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STEP1 > Biochemistry > Flashcards

Biochemistry Flashcards

1
Q

Which form of chromatin is condensed?

A

heterochromatin is condensed and euchromatin is relaxed

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2
Q

Describe the structure formed by DNA and histones.

A
  • negatively charged DNA wraps twice around a positively charged histone
  • histone octamers then form a nucleosome
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3
Q

Histones are rich in which amino acids?

A

lysine and arginine

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4
Q

When during the cell cycle does histone synthesis occur?

A

during S phase of the cell cycle

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5
Q

What is the effect of DNA methylation in prokaryotes? In eukaryotes?

A
  • in prokaryotes, C and A bases are methylated on the template strand to help repair mechanisms identify the old strand
  • in eukaryotes DNA methylation at CpG islands represses transcription
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6
Q

What is the effect of histone methylation and acetylation?

A
  • methylation usually stabilizes the heterochromatin state

- acetylation relaxes the DNA coiling and allows for transcription

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7
Q

Which nucleic acids are purines? How many rings does a purine have?

A
  • A and G are purines

- they have two rings

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8
Q

Uracil is derived from what nucleic acid?

A

it is deaminated cytosine

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9
Q

Which three amino acids are necessary for de novo purine synthesis?

A

glycine, glutamine, and aspartate

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10
Q

Draw the de novo pyrimidine synthesis pathway.

A

FA 49: glutamine + CO2 –> carbomyl phosphate –> orotic acid –> UMP –> UDP –> CTP (for use) or dUDP –> dUMP –> dTMP

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11
Q

Draw the de novo purine synthesis pathway.

A

FA 49: ribose-5-P –> PRPP –> IMP –> AMP or GMP

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12
Q

What is the mechanism of action of leflunomide?

A

it inhibits dihydroorotate dehydrogenase, which converts carbamoyl phosphate to orotic acid in the pyrimidine synthesis pathway

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13
Q

What is the difference between methotrexate, trimethoprim, and pyrimethamine?

A

they all inhibit dihydrofolate reductase but in humans, bacteria, and protozoans, respectively

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14
Q

What is the mechanism of action of methotrexate?

A

it inhibits human dihydrofolate reductase in the pyrimidine synthesis pathway

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15
Q

What is the mechanism of trimethoprim?

A

it inhibits bacterial dihydrofolate reductase in the pyrimidine synthesis pathway

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16
Q

What is the mechanism of pyrimethamine?

A

it inhibits protozoan dihydrofolate reductase in the pyrimidine synthesis pathway

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17
Q

What is the mechanism of action of 5-fluorouracil?

A

it forms 5-F-dUMP, which inhibits thymidylate synthase and the production of dTMP

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18
Q

What is the mechanism of action of 6-MP?

A

it inhibits conversion of PRPP to IMP within the de novo purine synthesis pathway

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19
Q

What is the mechanism of action of azathioprine?

A

it is the pro-drug of 6-MP and inhibits conversion of PRPP to IMP within the de novo purine synthesis pathway

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20
Q

What is the mechanism of action of mycophenolate?

A

it inhibits conversion of IMP to GMP within the de novo purine synthesis pathway

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21
Q

What is the mechanism of action of ribavirin?

A

it inhibits conversion of IMP to GMP within the de novo purine synthesis pathway

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22
Q

What is the mechanism of action of hydroxyurea?

A

it inhibits ribonucleotide reductase, which converts RNA bases to DNA bases, and inhibits purine and pyrimidine synthesis

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23
Q

Lesch-Nyhan Syndrome (cause, presentation, treatment)

A
  • an X-linked recessive absence of HGPRT, which results in a defective purine salvage pathway
  • presents with intellectual disability, self-mutilation, aggression, hyperuricemia, gout, and dystonia
  • treat with allopurinol or febuxostat (2nd line)
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24
Q

What is HGPRT? In what disease is it defective or absent?

