors that are necessary based on the name of the enzyme. A vitamin B1 (thiamine) derivative, thiamine pyrophosphate (TPP), is an important coenzyme for several reactions. some of which can be remembered with the mnemonic, ATP: α-ketoglutarate dehydrogenase, Transketolase. Pyruvate dehydrogenase. Vitamin B1 is also a cofactor for branched-chain ketoacid dehydrogenase. Vitamin B1 (thiamine) most often plays a role in decarboxylation of α-keto acids.

Answer 216

Impaired glucose breakdown causes ATP depletion worsened by glucose infusion. It is highly aerobic tissue (eg brain and heart) are affected first. In the United States, thiamine deficiency is most common in alcoholics (due to poor nutrition and that excess alcohol limits the body's ability to absorb and store thiamine.) Thiamine deficiency may lead to beriberi ("Ber1Ber1") and Wernicke-Korsakoff syndrome. Diagnosis of thiamine deficiency can be confirmed by an increase in RBC transketolase activity that occurs after thiamine is supplemented.

Answer 217

Beriberi has a dry (symmetric muscle wasting and neuropathy) and wet (dilated cardiomyopathy) component, high output cardiac failure.

Answer 218

Wernicke-Korsakoff syndrome is composed of Wernicke’s encephalopathy (triad of confusion, ophthalmoplegia, and ataxia) and Korsakoff’s psychosis (memory loss, confabulation and personality change). Damage to medial dorsal nucleus of thalamus and mammillary bodies.

Answer 219

Vitamin B2. They serve as component of flavins FAD and FMN, used as cofactors in redox reactions, eg the succinate dehydrogenase reaction in the TCA cycle. FAD and FMN are derived from riboFlavin (B2=2ATP).

Answer 220

Cheilosis (inflammation of lips, scaling and fissures at the corners of the mouth and Corneal vascularization (the 2 C's of B2).

Answer 221

Vitamin B3 (niacin) is a precursor for NADH and NADPH. It is used pharmacologically to increase HDL and decrease LDL, typically as alternative or supplemental therapy to other first-line anti-lipid medications. Niacin can be used to treat hyperlipidemia; side effects in this setting include acute skin flushing and the potential development of hyperuricemia and hyperglycemia. Niacin may also be endogenously synthesized from tryptophan in a process using vitamin B6. Prolonged and stark vitamin B6 deficiency may lead to niacin deficiency as well. NAD derived from niacin (B3=3ATP).

Answer 222

Niacin deficiency leads to glossitis and may lead to pellagra in severe deficiency. Pellagra is a syndrome of the "3 D's of B3 deficiency," which are: Diarrhea, Dermatitis (classically in a "necklace" distribution around the neck), Dementia. There is also hyperpigmentation of sun exposed areas. Carcinoid syndrome is a complication of carcinoid tumors (most commonly of the small bowel) in which serotonin is systemically elaborated in great excess. Tryptophan is compensatorily shunted to make serotonin, decreasing conversion to niacin. Therefore, niacin deficiency is a potential complication of carcinoid syndrome. Hartnup disease is an autosomal recessive defect in intestinal and renal transporters for neutral amino acids. This causes tryptophan excretion in urine and leads to pellagra.

Answer 223

Pantothenic acid. Vitamin B5 (pantothenic acid) is needed to form coenzyme-A (CoA a cofactor for acyl transfers) and fatty acid synthase.

Answer 224

Vitamin B5 deficiency is rare. The signs of deficiency include: Dermatitis, Enteritis, Alopecia, Adrenal insufficiency

Answer 225

Vitamin B6 is a cofactor for: Transamination, Decarboxylation, Glycogen phosphorylase, Vitamin B6 is also a cofactor for other reactions as well. Pyridoxine is needed to produce many different compounds, and is a cofactor in steps of many different pathways. Pyridoxine is a cofactor for the following 4 neurotransmitter synthesis reactions: Glutamate → GABA; Tryptophan → Serotonin; DOPA → Dopamine (dopamine can then go on to form norepinephrine and epinephrine); Histidine → Histamine

Answer 226

Pyridoxine deficiency causes: Neurological pathology: Peripheral neuropathy and convulsions (due to defective neurotransmitter synthesis). Anemia: Sideroblastic anemias due to defective heme synthesis. A core treatment in Parkinson's disease is L-DOPA therapy. Supplemental vitamin B6 can convert L-DOPA to dopamine peripherally (as opposed to in the CNS), rendering treatment less efficacious. Vitamin B6 is a cofactor in both cystathionine and heme synthesis.

Answer 227

Vitamin B7 (biotin): cofactor in several carboxylation reactions including: Acetyl-CoA carboxylase: converts acetyl-CoA (2C) to malonyl-CoA (3C) in fatty acid synthesis. Pyruvate carboxylase: converts pyruvate (3C) to oxaloacetate (4C) in gluconeogenesis. Propionyl-CoA carboxylase: converts propionyl-CoA (3C) to methylmalonyl-CoA (4C) in the metabolism of odd-chain fatty acids.

Answer 228

Biotin deficiency causes: Dermatitis, Alopecia, Enteritis. Although relatively rare, biotin deficiency can be caused by antibiotic use or excessive consumption of raw egg whites, which can be seen in individuals who are bodybuilders or boxers (e.g., Rocky Balboa). Raw egg whites contain avidin, which binds and sequesters biotin within the GI tract. In the presence of avidin, biotin is eliminated with the feces rather than absorbed. Heating egg whites denatures avidin, rendering it unable to bind biotin.

Answer 229

It is converted to tetrahydrofolic acid (THF), a coenzymes for 1-carbon transfer/methylation reactions. It is important for the synthesis of nitrogenous bases in DNA and RNA. It is found in leafy green vegetables. It is absorbed in the jejunum. Folate from foliage. Small reserve pool stored primarily in the liver.

Answer 230

Causes macrocytic anemia, megaloblastic anemia, hypersegmented polymorphonuclear cells (PMNs), glossitis, no neurologic symptoms (as opposed to vitamin B12 deficiency). Labs findings will show an increase in homoxysteine, normal methylmalonic acid levels. Most common vitamin deficiency in the United States. Seen in alcoholism and pregnancy. Deficiency can be caused by several drugs (eg phenytoin, sulfonamides, methotrexate). Supplemental maternal folic acid in early pregnancy decreases risk of neural tube defects.

Answer 231

Vitamin B12 (cobalamin) is a cofactor for: Methylmalonyl CoA mutase, which converts methylmalonyl CoA to succinyl CoA and homocysteine methyltransferase, which transfers methyl groups to homocysteine to form methionine. Vitamin B12 (cobalamin) is synthesized by bacteria. Vitamin B12 cannot be synthesized by plants or animals.

Answer 232

Cobalamin deficiency may occur with: Malabsorption (e.g. Diphyllobothrium latum, sprue, enteritis); Absence of intrinsic factor (e.g. pernicious anemia or gastric bypass surgery); Absence of terminal ileum (due to Crohn disease or resection); Vegan diet. Cobalamin deficiency leads to macrocytic anemia and neuropathy: Subacute combined degeneration: demyelination of the dorsal columns leading to loss of pressure/touch/vibratory sense in the extremities. The lateral corticospinal tract can also be affected, causing UMN type lesion with spastic paralysis.The hematologic symptoms of B12 deficiency can be corrected by folate replacement, e.g., in the case of a misdiagnosis. However, the neurological symptoms will persist due to methylmalonic acid buildup in the myelin sheaths. The metabolism of methylmalonic acid requires B12, not folate.

Answer 233

Histology: the megaloblastosis caused by folic acid deficiency cannot be differentiated from that caused by B12 deficiency; hypersegmented neutrophils may be seen in both. Laboratory tests may include: 1) Serum folate. Levels less than 3 μg/L indicate deficiency. Note that 2-5 % of the healthy population has folate levels of 2.5 μg/L or below, so serum folate cannot be used to make a definitive diagnosis. 2) Erythrocyte (RBC) folate. Reflects tissue stores of folate. A level of less then 140 μg/L indicates deficiency. 3) Serum vitamin B12. Note that patients with subclinical deficiency might have normal B12 levels. 4) Serum homocysteine. Elevated in both B12 and folate deficiency (reference range 5-16 mmol/L). Levels can also be affected by B6 levels, renal insufficiency. 5) Serum methylmalonic acid (MMA). Sensitive test for B12 deficiency. Can be used to differentiate folate and B12 deficiency. MMA levels (reference range 70-270 mmol/L) are elevated in B12 deficiency only.

Answer 234

Homocysteine is metabolized in two key pathways: Homocysteine + Serine converted into Cysteine via cystathionine synthase. Homocysteine converted into Methionine via homocysteine methyltransferase (methionine synthase). The reaction of homocysteine and serine to form cysteine requires pyridoxine (B6) as a cofactor. The conversion of homocysteine to methionine requires folate and cobalamin (B12) as a cofactor.

Answer 235

The primary methyl donor of the body. Helps methylate DNA. After donating its methyl group, SAM is hydrolyzed to homocysteine and adenosine; regeneration of methionine from homocysteine requires folate and vitamin B12

Answer 236

This enzyme that catalyzes the conversion of methylmalonyl CoA to succinyl CoA, requiring vitamin B12 as a cofactor (deficiency of this enzyme leads to methylmalonic acidemia). It is apart of the process that produces energy or glucose from odd-chain fatty acids or certain amino acids.

Answer 237

Propionyl CoA carboxylase is an enzyme that catalyzes the conversion of proprionyl CoA to methylmalonyl CoA (deficiency of this enzyme leads to propionic acidemia). Propionyl CoA carboxylase requires the coenzyme biotin, as do most other carboxylases. It is apart of the process that produces energy or glucose from odd-chain fatty acids or certain amino acids.

Answer 238

Vitamin C (ascorbate) is a water soluble vitamin. Vitamin C is an important hydrophilic antioxidant (versus vitamin E, which is an important hydrophobic antioxidant). Vit C serves as a cofactor for prolyl-4-hydroxylase and lysyl hydroxylase, an enzyme involved in collagen synthesis. Stable collagen cannot form without proline and lysine hydroxylation. This hydroxylation take place in the ER. Hydroxylation of proline secures the collagen chains in triple helix formation. The subsequent hydroxylation of lysine is required for cross-linking. Other roles of Vitamin C: Cofactor for dopamine hydroxylase (dopamine converted into norepinephrine). Reduces iron from Fe3+ converted into Fe2+, facilitating absorption in the duodenum.

Answer 239

Deficiency of vitamin C leads to scurvy due to defective collagen synthesis. Signs of scurvy include: Swollen, spongy and purplish gums that bleed often; Bleeding into the skin (bruising); Red spots under skin from burst capillaries (petechiae); Loose teeth; Bulging of the eyes (proptosis); Anemia; Dry, brittle hair that curls ("corkscrew" hair); Slow wound healing; Bleeding into the joints (hemarthrosis) and muscles, which causes swelling over the bones of the arms and legs

Answer 240

Excess consumption of Vitamin C can lead to calcium oxalate nephrolithiasis. Excess consumption of Vitamin C can further increase the risk of iron toxicity in patients already predisposed to iron toxicity. Those at risk includes patients that receive frequent transfusions and those with hereditary hemochromatosis.

Answer 241

There are two types of vitamin D: D2 (ergocalciferol) is ingested from plants, and D3 (cholecalciferol) is obtained through animal-product consumption, or formed in sun-exposed skin. D3 is made endogenously from its precursor (7-dehydrocholesterol) in the stratum basale of the skin, upon exposure to sunlight. 25-OH D3 is the storage form of vitamin D, while 1,25-(OH)2D3 is the active form of vitamin D. When its precursors are obtained from the diet (versus the skin), synthesis and appropriate function of the active form of vitamin D (1,25-OH2-cholecalciferol) requires a functional GI tract, liver, and kidney. D2/D3 absorbed from the GI tract is converted to 25-OH-cholecalciferol (aka calcifediol) by hepatic 25-hydroxylase in the liver. Next, 25-OH-cholecalciferol is converted to 1,25-(OH)2-cholecalciferol (aka calcitriol) by 1-α hydroxylase within the kidney (specifically, the proximal renal tubule cells).

Answer 242

The actions of Vitamin D produce a coordinated increase in both [Ca2+] and [phosphate] in the ECF in order to form a solubility product that favors the mineralization of bone. The effects of vitamin D in the intestines include increasing the absorption of Ca2+ via induction of vitamin-D dependent Ca2+-binding protein (calbindin-D-28K), and increasing the absorption of phosphate. Vitamin D weakly stimulates renal calcium reabsorption by increasing the number of calcium pumps. The bone is a major target of vitamin D. Its primary function is to facilitate the formation of bone (mineralization). In the setting of excess vitamin D (or hypocalcemia), vitamin D causes an increase in resorption of Ca2+ and phosphate.

Answer 243

The regulation of Vitamin D depends on the activity of renal 1α-hydroxylase. Factors that increase 1α-hydroxylase activity include: Low serum calcium; Low serum phosphate; High parathyroid hormone (PTH). 1,25-OH2 vitamin D inhibits its own production by inhibiting 1α-hydroxylase (negative feedback). Vitamin D also inhibits the transcription of PTH which activates 1α-hydroxylase.

Answer 244

Causes of hypovitaminosis D include: A lack of precursor molecules from a lack of sunlight or fat malabsorption. A lack of enzymes from liver failure and kidney failure. Increased deactivation of vitamin D in alcoholism (induction of CYP enzymes). Vitamin D deficiency causes rickets in children and osteomalacia in adults (bone pain and muscle weakness), and hypocalcemic tetany.

Answer 245

Vitamin D excess is seen in granulomatous diseases (notably sarcoidosis) due to the 1-α hydroxylase activity of activated macrophages. Signs of vitamin D excess include hypercalcemia and hypercalciuria, while symptoms include a loss of appetite and stupor.

Answer 246

It is an antioxidant and scavenger of free radicals that protects polyunsaturated fats and fatty acids in cell membranes from lipid peroxidation and protects LDL from oxidation.

Answer 247

Vitamin E deficiency is rare and primarily occurs in: children with cystic fibrosis (due to fat malabsorption secondary to decreased bile salts and pancreatic insufficiency); abetalipoproteinemia (fat malabsorption). Signs are hemolytic anemia, peripheral neuropathy, posterior column degeneration, retinal degeneration, and myopathy. Vitamin E deficiency signs can mimic those of vitamin B12 deficiency, but vitamin E deficiency is without increased methylmalonic acid levels or megaloblastic anemia.

Answer 248

Causes decreased synthesis of vitamin K-dependent coagulation factors in the liver, thereby working synergistically with warfarin.

Answer 249

Vitamin K ("Koagulations-Vitamin" in German) are gamma-carboxylates glutamate residues and thereby activates: 4 pro-coagulants: clotting factors IX, X, VII, II (prothrombin) and 2 anti-coagulants: protein C, protein S. Vitamin K is obtained from green leafy vegetables (supply K1, phylloquinone) and from bacterial synthesis in the colon (supply K2, menaquinone). Since vitamin K is synthesized by intestinal flora and neonatal intestines are not yet colonized by bacteria, infants are given a vitamin K injection at birth to prevent hemorrhagic disease of the newborn. (Vitamin K is also not in breast milk).

Answer 250

Vitamin K deficiency leads to hemorrhage with: a prolonged prothrombin time (PT) and a prolonged activated thromboplastin time (aPTT), with a normal bleeding time. Deficiency can occur after prolonged use of broad spectrum antibiotics.

Answer 251

Zinc is found in >100 enzymes and serves as a structural ion in transcription factors ("zinc-finger" motif).

Answer 252

Zinc deficiency can cause: Impaired immune function; Delayed healing of wounds (zinc is a cofactor for matrix metalloproteinases); Hair loss; Hypogonadism; Anosmia (loss of smell); Dysgeusia (taste abnormalities); Alcoholic cirrhosis

Answer 253

Acrodermatitis enteropathica is a very rare inherited zinc deficiency caused by mutations in a gene that encodes a zinc transporter in the small intestine. Symptoms include periorificial (especially mouth and anus) and acral (hand and feet) dermatitis as well as refractory diarrhea. You can remember this disease because Acrodermatitis = acral dermatitis, and enteropathica = pathology of enterocytes of the small intestine.

Answer 254

Protein malnutrition resulting in skin lesions, edema due to a decrease in plasma oncotic pressure, live malfunction (fatty change due to a decrease in apolipoprotein synthesis). Clinical picture is a small child with a swollen abdomen. Kwashiorkor results from a protein deficient MEAL: malnutrition, edema, anemia, and liver (fatty)

Answer 255

Total calorie malnutrition resulting in tissue and muscle wasting, loss of subcutaneous fat, and variable edema. Marasmus results in Muscle wasting.

Answer 256

Basic alcohol metabolism (low alcohol concentrations) occurs in hepatocytes and converts ethanol to acetate. The NADH generated from basic alcohol metabolism increases the NADH/NAD+ ratio, which inhibits dehydrogenase reactions, leading to acute and chronic alcohol toxicities. Chronically, protein synthesis is impaired, preventing assembly and secretion of VLDL, causing triglycerides to accumulate in the liver resulting in hepatic fatty change (hepatocellular steatosis) seen in chronic alcoholics.

Answer 257

In the cytosol, ethanol is oxidized by alcohol dehydrogenase (ADH) to form acetaldehyde and NADH. The limiting reagent is NAD+. ADH works via zero-order kinetics. Ethylene glycol is metabolized to oxalic acid (via alcohol dehydrogenase and several subsequent reactions). Oxalic acid combines with metal ions to deposit crystals in kidney tubules, leading to metabolic acidosis and acute renal failure.

Answer 258

Acetaldehyde enters the mitochondria and is oxidized by acetaldehyde dehydrogenase (ALDH) to form acetate and NADH. Most of the acetate enters the bloodstream, converted to acetyl-CoA by acetyl-CoA synthase in extrahepatic tissues and used to generate cellular energy.

Answer 259

Moonshine (illicitly produced liquor) can be contaminated by methanol, a highly toxic alcohol that is metabolized to formaldehyde. Ingestion of methanol results in: Metabolic acidosis with an increased anion gap. Reaction: methanol gets converted into formaldehyde (highly toxic) gets converted into formic acid. Blindness due to toxic injury to retinal ganglion cells.

Answer 260

Both alcohol dehydrogenase and acetaldehyde dehydrogenase require NAD+, converting it to NADH. As a result, the body increases reactions that generate NAD+ such as: The reduction of pyruvate to lactate (lactic acid) produces lactic acidosis. Reaction: Pyruvate + NADH gets converted into Lactate + NAD+. Oxaloacetate is reduced to malate to regenerate NAD+. Depletion of oxaloacetate inhibits the TCA cycle. Additionally, high NADH inhibits isocitrate dehydrogenase. Acetyl-CoA accumulates as a result of TCA cycle inhibition and is shunted into ketone production leading to ketoacidosis. Reaction: Oxaloacetate + NADH gets converted into Malate + NAD+. Pyruvate and oxaloacetate depletion leads to inhibition of gluconeogenesis and stimulation of fatty acid synthesis, which results in fasting hypoglycemia. Dihydroxyacetone phosphate is reduced to glycerol 3-phosphate, which further stimulates fatty acid synthesis. Reaction: Dihydroxyacetone phosphate + NADH gets converted into Glycerol 3-phosphate + NAD+

Answer 261

Fomepizole inhibits alcohol dehydrogenase (ADH) and is used as an antidote for methanol or ethylene glycol poisoning.

Answer 262

Disulfiram (Antabuse) inhibits acetaldehyde dehydrogenase (ALDH) leading to increased acetaldehyde concentrations and hangover symptoms. Acetaldehyde is responsible for facial flushing and headaches. Disulfiram is used in treatment of chronic alcoholism.

Answer 263

During acute high level alcohol ingestion, alcohol along with NADPH are oxidized by cytochrome P450 to acetaldehyde and NADP. Cytochrome P450 are present in the smooth endoplasmic reticulum and have a relatively high Km explaining why they are only active during high alcohol concentrations. Ethanol + NADPH + O2 gets converted into Acetaldehyde + NADP + H2O. The cytochrome P450 superfamily that metabolized alcohol are part of the microsomal ethanol oxidizing system (or MEOS). It has the ability to metabolize 10-20% of the ethanol to acetaldehyde. Alcohol can divert CYP450 metabolism of certain drugs (e.g., barbiturates) leading to drug toxicities.

Answer 264

Fatty acid oxidation (beta-oxidation), acetyl-CoA production, TCA cycle, oxidative phosphorylation, and ketogenesis.

Answer 265

Glycolysis, fatty acid synthesis, HMP shunt, protein synthesis (RER), steroid synthesis (SER), cholesterol synthesis.

Answer 266

Heme synthesis, Urea cycle, Gluconeogenesis (HUGs take two, ie both)

Answer 267

Uses ATP to add high energy phosphate group onto substrate (eg phosphofructokinase).