A
  • an enzyme of the purine salvage pathway, which converts hypoxanthine to IMP and guanine to GMP
  • defect is known as Lesch-Nyhan syndrome
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25
Q

What is the mechanism of action of allopurinol?

A

it inhibits xanthine oxidase of the purine metabolism pathway

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26
Q

What is the mechanism of action of febuxostat?

A

it inhibits xanthine oxidase of the purine metabolism pathway

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27
Q

Adenosine Deaminase Deficiency

A
  • deficiency of ADA, a protein required for degradation of adenosine and deoxyadenosine
  • absence causes an increase in dATP, which is toxic to lymphocytes
  • a major cause of autosomal recessive SCID
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28
Q

Draw the purine salvage pathway.

A

FA 50

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29
Q

Promoters and origins of DNA replication tend to have what sorts of sequences?

A

those rich in A and T

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30
Q

What is the function of single-stranded binding proteins?

A

prevent strands from re-annealing during DNA replication

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31
Q

What is the mechanism of action of fluoroquinolones?

A

they inhibit prokaryotic topoisomerase II (DNA gyrase) and topoisomerase IV

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32
Q

What is the difference between etoposide and a fluoroquinolone?

A

etoposides are selective for eukaryotic topoisomerase II whereas fluoroquinolones are selective for prokaryotic ones

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33
Q

What is the mechanism of action of etoposide?

A

inhibit eukaryotic topoisomerase II

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34
Q

What is the mechanism of action of teniposide?

A

inhibit eukaryotic topoisomerase II

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35
Q

DNA and RNA synthesis occur in which direct?

A

synthesis is 5’ to 3’

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36
Q

What is the difference between DNA polymerase I and III in prokaryotes?

A
  • III has 5’ to 3’ synthesis and 3’ to 5’ proofreading activity
  • I degrades RNA primers and replaces them with DNA
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37
Q

What is telomerase?

A

an RNA-dependent DNA polymerase that adds DNA to 3’ ends of chromosomes to avoid loss of genetic material

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38
Q

What is a transversion point mutation?

A

a point mutation from a purine to pyrimidine or pyrimidine to purine

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39
Q

What is a transition point mutation?

A

a point mutation from a purine to purine or pyrmidine to prymidine

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40
Q

What is a conservative missense mutation?

A

one in which the new amino acid is similar in chemical structure to the previous

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41
Q

What signals the Lac operon to turn on?

A
  • low glucose leads to more AC activity and the resulting cAMP activates CAP, an inducer which binds DNA and activates the transcription complex
  • high lactose binds the repressor protein and prevents it from binding the operator instead, which would otherwise block the transcription complex from moving downstream
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42
Q

What is the defect in those with xeroderma pigmentosum?

A

defect in nucleotide excision repair prevents repair of pyrimidine dimers formed by UV light

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43
Q

What sort of damage is addressed by nucleotide excision repair, base excision repair, and mismatch repair, and in what part of the cell cycle does each occur?

A
  • nucleotide excision: repairs bulky, helix-distorting lesions during G1
  • base excision repair: repairs altered bases (e.g. spontaneous/toxic deamination) throughout the cell cycle
  • mismatch repair: fixes mismatched pairs after DNA replication during G2
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44
Q

Lynch syndrome is due to a defect in what DNA repair mechanism?

A

aka HNPCC, this is caused by a defect in mismatch repair

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45
Q

Describe the process of nucleotide excision repair.

A
  • endonuclease release the damaged oligonucleotides

- DNA polymerase and ligase fill and reseal the gap

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46
Q

Describe the process of base excision repair.

A
  • base-specific glycosylase removes the altered base and creates an AP site
  • AP-endonuclease cleaves the 5’ end of the segment to be removed and lyase cleaves the 3’ end
  • DNA polymerase-beta fills the gap and ligase seals it
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47
Q

What is non-homologous end joining used to repair and how does it occur?

A
  • used to repair a double strand break
  • simply brings together and joins the ends of two DNA fragments without any requirement for homology and so some DNA may be lost
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48
Q

Protein synthesis occurs in which direct?