Answer 268

Adds inorganic phosphate onto substrate without using ATP (eg glycogen phosphorylase).

Answer 269

Removes phosphate group from substrate (eg fructose-1, 6-bisphophatase)

Answer 270

Catalyzes oxidation reduction reactions (eg pyruvate dehydrogenase)

Answer 271

Adds hydroxyl group (-OH) onto substrate (eg tyrosine hydroxylase)

Answer 272

Transfers CO2 groups with the help of biotin (eg pyruvate carboxylase)

Answer 273

Relocates a functional group within a molecule (eg vitamin B12 dependent methylmalonyl-CoA)

Answer 274

Phosphofructokinase-1 (PFK- 1). AMP and frutose-2, 6- bisphophate are activating, while ATP and citrate are inhibiting.

Answer 275

Fructose-1, 6-bisphosphatase. ATP and acetyl-CoA are activating, while AMP and frutose-2, 6- bisphophate are inhibiting.

Answer 276

Isocitrate dehydrogenase. ADP is activating, while ATP and NADH are inhibiting

Answer 277

Glycogen synthase. Glucose-6-phosphate, insulin, and cortisol are activating, while epinephrine and glucagon are inhibiting.

Answer 278

Glycogen phosphorylase. Epinephrine and glucagon are activating, while glucose-6-phosphate, insulin, and ATP are inhibiting.

Answer 279

Glucose-6-phosphate dehydrogenase (G6PD). NADP is activating, while NADPH is inhibiting.

Answer 280

Carbamoyl phosphate synthetase II. ATP is activating, while UTP is inhibiting.

Answer 281

Glutamine-phosphoribosylpyrophosphate (PRPP) amidotransferase. AMP, inosine monophosphate (IMP), and GMP are inhibiting

Answer 282

Carbamoyl phosphate synthase I. N-actylglutamate are activating.

Answer 283

Acetyl-CoA carboxylase (ACC). Insulin and citrate are activating, while glucagon and palmitoyl-CoA (apart of beta oxidation pathway) are inhibiting.

Answer 284

Carnitine actyltransferase I. Malonyl-CoA is inhibiting.

Answer 285

HMG-CoA synthase

Answer 286

HMG-CoA reductase. Insulin and thyroxine are activating, while glucagon and cholesterol are inhibiting.

Answer 287

Aerobic metabolism of glucose produces 32 net ATP via malate-aspartate shuttle (heart and liver), 30 net ATP via glycerol-3-phosphate shuttle (muscle). Anaerobic glycolysis produces only 2 net ATP per glucose molecule. ATP hydrolysis can be coupled to energetically unfavorable reactions. Arsenic causes glycolysis to produce zero net ATP.

Answer 288

Acyl groups

Answer 289

1-carbon units

Answer 290

CH3 groups.

Answer 291

Phosphoryl groups

Answer 292

Nicotinamides (NAD from vitamin B3, NADP) and flavin nucleotides (FAD from vitamin B2). NAD is generally used in catabolicprocesses to carry reducing equivalents away as NADH. NADPH is used in anabolic processes (steroid and fatty acid synthesis) as a supply of reducing equivalents. NADPH is a product of the HMP shunt. NADPH is used in anabolic processes, respiratory burst, cytochrome P-450 system, and glutathione reductase.

Answer 293

Hexokinase is inhibited by glucose-6-phosphate. The regulation of hexokinase by G6P prevents overconsumption of ATP during its reaction. Hexokinase has a high affinity (decreased Km) and a low capacity (decreased Vmax) for glucose. The high affinity allows for glycolysis to occur, depsite low blood glucose levels. Hexokinase is not triggered by insulin.

Answer 294

Glucokinase is not inhibited by G6P. Glucokinase has a low affinity (increased Km) and a high capacity (increased Vmax) for glucose. Remember, GLUcokinase is a GLUtton with an insatiable Vmax. Glucokinase is triggered by insulin. Glucokinase genetic mutations on chromosome 7 may result in maturity-onset diabetes of the young (MODY). Glucokinase, within the beta-cells of the pancreas, acts as a glucose sensor, thus when a mutation is present, impaired glucose sensation occurs leading to persistant hyperglycemia and impaired insulin secretion. Glucokinase is further regulated by fructose-6-phosphate. F6P binds to the same receptor as glucokinase regulatory protein (GKRP), thereby enhancing GKRP's ability to inhibit glucokinase.

Answer 295

Glycolysis occurs in the cytosol and has 2 phases: preparatory (requires energy) and payoff (generates energy). Energy-expending steps in the preparatory phase of glycolysis are the following: 1 ATP per glucose: Glucose is converted into G6P; 1 ATP per glucose: Fructose-6-phosphate is converted into F1,6BP. Energy-yielding steps in the payoff phase of glycolysis are the following: 2 NADH per glucose: GA3P is converted into 1,3BPG; 2 ATP per glucose: 1,3BPG is converted into 3-PG; 2 ATP per glucose: PEP is converted into Pyruvate

Answer 296

Phosphofructokinase-1 activity is increased in the presence of AMP and fructose-2,6-bisphosphate. Phosphofructokinase-1 activity is decreased by elevated concentrations of citrate and ATP.

Answer 297

Phosphofructokinase-2 (PFK2) / fructose-2,6-bisphosphatase (F26BPase) is a bifunctional enzyme regulating phosphofructokinase-1. PFK2 is favored under the following pathway: 1. High blood glucose causes insulin secretion. 2. Insulin activates protein phosphatase. 3. Protein phosphatase dephosphorylates PFK2. 4. PFK2 then predominates over F26BPase. 5. PFK2 synthesizes fructose-2,6-bisphosphate from fructose-6-phosphate. 6. F26BP is a potent activator of PFK-1

Answer 298

Phosphofructokinase-2 / fructose-2,6-bisphosphatase is a bifunctional enzyme regulating phosphofructokinase-1. F26BPase is favored under the following pathway: 1. Low blood glucose elevates glucagon secretion. 2. Glucagon secretion causes phosphorylation of PFK-2 via cAMP pathway. 3. F2,6BPase activity now predominate. 4. F26BPase synthesizes fructose-6-phosphate from fructose-2,6-bisphosphonate. 5. Lower concentrations of F26BP decreases the activity of PFK-1

Answer 299

Pyruvate kinase activity is increased by fructose 1,6-bisphosphate (F1,6BP) and phosphoenolpyruvate (PEP). Pyruvate kinase is allosterically inhibited by ATP and alanine. Pyruvate kinase may also be inhibited by low blood glucose levels, allowing for PEP to enter gluconeogenesis via the following pathway: 1. Low glucose levels detected. 2. Increased glucagon secretion. 3. Increased cAMP and protein kinase A activity. 4. Phosphorylation leads to inactivation of pyruvate kinase.

Answer 300

Mitochondrial enzyme complex linking glycolysis and TCA cycle. Differentially regulated in fed/fasting states (active in fed state). Pyruvate + NAD+ + CoA gets converted into acetyl-CoA + CO2 + NADH. The PDC consists of multiple copies of three catalytic enzymes: E1 (pyruvate dehydrogenase), E2 (dihydrolipoyl transacetylase), and E3 (dihydrolipoyl dehydrogenase). The complex is similar to the alpha ketoglutarate dehydrogenase complex (same cofactors, similar substrate and action), which converts alpha-ketoglutarate into succinyl-CoA (TCA cycle). It is activated by exercise, which increases NAD/NADH ratio, increase ADP, increase Ca. Arsenic inhibits lipoic acid, causing vomiting, rice-water stools, garlic breath.

Answer 301

Pyrophosphate (B1, thiamine, TPP), FAD (B2, riboflavin), NAD (B3, niacin), CoA (B5, pantothenic acid), lipoic acid.

Answer 302

Causes a buildup of pyruvate that gets shunted to lactate (via LDH) and alanine (via ALT). It is X-linked. Findings include neurologic defects, lactic acidosis, increases serum alanine starting in infancy. Treatment includes an increase intake of ketogenic nutrients (eg high fat content or increase lysine and leucine). Lysine and leucine are the onLy pureLy ketogene amino acids.

Answer 303

Transamination by alanine aminotransferase (ALT) to yield alanine. Pyridoxal phosphate (vitamin B6 is a cofactor). This process functions to carry amino groups from the muscle to the liver. The reaction is: L-glutamate + pyruvate can interconvert α-ketoglutarate + L-alanine. Alanine is transported to the liver, which then regenerates pyruvate using the same enzyme (ALT). The pyruvate undergoes gluconeogenesis and the resulting glucose can be again used by the muscle, hence the name alanine-glucose cycle. The nitrogen from the glutamate ultimately enters the Urea Cycle and gets converted to urea (nitrogen excretion).

Answer 304

Biotin is a cofactor of the pyruvate conversion to oxaloacetate reaction catalyzed by pyruvate carboxylase. Pyruvate carboxylase requires acetyl-CoA as an allosteric activator. This is intuitive, as acetyl-CoA is the next downstream metabolite for pyruvate in glycolysis; excess acetyl-CoA is indicative of a need for a shift from glycolysis to gluconeogenesis. Oxaloacetate can replenish the TCA cycle or can be used in gluconeogenesis.

Answer 305

Interconverts pyruvate and lactate as the end of anaerobic glycolysis (the major pathway in RBCs, WBCs, kidney medulla, lens, testes, and cornea). Cofactor is vit B3.

Answer 306

Citric Acid Cycle is the central catabolic pathway used to generate energy through the oxidization of acetyl CoA (derived from carbohydrates, fats, and proteins) into CO2 and H2O. Ultimately, the energy derived from this oxidation is used to generate ATP. In addition to generating ATP, the citric acid cycle generates important molecules for other metabolic pathways: succinyl CoA is used in heme synthesis; oxaloacetate is used in gluconeogenesis; oxaloacetate and α-ketoglutarate are used in amino acid synthesis; citrate is involved in the pathway of fatty acid synthesis. The citric acid cycle (tricarboxylic acid cycle or Krebs cycle) takes place in the mitochondrial matrix

Answer 307

The order of the citric acid cycle can be remembered with the following mnemonic: "Citrate Is Krebs’ Starting Substrate For Making Oxaloacetate." 1. Citrate. 2. Isocitrate. 3. α-Ketoglutarate. 4. Succinyl CoA. 5. Succinate. 6. Fumarate. 7. Malate. 8. Oxaloacetate

Answer 308

For each turn, the citric acid cycle produces: 1 GTP, 3 NADH, 1 FADH2, 2 CO2. The net result of the oxidation (using both substrate level and oxidative phosphorylation) of one molecule of acetyl CoA is: 3 NADH x 3 ATP/NADH converted into 9 ATP, 1 FADH2 x 2 ATP/FADH2 converted into 2 ATP, 1 GTP converted into 1 ATP equivalent. For a total of 10-12 ATP molecules per acetyl CoA (12 is the ideal yield but the actual yield may be given as 10 is some texts because of imperfect efficiency.)