A

mRNA is read in the 5’ to 3’ direction and protein synthesis occurs from the N- to C-terminus

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49
Q

What is the start codon?

A

AUG (codes for methionine in eukaryotes and fMet in prokaryotes)

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50
Q

What are the stop codons?

A

UGA, UAA, UAG

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51
Q

Anti-metabolites that block DNA replication often have a modification at what position?

A

they often have a modified 3’OH, which prevents addition of the next nucleotide

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52
Q

What is the TATA box?

A

a promoter sequence

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53
Q

What is a promoter?

A

a site upstream from the gene locus which is AT-rich and is where RNA polymerase II and other transcription factors bind DNA

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54
Q

What is a silencer?

A

a site on DNA where negative regulators (i.e. repressors) bind

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55
Q

What is the function of RNA polymerase I, II, and III?

A
  • I makes rRNA
  • II makes mRNA
  • III makes 5S rRNA and tRNA
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56
Q

What is a-amanitin? Where is it found and why is it toxic?

A
  • a compound found in Amanita phalloides (i.e. death cap mushrooms)
  • causes severe hepatotoxicity because it inhibits RNA polymerase II
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57
Q

What is the mechanism of action of rifampin?

A

it inhibits RNA polymerase in prokaryotes

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58
Q

What is the mechanism of action of actinomycin D?

A

it inhibits RNA polymerase in both prokaryotes and eukaryotes

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59
Q

What is hnRNA?

A

aka heterogeneous nuclear RNA, it is the initial transcript that is then modified to become mRNA

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60
Q

What three things must happen for hnRNA to become mRNA? Where do these things occur?

A
  • it must acquire a 5’ cap, undergo polyadenylation of the 3’ end, and undergo splicing out of introns
  • these processes all occur in the nucleus
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61
Q

What are P-bodies?

A
  • aka cytoplasmic processing bodies, they are responsible for mRNA quality control as well as occasionally the storage of mRNAs for future translation
  • have exonuclease activity, decapping enzymes, and miRNAs
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62
Q

What is the polyadeylation signal?

A

AAUAAA

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63
Q

What are snRNPs?

A

small nuclear ribonucleoproteins responsible for splicing of pre-mRNA

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64
Q

What is a Lariat intermediate?

A

a lopped intermediate that is generated during the coursing of intron splicing

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65
Q

What are anti-Smith antibodies directed against and indicative of?

A

they are directed against spliceosomal snRNPs and are highly specific for SLE

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66
Q

What are anti-U1 RNP antibodies and what are they indicative of?

A
  • they are antibodies against sliceosomal snRNPs

- associated with mixed connective tissue disease

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67
Q

What are miRNAs? Where are they often found and through what mechanism do they complete their function?

A
  • small, noncoding RNA molecules that post-transcriptionally regulate protein expression
  • binding triggers degradation or inactivation of the target mRNA
  • they are often contained within introns and can have multiple mRNA targets
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68
Q

What is unique about the structure and function of the acceptor stem, T-arm, and D-arm of tRNA?

A
  • the acceptor stem is a conserved CCA 3’ terminus on all tRNA that is covalently bound to the matching amino acid
  • T-arm contains a sequence necessary for tRNA-ribosome binding
  • D-arm contains dihydrouridine residues necessary for tRNA recognition by the correct aminoacyl-tRNA synthetase
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69
Q

What is aminoacyl-tRNA synthetase?

A

an ATP-dependent enzyme that charges tRNA with the matching amino acid

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70
Q

Eukaryotes and prokaryotes rely on what ribosome complex for translation?

A

eukaryotes on an 80S complex and prokaryotes on a 70S

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71
Q

ATP and GTP are used for what steps in translation?

A
  • ATP is required for charging tRNA

- GTP is required for binding and translocation

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72
Q

The 80S ribosomal complex has what three sites?