Answer 309

Citrate synthase catalyzes the transfer of a 2-carbon acetyl group from acetyl-CoA to oxaloacetate, forming the 6-carbon molecule citrate in the first step of the TCA cycle.

Answer 310

Aconitase catalyzes the isomerization of citrate into isocitrate in the second step of the TCA cycle. Fluorocitrate, a metabolite of the pesticide fluoroacetate, inhibits the enzyme aconitase.

Answer 311

Isocitrate dehydrogenase catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate in the third step of the TCA cycle. In the isocitrate dehydrogenase reaction, NAD+ is converted into NADH, 1st molecule of CO2 is released. Isocitrate dehydrogenase is stimulated by ADP (low energy state). Isocitrate dehydrogenase is inhibited by ATP and NADH (high energy state).

Answer 312

The α-ketoglutarate dehydrogenase complex converts α-ketoglutarate to succinyl-CoA in the fourth step of the TCA cycle. The α-ketoglutarate dehydrogenase reaction catalyzes: NAD+ is converted into NADH, 2nd molecule of CO2 is released. The α-ketoglutarate dehydrogenase complex is one of the three regulated steps of the citric acid cycle. It requires many cofactors, including: Vitamin B1, Vitamin B2, Vitamin B3, CoA, Lipoic acid. Note: these are the same cofactors as in the pyruvate dehydrogenase complex. α-ketoglutarate dehydrogenase is inhibited by: NADH, Succinyl CoA, ATP, GTP

Answer 313

Succinyl-CoA synthetase converts succinyl-CoA to succinate and CoA in the fourth step of the TCA cycle. In the process, substrate-level phosphorylation produces GTP. The entire reaction is: Succinyl CoA + Pi + GDP is reversible with Succinate + CoA + GTP.

Answer 314

The succinate dehydrogenase complex catalyzes oxidation of succinate to fumarate in the fifth step of the TCA cycle. Note that succinate dehydrogenase is embedded in the inner mitochondrial membrane as complex II of the electron transport chain. FADH2 is produced in the conversion of succinate to fumarate. This reaction is catalyzed by succinate dehydrogenase.

Answer 315

Mitochondrial fumarase converts fumarate to malate in the sixth step of the TCA cycle.

Answer 316

Malate dehydrogenase oxidizes malate to oxaloacetate, and the cycle can begin anew in the seventh step of the TCA cycle.

Answer 317

Electron transport chain (oxidative phosphorylation): uses NADH and FADH2 electrons (from glycolysis, pyruvate dehydrogenase complex, and the citric acid cycle) to form a proton gradient. The proton gradient drives the production of ATP. The ETC (electron transport chain) is composed of 5 multi-enzyme complexes, numbered I-V. It is embedded in the inner mitochondrial membrane.

Answer 318

Since NADH cannot cross the mitochondrial membrane, cytosolic electrons carried by NADH are carried across the mitochondrial membrane via two shuttle pathways: The primary NADH electron transport system is the malate-aspartate shuttle, which transports NADH electrons to complex I in the mitochondria. The less commonly used NADH electron transport system is the glycerol-3-phosphate (G3P) shuttle. In the G3P shuttle, NADH reduces dihydroxyacetone-phosphate to G3P, which can cross the inner mitochondrial membrane. G3P is then oxidized back to dihydroxyacetone-phosphate by FAD+ to form FADH2. FADH2 donates its electrons to complex II. Because NADH is converted to FADH2 in this system, it is less efficient than the malate-aspartate shuttle.

Answer 319

1 NADH yields 2.5 ATP and 1 FADH2 yields 1.5 ATP. The reason for the lower energy yield of FADH2 is that NADH electrons are transferred to complex I while FADH2 electrons are transferred to complex II. Complex II is succinate dehydrogenase of the citric acid cycle. The flow of electrons (provided by NADH and FADH2) through the ETC provides the energy to pump protons into the mitochondrial inter-membrane space. This creates an electrochemical proton gradient. Mobile electron carriers coenzyme Q and cytochrome c shuttle electrons between enzyme complexes of the ETC. coenzyme Q shuttles electrons from complexes I and II to complex III. cytochrome c shuttles electrons from complex III to complex IV. Molecular oxygen, O2, is the final electron acceptor.

Answer 320

ATP Synthase (Complex V) uses the electrochemical proton gradient created by the ETC to produce ATP from ADP and Pi.

Answer 321

Toxins that disrupt any component of the ETC disrupt the aerobic production of ATP. Tissues that depend highly on aerobic respiration, such as the CNS and the heart, are particularly affected.

Answer 322

Amobarbital (known as amytal) and rotenONE bind to NADH dehydrogenase (complex I) and directly inhibit electron transport.

Answer 323

Antimycin A ("AnTHREEmycin") binds to cytochrome c reductase (complex III) and directly inhibits electron transport.

Answer 324

Carbon monoxide and Cyanide bind to Cytochrome C oxidase (complex IV) and directly inhibit electron transport. Oligomycin (a macrolide) inhibits ATP synthase (complex V) by blocking its proton channel (specifically the Fo subunit, "o" for oligomycin).

Answer 325

2,4-Dinitrophenol and increased doses of aspirin increase the permeability of the inner mitochondrial membrane leading to a decreased proton gradient and increased oxygen consumption. Heat is generated instead of ATP (this explains the fever generated following toxic doses of aspirin.)

Answer 326

Thermogenin in brown fat is an uncoupling agent that disrupts the proton gradient. This is physiologically used to generate heat in infants, who possess brown fat.

Answer 327

Gluconeogenesis is the formation of new glucose from various metabolic substrates, and occurs in the fasting state. Gluconeogenesis occurs predominantly in the liver, but enzymes are also found in the kidney and intestinal epithelium. Muscle cells cannot raise blood glucose via gluconeogenesis because they lack glucose-6-phosphatase. Because phosphorylated glucose is unable to exit the cell, glucose remains trapped in the myocytes. The 3 regulated steps of glycolysis are essentially irreversible, so different enzymes are required to regenerate glucose. Recall that the 3 irreversible steps of glycolysis are: 1) Glucose is converted into G6P (glucokinase/hexokinase). 2) F6P is converted into F1,6BP (phosphofructokinase-1). 3) PEP is converted into pyruvate (pyruvate kinase). Gluconeogenesis utilizes different enzymes to perform these steps in the opposite direction.

Answer 328

There are four non-pyruvate carbon substrates that can enter gluconeogenesis through various metabolic conversions. Alanine (from protein breakdown and the Cahill cycle) and lactate (the most significant substrate) are converted directly to pyruvate to enter gluconeogenesis. All triacylglycerides (TAGs) can be metabolized to form glycerol, which can enter gluconeogenesis through several reactions resulting in the formation of DHAP. This entry point is the furthest upstream among the non-pyruvate substrates. Metabolites from fatty acid metabolism can enter gluconeogenesis as propionyl-CoA. They are converted in the following way: Propionyl-CoA gets converted into Methylmalonyl-CoA gets converted into Succinyl-CoA. Succinyl-CoA eventually gets converted into Oxaloacetate, via the TCA cycle. Note that only odd-chain fatty acids can produce metabolites that undergo this pathway; even-chain fatty acids do not produce propionyl-CoA.

Answer 329

1st reaction of gluconeogenesis: Pyruvate gets converted into Oxaloacetate. Pyruvate carboxylase catalyzes this reaction, which occurs in the mitochondria. Biotin is a cofactor of the pyruvate gets converted into oxaloacetate reaction catalyzed by pyruvate carboxylase. Pyruvate carboxylase requires acetyl-CoA as an allosteric activator. This is intuitive, as acetyl-CoA is the next downstream metabolite for pyruvate in glycolysis; excess acetyl-CoA is indicative of a need for a shift from glycolysis to gluconeogenesis.

Answer 330

PEP carboxykinase catalyzes this reaction, which occurs in the cytosol. 1 GTP is consumed in the conversion of oxaloacetate to PEP (2 GTPs per glucose). Oxaloacetate is transported to the cytosol using the malate shuttle.

Answer 331

A series of reactions that are simply reversed versions of glycolysis convert PEP to fructose-1,6-bisphosphate. The 3rd reaction unique to gluconeogesis is: Fructose-1,6-bisphosphate gets converted into Fructose-6-phosphate. Fructose-1,6-bisphosphatase catalyzes this reaction, which occurs in the cytosol. The conversion of fructose-1,6-bisphosphate to fructose-6-phosphate, catalyzed by fructose-1,6-bisphosphatase, is the rate-limiting step of gluconeogenesis.

Answer 332

Recall that the equivalent glycolysis step (i.e. fructose-6-phosphate to fructose-1,6-bisphosphatase) is the rate-limiting step of glycolysis. As the rate-limiting step of gluconeogenesis, fructose-1,6-bisphosphatase has many allosteric activators and inhibitors. Citrate, ATP, and acetyl-CoA allosterically activate fructose-1,6-bisphosphatase, as they are indicative of a heavily glycolytic environment. Fructose-2,6-bisphosphate and AMP inhibit fructose-1,6-bisphosphatase, as they are indicative of an ATP-exhausted, sparsely glycolytic environment.

Answer 333

Fructose-6-phosphate is isomerized to glucose-6-phosphate by the same enzyme in glycolysis. The final reaction unique to gluconeogenesis is glucose-6-phosphate gets converted into glucose. Glucose-6-phosphatase catalyzes this reaction, which occurs in the smooth endoplasmic reticulum. The sequestration of this enzyme assures it does not compete with glucokinase/hexokinase during glycolysis.

Answer 334

HMP Shunt is a 2 phase pathway consisting of an oxidative (irreversible) phase and nonoxidative (reversible) phase that uses available glucose-6-phosphate to mainly produce NADPH and ribose-5-phosphate. Both phases of the HMP shunt occur in cytosol. ATP is not used or produced in the HMP shunt. Overall reactions: Oxidative phase: Glucose-6-Phospate gets converted into Ribulose-5-Phospate + 2 NADPH. Key enzyme: Glucose-6-Phosphate Dehydrogenase. Non-oxidative phase: Ribulose-5-Phosphate gets converted into Ribose-5-Phosphate + G3P + F6P. Key enzyme: Transketolase (uses thiamine cofactor)

Answer 335

The rate limiting enzyme in the oxidative phase of the HMP shunt is glucose 6 phosphate dehydrogenase (G6PD). It generates 6-phosphogluconolactone and NADPH. NADPH is used to reduce glutathione, a coenzyme for glutathione peroxidase which prevents oxidative damage by converting H2O2 get converted into H2O. This is especially important in RBCs. Increased in tissues that consume NADPH in reductive pathways like adipose tissue for fatty acid synthesis, gonads and adrenal cortex for steroid synthesis, liver for fatty acid and cholesterol synthesis, and glutathione reduction inside RBCs.

Answer 336

In the nonoxidative phase, the key enzyme is transketolase (cofactor is thiamine); all steps are reversible and are used to convert sugars to produce ribose-5-phosphate and intermediates for glycolysis and gluconeogensis. Pentose sugars like ribose-5-phosphate are used for nucleotide synthesis. Glucose-6-phosphate, fructose-6-phosphate and glyceraldehyde 3-phosphate (products of the non-oxidative phase) are used as substrates for glycolysis in fed state, and for intermediates in gluconeogenesis in the fasting state.

Answer 337

G6PD deficiency causes a hemolytic anemia when RBCs are exposed to oxidative stress because of inadequate NADPH production which impairs glutathione reductase activity. Causes of oxidizing stress include infections, fava beans, drugs (e.g. sulfonamides, dapsone, primaquine, anti tuberculosis drugs). G6PD deficiency is transmitted in an X-linked recessive fashion. G6PD deficiency is predominantly observed in Asia, the Mediterranean, and Africa. G6PD deficiency confers resistance towards malaria. On a peripheral smear look for Heinz bodies (inclusions in RBCs composed of denatured Hemoglobin) and degmacytes (bite cells) (result of splenic macrophages removing Heinz bodies.)

Answer 338

Essential fructosuria is caused by defective fructokinase. Defective fructokinase prevents fructose sequestration leading to benign fructosuria and fructosemia. Essential fructosuria exhibits an autosomal recessive pattern of inheritance. Symptoms include fructose appearing in the blood and urine. Disorders of fructose metabolism cause milder symptoms than analogous disorders of galactose metabolism

Answer 339

Hereditary fructose intolerance is caused by a deficiency of liver aldolase B. Liver aldolase B catalyzes the following reaction: Fructose-1-phosphate gets converted into Dihydroxyacetone-P + Glyceraldehyde. A deficiency in aldolase B leads to accumulation of phosphorylated fructose gets converted into available phosphate levels drop gets converted into gluconeogenesis and glycogenolysis are blocked. Hereditary fructose intolerance exhibits an autosomal recessive pattern of inheritance. Symptoms of hereditary fructose intolerance include: Hypoglycemia, Vomiting, Jaundice, Cirrhosis. Symptoms present following consumption of fructose containing foods. Treatment is avoiding intake of fructose and sucrose (combination of glucose and fructose).

Answer 340

Fructose enters glycolysis/gluconeogenesis by first being phosphorylated by fructokinase to fructose-1-phosphate. (Essential Fructosuria is an autosomal recessive defect in fructokinase.) Fructose-1-phosphate is then cleaved by aldolase B (the rate limiting enzyme) to dihydroxyacetone-phosphate and glyceraldehyde both of which are intermediates in glycolysis and go on to make pyruvate. (Hereditary Fructose Intolerance is an autosomal recessive deficiency of aldolase.) Aldolase B is found in liver while aldolase A is in other tissues. Both of these enzymes participate in glycolysis.

Answer 341

Classic galactosemia is caused by a deficiency in GALT (galactose-1-phosphate uridyltransferase). Galactose-1-phosphate uridyltransferase catalyzes the following reaction: Galactose-1-P + UDP-Glucose gets converted into Glucose-1-P + UDP-Galactose. UDP-Galactose is converted to UDP-Glucose by 4-epimerase. Absence of GALT leads to galactose and galactose-1-phosphate accumulation which are converted to toxic substances such as galactitol, which damages the lens of the eye. All states mandate neonatal screening because lactose (i.e. milk) is metabolized to glucose and galactose. Symptoms of classic galactosemia include: Poor growth, Hepatic dysfunction (jaundice, hepatomegaly, ascites), Cataracts, Mental retardation, Increased risk of neonatal E. coli septicemia. The treatment for classic galactosemia is to exclude galactose and lactose from diet. Classic galactosemia exhibits an autosomal recessive pattern of inheritance.

Answer 342

Galactokinase deficiency is an autosomal recessive condition. Galactokinase catalyzes the following reaction: Galactose + ATP gets converted into Galactose-1-P + ADP. Galactokinase deficiency is a mild condition presenting with: Galactosemia, Galactosuria, Infantile cataracts, Inability to track objects, Failure to develop a social smile. Galactosemia leads to cataracts because the lens of the eye contains aldose reductase, which converts galactose to galactitol, an osmotically active alcohol.

Answer 343

Galactose is a monosaccharide sugar that is a C-4 epimer of glucose. Principally there are 2 enzymes involved in the metabolism of galactose, they are galactokinase (GAL-K) and galactose-1-phosphate uridyltransferase (GAL-T). Note there are also UDP-galactose-4’-epimerase (GAL-E) and mutarotase (GAL-M) which are involved in the process but are less clinically significant.

Answer 344

Dietary galactose enters glycolysis/gluconeogenesis by first being phosphorylated to galactose-1-phosphate by galactokinase. This enzyme is present in many tissues but is most active in the liver. Clinical correlation: A deficiency of galactokinase leads to non-classical galactosemia, a rare and mild galactosemia.

Answer 345

The galactose in galactose-1-phosphate is then transferred to UDP-glucose by galactose-1-phosphate uridyltransferase to yield UDP-galactose and glucose 1-phosphate. UDP-galactose is then converted back to UDP-glucose by GAL-E and the cycle repeats. Clinical correlation: A deficiency of galactose-1-phosphate uridyltransferase leads to the genetic disease Classic Galactosemia, which is a severe disorder if not caught early by infant screening.

Answer 346

Aldose reductase catalyzes the following reactions: Glucose + NADPH + H+ gets converted into Sorbitol + NADP+. Galactose + NADPH + H+ gets converted into Galactitol + NADP+. Note that glucose and galactose are converted to alcohols in both reactions.

Answer 347

Sorbitol is converted to fructose by sorbitol dehydrogenase using NAD+. Both aldose reductase and sorbitol dehydrogenase are present in liver, ovaries and seminal vesicles. Some tissues such as Schwann cells, retina, kidneys, and lens have only aldose reductase or express insufficient sorbitol dehydrogenase, so these tissues are at risk for accumulation of sorbitol, causing osmotic damage such as peripheral neuropathy, retinopathy, and cataracts. These symptoms are seen with chronic hyperglycemia in diabetes.

Answer 348

Lactase deficiency has three causes: Age dependent decline in lactase enzyme; Loss of brush border enzyme due to disease (viral, autoimmune, etc.); Defective lactase gene. Age dependent decline in lactase activity is prevalent among people of Asian, African, and Native American descent. Lactose tolerance tests show increased hydrogen content in breath, and decreased stool pH. The intestinal mucosa appears normal in individuals with congenital lactase deficiency. Lactase deficiency presents with: Bloating, Cramps, Flatulence, and Osmotic diarrhea.

Answer 349

The 9 essential amino acids are histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. These amino acids cannot be synthesized in human cells and must be obtained from the diet. Only L-form (optical isomer) amino acids can be found in proteins. Mnemonic: “Help In Learning These Little Molecules Proves Truly Valuable": Help = Histidine, In = Isoleucine, Learning = Leucine, These = Threonine, Little = Lysine, Molecules = Methionine, Proves = Phenylalanine, Truly = Tryptophan, Valuable = Valine. Arginine and histidine are only essential during periods of growth.

Answer 350

The acidic amino acids are aspartic acid and glutamic acid. They are negatively charged at physiologic pH.

Answer 351

The basic amino acids are arginine, lysine, and histidine. Arginine is the most basic. Histidine does not have a charge at physiologic pH. Basic amino acids are found in high concentrations in proteins that need to bind strongly to negative substrates. For instance, arginine and lysine are over-expressed in histones because the histones need to bind negatively charged DNA.

Answer 352

Urea cycle is a series of reactions that occur in the liver in order to convert toxic ammonia (product of amino acid catabolism) to urea (molecule with two amine groups)

Answer 353

Failure of the urea cycle (mainly genetic vs. cirrhosis) leads to hyperammonemia, which can lead to hepatic encephalopathy. Symptoms of hyperammonemia include: Vomiting, Lethargy, Cerebral edema, Slurred speech, Blurred vision, Asterixis (flapping hand tremor). Excess ammonium (NH4) depletes α-ketoglutarate (α-ketoglutarate + NH4 gets converted into glutamate), which leads to inhibition of the TCA cycle. Treatment for hyperammonemia: Limit protein intake. Benzoate or phenylbutyrate (bind amino acids and cause their excretion). Lactulose to acidify the gut and convert NH3 to NH4+ preventing ammonia absorbtion

Answer 354

In the first step of urea cycle, the conversion of CO2 and ammonia to carbamoyl phosphate, is rate-limiting. Enzyme: carbamoyl phosphate synthetase I. Obligate activator: N-acetyl-glutamate. This step consumes 2 ATP. This step takes place in the mitochondria. The ammonia in this reaction provides the 1st amine groups in urea. Note: HCO3- + NH4+ is equivalent to CO2 + NH3 + H2O

Answer 355

In the second step of urea cycle, the carbamoyl moiety is transferred to the non-proteinogenic amino acid ornithine to form citrulline. Takes place in mitochondria, then Citrulline is transported into the Cytoplasm. Enzyme: ornithine transcarbamylase

Answer 356

The most common inherited urea cycle disorder is a deficiency of ornithine transcarbamylase (X-linked recessive unlike the other urea cycle enzyme deficiencies which are autosomal recessive). X-linked disorder are more common in males. Signs and symptoms of ornithine transcarbamylase deficiency: often evident in the first few days of life (but may appear later); an increase of orotic acid in blood and urine (excess carbomyl phosphate converted to orotic acid, a pyrimidine synthesis intermediate); a decrease in BUN (no urea produced due to enzyme deficiency); hyperammonemia. Ornithine transcarbamylase deficiency can be distinguished from orotic aciduria: orotic acidemia/aciduria is seen in both ornithine transcarbamylase deficiency and orotic aciduria; hyperammonemia is seen only in ornithine transcarbamylase deficiency; megaloblastic anemia is seen only in orotic aciduria.