A
  • A: binding site for charged tRNA
  • P: accommodates the growing peptide
  • E: holds empty tRNA as it exits
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73
Q

What is the relationship between cyclins and CDKs?

A

CDKs are constitutively expressed but inactive until they bind a phase-specific cyclin

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74
Q

Describe the p53 cascade.

A
  • induces p21, which inhibits CDK
  • results in hypophosphorylated Rb, which is the active form
  • Rb binds and inactivates E2F
  • this inhibits the G1-S progression
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75
Q

What is the active form of Rb?

A

the hypophosphorylated form

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76
Q

What are stable (aka quiescent) cells? Give two examples.

A
  • those that remain in Go unless stimulated to enter G1

- includes hepatocytes and lymphocytes

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77
Q

What is the function of the RER?

A

it is the site of synthesis of secretory proteins

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78
Q

What are Nissl bodies?

A

RER in neurons, which synthesize peptide neurotransmitters for secretion

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79
Q

What is the function of the SER? Which cells have abundant SER?

A
  • site of steroid synthesis and detoxification of drugs and poisons
  • hepatocytes and steroid-hormone producing cells of the adrenal cortex and gonads
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80
Q

What is the function of the Golgi?

A

it is the distribution center for proteins and lipids from the ER to the vesicles and plasma membrane

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81
Q

Mannose-6-phosphate is added to proteins for what reason?

A

this is added in the golgi and is added to proteins to be trafficked to lysosomes

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82
Q

What are endoscopes?

A

a kind of sorting center for material from outside the cell or from the Golgi, which sends these items to lysosomes for destruction or back to the membrane/golgi for continued use

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83
Q

I-Cell Disease (cause and presentation)

A
  • an inherited lysosomal storage disorder
  • arises from a defect in N-acetylglucosaminyl-1-phosphotransferase
  • the defect causes a failure of the Golgi to phosphorylate mannose residues on glycoproteins, so proteins necessary for the functioning of lysosomes are secreted extracellularly rather than delivered to lysosomes
  • presents with coarse facial features, clouded corneas, restricted joint movement, and high plasma levels of lysosomal enzymes; usually fatal in childhood
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84
Q

What is the function of signal recognition particle? What is the result of a deficiency?

A
  • it is a cytosolic ribonucleoprotein that traffics proteins form the ribosome to the RER
  • without it, proteins accumulate in the cytosol
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85
Q

What are COPI, COPII, and clathrin?

A
  • COPI is responsible fo retrograde transport within the golgi and from the cis-Golgi to the RER
  • COPII is responsible for anterograde transport from the RER to the cis-Golgi
  • Clathrin is responsible fo transport from the trans-Golgi to lysosomes and from the plasma membrane to endosomes
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86
Q

What is clathrin?

A

a transport protein responsible for moving vesicles from the trans-Golgi to lysosomes and from the plasma membrane to endosomes

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87
Q

What is the peroxisome?

A

a membrane-enclosed organelle involved in catabolism of VLCFAs, branched-chain FAs, amino acids, and ethanol

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88
Q

What is the function fo the proteasome?

A

it is a barrel-shaped protein complex that degrades damaged or ubiquitin-tagged proteins

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89
Q

What is the function of microfilaments, intermediate filaments, microtubules?

A
  • microfilaments mediate muscle contraction and cytokinesis
  • intermediate filaments maintain cell structure
  • microtubules mediate movement and cell division
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90
Q

Which cell types express each of the following intermediate filaments: vimentin, design, cytokeratin, GFAP, and neurofilament?

A
  • vimentin: mesenchymal tissue
  • design: muscle
  • cytokeratin: epithelial cells
  • GFAP: neuroglia (astrocytes, Schwann cells, oligodendroglia)
  • neurofilaments: neurons
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91
Q

Describe the structure of a microtubule.

A

alpha- and beta-tubulin heterodimers polymerize to form a hollow cylindrical structure

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92
Q

What are the functions of dynein and kinesin?

A
  • dynein is responsible for retrograde transport

- kinesin is responsible for anterograde transport

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93
Q

Describe the structure of a cilia.

A
  • the length has a 9+2 arraignment of microtubule doublets

- the base, called the basal body, consists of 9 microtubule triplets without a central microtubule

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94
Q

What drives movement of a cilia?

A

an ATPase called axonemal dynein links peripheral microtubule doublets and causes bending via differential sliding

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95
Q

What is the cause and presentation of Kartagener syndrome, also known as primary ciliary dyskinesia?

A
  • a dynein arm defect, which leaves cilia immotile
  • results in male and female infertility, increases the risk of ectopic pregnancy, causes bronchiectasis, recurrent sinusitis, and situs inversus
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96
Q

What direction does the Na/K-ATPase pump ions?

A
  • 3 sodium go out of the cell upon pump phosphorylation using ATP
  • 2 potassium come into the cell upon dephosphorylation
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97
Q

Where do we find type I, II, III, and IV collagen?

A
  • I: bone, skin, tendon, dentin, fascia, cornea, and late wound repair
  • II: cartilage, vitreous body, and nucleus pulposus
  • III: blood vessels, granulation tissue, skin, uterus, and fetal tissue
  • IV: basement membrane, basal lamina, lens
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98
Q

Describe the synthesis of collagen.

A
  • translation of collagen alpha chains known as preprocollagen with the form of Gly-X-Y where X and Y usually represent proline or lysine
  • hydroxylation of specific proline and lysine residues in a reaction that requires vitamin C
  • glycosylation of hydroxylysine residues
  • formation of procollagen, a triple helix of 3 alpha chains, via hydrogen and disulfide bond formation
  • exocytosis of procollagen into the extracellular space
  • cleavage of disulfide-rich terminal regions of pro collagen to form insoluble tropocollagen
  • cross-linking and reinforcement of staggered tropocollagen molecules via covalent lysine-hydroxylysine bonds by copper-containing lysyl oxidase, forming fibrils
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99
Q

What is the most abundant amino acid in collagen?

A

glycine

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100
Q

What is the pathogenesis of scurvy?

A

lack of vitamin C prevents the hydroxylation of collagen

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101
Q

Name three diseases that arise from collagen synthesis defects and what those defects are.

A
  • scurvy: lack of vitamin C necessary for hydroxylation of proline and lysine residues of preprocollagen
  • osteogenesis imperfecta: problems forming the triple helix (procollagen)
  • Ehlers-Danlos: problems cross-linking tropocollagen
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102
Q

Why is copper required for collagen synthesis?

A

it is required by copper-containing lysyl oxidase, which catalyzes cross-linkage of staggered, insoluble tropocollagen units to form fibrils

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103
Q

Ehlers-Danlos Syndrome

A
  • faulty collagen synthesis due to problems with cross-linking of tropocollagen units
  • presents with hyper extensible skin, a tendency to bleed, and hyper mobile joints
  • may also be associated with joint dislocation, berry and aortic aneurysms, or organ rupture
  • three types: hypermobility, classical, and vascular
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104
Q

What are the three types of Ehlers-Danlos syndrome?

A
  • hypermobility: aka joint instability type, this is most common
  • classical: presents with joint and skin symptoms and is caused by a mutation in type V collagen
  • vascular: presents with vascular and organ rupture due to a deficiency of type III collagen
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105
Q

Menkes Disease

A
  • an X-linked recessive connective tissue disease
  • caused by a defect in ATP7A, a protein responsible for copper absorption and transport, which leads to diminished activity of lysyl oxidase, the enzyme that links tropocollagen units to form fibrils
  • presents with brittle, kinky hair, growth retardation, and hypotonia
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106
Q

The activity of elastase is opposed by what other enzyme?

A

a1-antitrypsin

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107
Q

Elastin is rich in what sorts of amino acid residues?

A

nonhydroxylated proline, glycine, and lysine

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108
Q

What is fibrillin?