Answer 357

In the third step of urea cycle, aspartate condenses with citrulline to form argininosuccinate in a reaction catalyzed by argininosuccinate synthetase. Requires the cleavage of ATP gets converted into AMP + PPi

Answer 358

In the fourth step of urea cycle, argininosuccinate is cleaved into arginine and fumarate by argininosuccinate lyase. Fumarate gets converted into malate, which gets converted into oxaloacetate. (this series of reactions occurs in the cytosol and generates a reduced NADH). Oxaloacetate is converted to aspartate by transaminases, ensuring that the flow of nitrogen into the cycle is maintained

Answer 359

In the fifth step of urea cycle, arginase I catalyzes hydrolysis of arginine to yield urea and regenerate ornithine

Answer 360

In the Cori cycle, the lactate produced in the muscle cells during anaerobic metabolism enters the bloodstream and is taken up by the liver. In the liver, gluconeogenesis converts lactate into glucose. Glucose enters the bloodstream and is used by muscle cells, restarting the cycle. Red blood cells, which lack mitochondria, produce lactate and thus also participate in the Cori cycle. During strenuous exercise, when oxygen supply is insufficient, muscle cells must resort to anaerobic metabolism. Instead of entering the Tricarboxylic Acid (TCA) Cycle, pyruvate is reduced to form lactate. NADH is oxidized to regenerate NAD+, which can be used to continue glycolysis. Lactate dehydrogenase (LDH) is the enzyme responsible for this reaction. Glycolysis and anaerobic metabolism in the muscle cells generate 2 ATP per glucose; gluconeogenesis in the liver consumes 6 ATP to generate one glucose from two lactate. Overall, 4 net ATP are consumed for each round of the Cori cycle; therefore, there is a metabolic shift to the liver.

Answer 361

It is the required cofactor for carbamoyl phosphate synthetase I. This deficiency stops the urea cycle and causes hyperammonia. It presents in neonates as poorly regulated respiration and body temperature, poor feeding, developmental delay, intellectual disability (identical to presentation of carbamoyl phosphate synthetase I deficiency).

Answer 362

The derivatives of tryptophan are serotonin, melatonin, and NAD and NADP. Serotonin synthesis from tryptophan requires BH4 and vitamin B6 as cofactors. Serotonin is acetylated by acetyl CoA then methylated by S-adenosylmethionine (SAM) to produced melatonin, a hormone in the sleep/wake cycle. Niacin (Vitamin B3), a necessary functional group of NAD and NADP, can be synthesized from tryptophan; however, the body’s primary source of niacin is dietary. A lack of proper dietary niacin leads to pellagra.

Answer 363

Histamine is a derivative of the amino acid histidine. The decarboxylation of histidine produces histamine. Histamine is a vasodilator and bronchoconstrictor and a neurotransmitter that stimulates the secretion of hydrochloric acid (HCl) in the stomach.

Answer 364

Some of the derivatives of arginine are creatine, urea, and nitric oxide. Creatine phosphate is a short term energy reservoir primarily used during the early stages of muscular exercise. NO is an important vasodilator, synthesized from arginine via nitric oxide synthase (NOS).

Answer 365

The derivatives of glutamate are γ-aminobutyric acid (GABA) and glutathione (GSH). GABA, an inhibitory neurotransmitter, is synthesized by the decarboxylation of glutamate. GSH is a tripeptide, γ-glutamylcysteinylglycine, consisting of glutamate, cysteine, and glycine.

Answer 366

Tyrosine is a precursor for many important molecules such as: Epinephrine and norepinephrine, Dopamine, Melanin, Thyroid hormones

Answer 367

Tyrosine hydroxylase is the enzyme that converts tyrosine to the L isomer of Di-hydrOxy-PhenylAlanine (or L-DOPA, often just referred to as DOPA). THB (tetrahydrobiopterin) is a necessary cofactor for the enzyme tyrosine hydroxylase. THB is also a cofactor for phenylalanine hydroxylase.

Answer 368

Tyrosinase is similar to tyrosine hydroxylase in that it converts tyrosine to DOPA, but tyrosinase has further catalytic activity that results in the production of melanin from DOPA. Albinism is an autosomal recessive defect in tyrosinase leading to absence of melanin in hair (white hair), eyes (photophobia), and skin. Due the the lack of melanin in the skin of patients with albinism, they are at increased risk of skin cancer.

Answer 369

Homogentisic acid dioxygenase (HGD) is an enzyme that is part of the degradative pathway of tyrosine into fumarate. It is alternatively called homogentisate oxidase, homogentisate oxygenase, homogentisic acid oxidase, and homogentisate dioxygenase. Congenital deficiency of HGD (or alkaptonuria) is an autosomal recessive disease with the following symptoms: Homogentisate (an intermediate in the degradation pathway) is excreted in urine (if the urine is left standing it will turn black). Arthritis, ankylosis, and arthralgias (toxic to cartilage) due to homogentisate deposition in joints. Dark connective tissue (called ochronosis). Brown hyperpigmented sclera

Answer 370

Congenital deficiency of HGD (or alkaptonuria) is an autosomal recessive disease with the following symptoms: Homogentisate (an intermediate in the degradation pathway) is excreted in urine (if the urine is left standing it will turn black). Arthritis, ankylosis, and arthralgias (toxic to cartilage) due to homogentisate deposition in joints. Dark connective tissue (called ochronosis). Brown hyperpigmented sclera

Answer 371

Epinephrine is synthesized and secreted from the adrenal medulla. Phenylethanolamine-N-methyltransferase (PNMT) is the enzyme which mediates the conversion from norepinephrine to epinephrine and is activated by cortisol. .

Answer 372

DOPA is converted to Dopamine (via DOPA decarboxylase, which is inhibited by carbidopa).

Answer 373

Phenylketonuria (PKU) is caused by autosomal recessive defects in the enzyme phenylalanine hydroxylase (PAH). This causes phenylalanine to accumulate and leads to the following symptoms: Neurologic defects (e.g. seizures and mental retardation); Albinism (tyrosine required for melanin synthesis); "Musty” or “mousey” odor to their sweat & urine (due to accumulated phenylalanine conversion to phenylketones); Growth retardation; Eczema. Screening for PKU happens on the 2nd or 3rd day of life. It cannot happen prior to this due to presence of maternal enzyme at birth. Phenylketonuria leads to excretion of phenylketones (phenylacetate, phenyllactate, and phenylpyruvate) in urine.

Answer 374

Treatment for PKU includes the restriction of phenylalanine and aspartame (contains phenylalanine) in diet and increased tyrosine intake. In patients with PKU, tyrosine becomes an essential amino acid since it cannot be created from phenylalanine.

Answer 375

Maternal phenylketonuria (PKU) is caused by a lack of proper dietary treatment in a pregnant woman with PKU. The child (who does not have PKU) may be born with microcephaly, congenital heart defects, and mental and growth retardation.

Answer 376

Malignant phenylketonuria (PKU) is an autosomal recessive defect in the enzyme dihydrobiopterin reductase. This disease is called “malignant” because restricting phenylalanine does not correct neurological problems. Because dihydrobiopterin (DHB) cannot be converted back to tetrahydrobiopterin (THB), L-DOPA, carbidopa, serotonin, and THB must be supplemented.

Answer 377

Branched chain ketoaciduria (maple syrup urine disease) is a defect in the branched chain α-ketoacid dehydrogenase complex (BCKD). The defect in this enzyme causes an inability to metabolize branched-chain amino acids, and subsequent excretion of these amino acids in the urine. The BCKD enzyme complex catalyzes the breakdown of isoleucine, leucine, and valine (branched chain amino acids). Mnemonic: I Love Vermont maple syrup from trees with branches. Isoleucine gives the characteristic maple syrup/burnt sugar odor of the urine observed in branched chain ketoaciduria. The inheritance of branched chain ketoaciduria is autosomal recessive. Symptoms typically present in the first few days of life (days 4-7) with nonspecific vomiting, lethargy, and poor feeding. Long-term sequelae center around intellectual disability and CNS manifestations. Leucine readily crosses the blood-brain barrier and is responsible for the neurological symptoms.

Answer 378

The treatment of branched chain ketoaciduria is to restrict branched-chain amino acid intake. A small number of patients respond to thiamine (vitamin B1) supplementation, as thiamine is a one of the cofactors for the branched chain α-ketoacid dehydrogenase complex.

Answer 379

Homocystinuria results from severe homocysteinemia where plasma concentration is elevated such that homocysteine spills into the urine. Elevated levels of homocysteine are associated with an increased risk of atherosclerotic events, because homocysteine has prothrombotic effects. Homocysteinemia/homocystinuria is inherited in an autosomal recessive manner.

Answer 380

The clinical presentation of homocystinuria can be easily remembered because it shares some similar skeletal and ocular features with Marfan Syndrome. The most common presentation of homocysteinemia/homocystinuria is normal at birth with failure to thrive and developmental delay occurring later. In homocystinuria the lens dislocation is “down and in” as opposed to the lens dislocation in Marfan syndrome, which is “up and out.” Hyperhomocysteinemia has been linked to an elevated risk of the following cardiovascular problems: Myocardial infarction of other acute coronary syndromes; Premature coronary artery disease; Carotid artery stenosis; Stroke. Newborns are typically not screened for homocysteinemia. Hyperhomocysteinemia can be detected by measuring serum levels of homocysteine. An oral methionine challenge can be given to patients with suspected hyperhomocysteinemia, but with normal fasting homocysteine levels.

Answer 381

The treatment of homocysteinemia is based on lowering plasma homocysteine levels. This involves vitamin supplementation with the following: Folate, Vitamin B6, Vitamin B12

Answer 382

Patients with cystinuria have an impaired renal cystine transport. There is decreased proximal tubular reabsorption of cystine which causes urinary cystine excretion and stones. Cystinuria is an autosomal recessive defect of tubular transporters, leading to decreased reabsorption of: Cysteine, Ornithine, Arginine, Lysine. Mnemonic: COAL. Excess tubular concentration of cystine allows for crystal formation, ultimately leading to cystine kidney stones. Patients with cystinuria have a positive sodium cyanide-nitroprusside test. Sodium cyanide-nitroprusside test mechanism: Cyanide converts cystine to cysteine; cysteine binds nitroprusside, turning the reaction purple. Both ammonium magnesium phosphate stones and cystine stones may form staghorn calculi. Urinalysis of patients with cystine stones shows hexagonal or benzene-shaped crystals. Cystine stones are radiopaque on X-ray. Treatment of cystine stones is hydration and alkalinization of the urine.

Answer 383

Glycogen is a highly branched (branching every ~10 glucosyl residues) glucose polymer used as the main storage form of glucose in the body. In glycogen, the linear bonds are α-(1,4) glycosidic linkages whereas the branching bonds are α-(1,6) glycosidic linkages. Glycogen is synthesized and stored primarily in the cytoplasm of hepatocytes and skeletal muscle cells. Glycogen can provide energy for about one hour of exercise, depending on intensity.

Answer 384

The first step in glycogenesis is: Glucose + 1 ATP gets converted into Glucose-6-Phosphate + ADP, this reaction requires magnesium as a cofactor. The enzyme that converts glucose to glucose-6-phosphate is either hexokinase or glucokinase. Hexokinase and glucokinase both catalyze the same reaction however are different in regards to location and glucose levels: Glucokinase is found in liver and pancreatic cells, active with high levels of glucose (think glucokinase likes glucose). Hexokinase is found in most cell types, most efficient with low levels of glucose

Answer 385

In the second step of glycogenesis, glucose-6-phosphate is isomerized (“mutated”) to glucose-1-phosphate in a reversible reaction. The enzyme that isomerizes (“mutates”) glucose-6-phosphate to glucose-1-phosphate is phosphoglucomutase.

Answer 386

In the third step of glycogenensis, glucose-1-phosphate + UTP gets converted into UDP-glucose + 2Pi. The enzyme for the conversion of glucose-1-phosphate to UDP-glucose is glucose-1-phosphate uridylyltransferase (aka UDP-glucose pyrophosphorylase).

Answer 387

The rate-determining step of glycogen synthesis is the addition of UDP-glucose to a pre-existing glycogen chain via a α(1,4)-glycosidic linkage. The enzyme that catalyzes the addition of UDP-glucose to an existing glycogen molecule is glycogen synthase. Glycogen synthase is activated by insulin and glucose. Glycogen synthase is inhibited by glucagon and epinephrine.

Answer 388

Branching enzyme makes branch points in a linear glycogen molecule using α-(1,6) glycosidic bonds, about every 10 glucosyl residues, allowing for more compact storage of a greater number of glucose molecules.

Answer 389

Glycogenolysis is the breakdown of glycogen so that stored glucose may be utilized.

Answer 390

The first (and rate-determining) step of glycogenolysis is: Glycogenn + Phosphate gets converted into Glycogenn-1 + glucose-1-phosphate. The enzyme that catalyzes the rate-determining step of glycogenolysis is glycogen phosphorylase.

Answer 391

Glycogen phosphorylase only acts upon α-1,4-glycosidic bonds and stops within 4 glucose polymers of a branch point. When 4 glucose residues are left on a branch, debranching enzyme (aka alpha-1,6-glucosidase) uses its transferase ability, moving 3 residues to the end of another branch forming α-1,4-glycosidic bonds and leaving one residue with alpha-1,6 linkage. The debranching enzyme then hydrolyzes this remaining residue to yield one free glucose molecule.

Answer 392

Glycogen phosphorylase is activated via the G-protein cascade: G-protein is activated; Adenylyl Cyclase; cAMP; Protein Kinase A; Phosphorylase kinase. Glycogen phosphorylase is activated by: Epinephrine; Glucagon; Adenosine Monophosphate (AMP); Calcium. Calcium activates glycogen phosphorylase kinase (GPK) via a calcium-calmodulin complex. GPK then phosphorylates glycogen phosphorylase, thereby activating the muscle so that glycogenolysis is coupled with muscle contraction.

Answer 393

Glycogen phosphorylase is inhibited by ATP and insulin. Insulin deactivates glycogen phosphorylase by activating a protein phosphatase (via increasing the propensity of itself being phosphorylated) that ultimately dephosphorylates glycogen phosphorylase. Vitamin B6 is a required cofactor for glycogen phosphorylase.

Answer 394

Glucose 6-phosphatase removes the phosphate from glucose-6-phosphate to create free glucose. Glucose-6-phosphate is utilized different in the liver when compared to the muscles, dependent upon the expression of the enzyme glucose-6-phosphatase: The liver expresses glucose 6-phosphatase leading to free glucose production which is sent into the bloodstream. The muscle minimally expresses glucose-6-phosphatase, trapping glucose-6-phosphate for intrinsic use

Answer 395

Glycogen storage disorders result in either decreased glycogen breakdown (eg, Pompe) or increased glycogen synthesis (eg, von Gierke) which leads to intracellular glycogen accumulation and organ failure. Mnemonic: Von Gierke Put Coors And McDonalds in Her Taurus. (Imagine Von Gierke loading up his girlfriend's Ford Taurus with Coors and McDonalds for a picnic). Type 1: Von Gierke; Type 2: Pompe; Type 3: Cori; Type 4: Andersen; Type 5: McArdle; Type 6: Hers; Type 7: Tarui. All glycogen storage disorders exhibit autosomal recessive inheritance. An association between glycogen storage diseases and osteoporosis has been documented. The pathophysiology is unknown.

Answer 396

Type I (von Gierke) is caused by deficient glucose-6-phosphatase. Glycogen structure is normal in von Gierke disease. Type I (von Gierke) glycogen storage disease presents with: Severe fasting hypoglycemia; Elevated blood lactate; Elevated triglycerides; Elevated uric acid; Hepatorenomegaly. Glycogen accumulates in the liver and kidneys because excess glucose-6-phosphate stimulates glycogen synthesis and inhibits glycogenolysis. Hyperlipidemia seen in von Gierke disease manifests as xanthomas and elevated VLDL. Decreased free phosphate due to defective glucose-6-phosphatase causes increased AMP. AMP is degraded to uric acid causing hyperuricemia. This predisposes patients to gout. Fasting lactic acidosis causes elevated blood lactate levels. Lactate competes with uric acid for excretion, leading to decreased uric acid excretion by kidneys. Patients with Type I (von Gierke) glycogen storage disease should avoid fructose and galactose. Administration of glucagon, epinephrine, or other gluconeogenic stimuli does not lead to an increase in blood glucose in patients with Type I (von Gierke) glycogen storage disease. The treatment for hypoglycemia caused by von Gierke disease is oral glucose/cornstarch.

Answer 397

Type II (Pompe) is caused by defective lysosomal α-1,4-glucosidase (acid maltase). Lysosomal α-1,4-glucosidase is responsible for only ~3% of glycogenolysis, so defects don’t cause hypoglycemia. Organs most affected in Pompe disease are those that store glycogen, especially the liver, heart, and skeletal muscle. Pompe disease causes left ventricular hypertrophy which leads to outflow tract obstruction and cardiac failure. Mortality in the infantile form of Pompe disease is due to cardiac failure from massive cardiomegaly. Death usually occurs before age 2.

Answer 398

``` Type III (Cori’s) is caused by defective α-1,6-glucosidase (glycogen debrancher enzyme). Cori's disease presents with hepatomegaly and mild fasting hypoglycemia. Note that lactic acid levels are normal, in contrast to Von Gierke disease. Glycogen molecules have shorter outer branches in Cori disease, often referred to as "dextrin like". Glycogenolysis is defective but gluconeogenesis is still functional. Cori disease presents in infancy with hepatomegaly, mild hypoglycemia, and stunted growth. ```

Answer 399

Type V (McArdle’s) is caused by defective skeletal muscle glycogen phosphorylase (myophosphorylase). Defective myophosphorylase prevents glycogen breakdown in muscle. Common clinical findings of McArdle disease include: Myoglobinuria; Muscle cramps; No change in blood lactate levels post exercise; Electrolyte abnormalities. Note that blood glucose levels are unaffected. Glycogen structure is unaffected in McArdle disease.

Answer 400

Lysosomal storage disorders arise from the incomplete digestion of macromolecules causing the lysosomes to become large and numerous enough to interfere with normal cell functions. All lysosomal storage disorders are autosomal recessive, EXCEPT: Fabry’s disease and Hunter’s syndrome. These are X-linked recessive.

Answer 401

Fabry Disease presents with: Peripheral neuropathy of the hands and feet; Angiokeratomas; Cardiovascular disease; Renal disease. Patients also have a 20-fold increased risk in stroke. Fabry disease is caused by a deficiency in α-galactosidase A. This leads to an accumulation of ceramide trihexoside. X-linked recessive.

Answer 402

Gaucher Disease presents with: Hepatosplenomegaly; Aseptic necrosis of the femur; Bone crises; Pancytopenia or thrombocytopenia. Neurological symptoms occur in less frequent sub-types of Gaucher’s disease. Gaucher disease is caused by a deficiency in β-glucocerebrosidase. This leads to an accumulation of glucocerebroside. Gaucher cells are lipid filled macrophages that appear like crumpled paper seen in Gaucher disease. Gaucher disease is the most common lysosomal storage disease. The treatment for Gaucher disease is recombinant glucocerebrosidase. It is autosomal recessive

Answer 403

Niemann-Pick Disease presents with: Progressive neurodegeneration; Hepatosplenomegaly; Cherry-red spots on the macula; Foam cells (lipid filled macrophages). Niemann-Pick Disease is caused by deficiency in sphingomyelinase. This leads to an accumulation of sphingomyelin, with CNS involvement.

Answer 404

Tay-Sachs Disease presents with: Progressive neurodegeneration; Developmental delay; Cherry-red spot on the macula; Lysosomes that appear like onion skins (whorled membranes). Note that there is no hepatosplenomegaly. Tay-Sachs Disease has a deficiency in hexosaminidase A. This leads to the accumulation of GM2 gangliosides. Tay-Sachs Disease is prevalent among Ashkenazi Jews.

Answer 405

Krabbe Disease presents with: Peripheral neuropathy; Developmental delay; Optic atrophy; Globoid cells; Fever in the absence of infection; Irritability (Krabbe presents with crabbiness). Krabbe Disease has a deficiency in galactocerebrosidase (galactocerebroside β-galactosidase). This leads to an accumulation of galactocerebroside and psychosine.

Answer 406

Metachromatic leukodystrophy presents with central and peripheral demyelination with ataxia and dementia. Metachromatic leukodystrophy has a deficiency in Arylsulfatase A. This leads to an accumulation of cerebroside sulfate.

Answer 407

Hurler syndrome presents with: Developmental delay; Airway obstruction; Corneal clouding; Hepatosplenomegaly; "Gargoylism" (a somewhat outdated term that refers to the physical features typical of Hurler syndrome: clawed hands and thick, coarse facial features with a low nasal bridge). Hurler syndrome has a deficiency in α-L-iduronidase. This leads to an accumulation of heparan sulfate and dermatan sulfate. Deposition in coronary arteries leads to ischemic heart disease.

Answer 408

Hunter syndrome presents as a mild form of Hurler’s syndrome, but also includes aggressive behavior and lacks corneal clouding. Mnemonic: "A hunter needs to see clearly" (i.e. no corneal clouding). Hunter syndrome has a deficiency in iduronate sulfatase. This leads to an accumulation of heparan sulfate and dermatan sulfate. Hunter syndrome has X linked recessive inheritance.

Answer 409

Fatty acid synthesis is a process occurring within the cytosol of: Hepatocytes (predominantly), Adipose tissue, Lactating mammary glands. Acetyl-CoA is the primary substrate in the repeated condensation, reduction, and dehydration reactions of fatty acid synthesis. Fatty acids are elongated by repeated addition of malonyl-CoA, which is derived from acetyl-CoA. The citrate shuttle is a mechanism to transport acetyl-CoA out of the mitochondria for fatty acid synthesis which takes place in the cytoplasm. Acetyl-CoA combines with oxaloacetate to form citrate which travels across the mitochondrial membrane to the cytoplasm where it is cleaved back into oxaloacetate and acetyl-CoA. Acetyl-CoA must be converted to malonyl-CoA prior to being added to the growing fatty acid chain. This reaction requires biotin and ATP. Acetyl-CoA carboxylase is the rate limiting enzyme in fatty acid synthesis.

Answer 410

During well fed states, citrate is shunted into fatty acid synthesis as opposed to the citric acid cycle through inhibition of isocitrate dehydrogenase by ATP and NADH. Insulin leads to dephosphorylation and activation of acetyl-CoA carboxylase, as well as upregulation of SREBP, a transcription factor involved in the production of lipogenic molecules. Glucagon leads to phosphorylation and inactivation of acetyl-CoA carboxylase. Acetyl-CoA carboxylase is allosterically activated by citrate, and inhibited by palmitoyl-CoA.

Answer 411

Before fatty acid oxidation can occur in the mitochondria, fatty acids longer than 14 carbons must be converted to fatty acyl-CoA by the enzyme fatty acyl-CoA synthetase within the cytosol. Fatty acyl-CoA reacts with carnitine to form fatty acyl-carnitine in a reaction catalyzed by carnitine acyltransferase 1 (CAT1) on the outer mitochondrial membrane. Fatty acyl-CoA + carnitine gets converted into Fatty acyl carnitine + CoA. The reaction catalyzed by carnitine acyltransferase 1 (CAT1) is the rate limiting step of fatty acid oxidation. Malonyl-CoA, a product of lipogenesis, allosterically inhibits carnitine acyltransferase 1 to prevent fatty acid oxidation from occurring at the same time as lipogenesis.

Answer 412

Fatty acyl carnitine is transported into the mitochondria via a fatty acyl carnitine/carnitine antiporter, which regenerates carnitine on the cytoplasmic side for further transport of fatty acids. Within the mitochondria, fatty acyl-CoA is regenerated by carnitine acyltransferase 2 (CAT2) in a reaction that also yields free carnitine. Fatty acyl carnitine + CoA gets converted into Fatty acyl-CoA + carnitine

Answer 413

Carnitine deficiency is an inherited disorder that prevents the metabolism of long chain fatty acids from occurring. The symptoms of carnitine deficiency include: Hypoketotic hypoglycemia, Weakness, Hypotonia. The treatment is carnitine supplementation

Answer 414

Medium and short chain fatty acids (less than 14 carbons long) do not need to pass through the carnitine shuttle system to enter the mitochondria. Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is an autosomal recessive disorder that leads to an accumulation of 8-10 carbon fatty acyl carnitines in the blood.

Answer 415

MCAD is a enzyme required for metabolism of medium length fatty acids. MCAD deficiency results in an inability to oxidize medium length fatty acids (6-12 carbons). In a typical presentation a previously healthy infant/child presents with hypoketotic hypoglycemia, vomiting, and lethargy triggered by a common illness (such as the flu). In prolonged fasting or stressed with an infection the body depletes glucose stores and cannot metabolize medium-chain fatty acid stores to compensate. The treatment is avoid prolonged fasting, increase carbohydrate and protein intake, and decrease fat intake.

Answer 416

Adrenoleukodystrophy is an an X-linked recessive disease that is characterized by impaired peroxisomal catabolism of very long chain fatty acids. Patients with adrenoleukodystrophy accumulate very long chain fatty acids in the: Nervous system, leading to demyelination; Adrenal cortex, leading to primary adrenocortical insufficiency and/or adrenal gland crisis; Testes, leading to hypogonadism. Adrenoleukodystrophy classically presents in young male patients with behavioral changes, neurological findings (e.g. ataxia), and signs and symptoms of primary adrenocortical insufficiency (e.g. hypotension, hyperkalemia, metabolic acidosis). Adrenoleukodystrophy is a progressive disease that is ultimately fatal.

Answer 417

In the liver, fatty acids and amino acids are metabolized to acetoacetate and beta-hydroxybutyrate (to be used in muscles and brain). In prolonged starvation and diabetic ketoacidosis, oxaloacetate is depleted for gluconeogenesis. In alcoholism, excess NADH shunts oxaloacetate to malate. Both processes causes a buildup of acetyl-CoA, which shunts glucose and FFA toward the production of ketone bodies. Breath smells like acetone (fruity). Urine test for ketones does not detect beta-hydroxybutyrate.

Answer 418

Lasts about 2 seconds

Answer 419

Lasts about 10 seconds

Answer 420

Lasts about 1 min

Answer 421

Can last for hours

Answer 422

1g of protein or carbohydrate= 4kcal. 1 g fat= 9kcal. 1g of alcohol=7kcal.

Answer 423

priorities are to supply sufficient glucose to the brain and RBCs and to preserve protein.

Answer 424

glycolysis and aerobic respiration is active. Insulin stimulates storage of lipids, proteins, and glycogen.

Answer 425

Hepatic glycogenolysis is the major active pathway. Hepatic gluconeogenesis and adipose release of FFA play a more minor role. Glucagon and epinephrine stimulate use of fuel reserves.

Answer 426

Blood glucose levels are maintains by hepatic glycogenolysis, adipose release of FFA, muscle and liver shift their fuel use from glucose to FFA, hepatic gluconeogenesis from peripheral tissue lactate and alanine and from adipose tissue glycerol and propionyl-CoA (from odd chain FFA, the only triacylglycerol components that contribute to gluconeogenesis. Glycogen reserves depleted after day 1. RBCs lack mitochondria and therefore cannot use ketones.

Answer 427

Adipose stores (ketones bodies become the main source of energy for the brain). After these are depleted, vital protein degradation accelerates, leading to organ failure and death. Amount of excess stores determines survival time.

Answer 428

Cholesterol needed to maintain cell membrane integrity and to synthesize bile acid, steroids, and vitamin D. Rate-limiting step is catalyzed by HMG-CoA reductase (induced by insulin), which converts HMG-CoA to mevalonate. 2/3 of plasma cholesterol are esterfied by lecthin-cholesterol acyltransferase (LCAT). Statins (eg atorvastatin) competitively and reversibly inhibit HMG-CoA reductase.

Answer 429

degradation of dietary triglycerides (TGs) in small intertine

Answer 430

Degradation of TGs circulating in chylomicrons and VLDLs. Found on the vascular endothelial surface.

Answer 431

degradation of TGs remaining in IDL.

Answer 432

degradation of TGs stored in adipocytes.

Answer 433

LCAT esterifies cholesterol to HDL, allowing HDL to take cholesterol in the bloodstream and return it to the liver via reverse cholesterol transport

Answer 434

CETP (cholesterol ester transfer protein) catalyzes the transfer of cholesterol from HDL to VLDL, and TGs from VLDL to HDL activates CETP activity is linked to increased cholesterol levels and coronary artery disease.

Answer 435

ApoE mediates chylomicron remnant and IDL uptake in the liver.

Answer 436

ApoC-II activates lipoprotein lipase (LPL) in capillaries.

Answer 437

ApoB-48 lacks the LDL-receptor binding sequence that ApoB-100 has. It is a component of chylomicrons.

Answer 438

ApoB-100 is the sole protein component of LDL.

Answer 439

ApoA-I activates LCAT.

Answer 440

Lipoprotein complexes are composed of cholesterol, TGs (triglycerides), phospholipids and apolipoproteins. Lipoprotein complexes include: chylomicrons, VLDL, IDL, LDL, and HDL. Most cholesterol is carried by HDL and LDL. LDL transports cholesterol from liver to tissues. HDL transports cholesterol from periphery to liver (LDL is lousy, HDL is healthy).

Answer 441

Delivers dietary TGs to peripheral tissue. Delivers cholesterol to liver in the form of chylomicron remnants, which are mostly depleted of their TGs. Secreted by intestinal epithelial cells.

Answer 442

Delivers hepatic TGs to peripheral tissue. Secreted by liver

Answer 443

Formed in the degradation of VLDL. Delivers TGs and cholesterol to liver.

Answer 444

Delivers hepatic cholesterol to perpheral tissues. Formed by hepatic lipase modification of IDL in the peripheral tissue. Taken up by target cells via receptor mediated endocytosis.

Answer 445

Mediates reverse cholesterol transport from periphery to liver. Acts as a repository for apolipoproteins C and E (which are needed for chylomicron and VLDL metabolism). Secreted from both liver and intestine. Alcohol increases synthesis.

Answer 446

Chylomicrons, TG, and cholesterol are increased in blood. It is autosomal recessive due to a lipoprotein lipase deficiency or altered apolipoprotein C-II. It causes pancreatitis, hepatosplenomegaly, and eruptive/ pruritic xanthomas (no increase risk for atherosclerosis). It is the creamy layer in supernatant.

Answer 447

LDL and cholesterol are elevated in blood. It is autosomal dominant and due to absent or defective LDL receptors. Heterozygotes (1:500) have cholesterol around 300 mg/dL; homozygotes (very rare) have cholesterol over 700 mg/gL. It causes accelerated atherosclerosis (may have an MI before age 20), tendon (Achilles) xanthomas, and corneal arcus.

Answer 448

VLDL and TG are increased in the blood. It is autosomal dominant. It occurs due to hepatic overproduction of VLDL. Hypertriglyceridemia can be over 1000 mg/dL and can cause acute pancreatitis.