A

a glycoprotein scaffold for tropoelastin

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109
Q

Marfan Syndrome (cause, presentation, complications)

A
  • a connective tissue disorder affecting skeleton, heart, and eyes
  • due to a FBN1 gene mutation on chromosome 15 leads to defective fibrillin, a glycoprotein scaffold for elastin
  • presents as a tall, lengthy individual with pectus excavatum, hypermobile joints, and long, tapering fingers and toes
  • complications include necrosis of the aorta leading to incompetence and dissection, floppy mitral valve, and subluxation of the lenses (typically upward and temporally)
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110
Q

The wrinkles of aging are due to what?

A

a decrease in collagen and elastin production

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111
Q

What are the three steps of PCR?

A
  • denaturation (95 Celsius)
  • annealing (55 Celsius)
  • elongation (72 Celsius)
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112
Q

What are southern, northern, western, and southwestern blots used to identify?

A

SNoW DRoP

  • southern: looking for specific DNA sequences using a complementary DNA probe
  • northern: looking for specific RNA sequences using a complementary DNA probe
  • western: looking for protein using a labeled antibody
  • southwestern: looking for DNA-binding proteins (e.g. transcription factors) using labeled oligonucleotide probes
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113
Q

What kind of blotting procedure would you use if you wanted to measure mRNA levels?

A

a northern blot

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114
Q

Describe a microarray and it’s uses.

A
  • thousands of nucleic acid sequences are arranged in grids on glass or silicon and DNA or RNA probes are applied, after which a scanner detects the relative amounts of complementary binding
  • useful in detecting SNPs and copy number variations
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115
Q

Describe an ELISA.

A
  • antibodies in a well specific for the target are linked to an enzyme
  • a substrate is added and reacts with the enzyme, producing a detectable signal, which can be measured
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116
Q

What is fluorescence in situ hybridization?

A

use of a fluorescent DNA or RNA probe, which binds to a specific gene site of interest on chromosomes in vitro, to indentify translocations, duplications, or microdeletions

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117
Q

What is the difference between DNA and cDNA?

A

cDNA lacks introns because it is formed from mRNA using a reverse transcriptase

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118
Q

Describe the process of cloning.

A
  • mRNA is isolated and exposed to reverse transcriptase, which produces cDNA
  • that cDNA is inserted into bacterial plasmids containing antibiotic resistance genes
  • the plasmid is transformed into bacteria
  • those bacteria are grown on an antibiotic medium and those that survive are known have the cDNA
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119
Q

What is a Cre-Lox system?

A

a method used in mice to inducible manipulate genes (KO or knock-in) at specific developmental points

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120
Q

What is codominance?

A

both alleles contribute to the phenotype of the heterozygote as in blood groups

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121
Q

What is variable expressivity?

A

a genetic trait for which the phenotype varies among individuals of the same genotype

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122
Q

What is incomplete penetrance?

A

a genetic trait for which not all individuals with a mutant genotype show the mutant phenotype as in BRCA1 mutations

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123
Q

What is pleiotropy?

A

the idea that one gene contributes to multiple phenotypic effects

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124
Q

What is a dominant negative mutation? Give an example.

A
  • one that exerts a dominant effect because the heterozygote produces a nonfunctional, altered protein that also prevents the normal gene product from functioning
  • mutation of a transcription factor in its allosteric site will allow it to continue to bind DNA and prevent the wild-type from binding DNA
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125
Q

What is linkage dysequilbrium?

A

the tendency for certain alleles at two linked loci to occur together more or less often than expected by chance

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126
Q

What is mosaicism?

A

the presence of genetically distinct cell lines in the same individual

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127
Q

What is the difference between somatic and gonadal mosaicism?

A
  • somatic: mutation arises from mitotic errors after fertilization and propagates through multiple tissues
  • gonadal: the mutation is only in egg or sperm cells
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128
Q

What is locus heterogeneity?

A

the idea that mutations at different loci can produce a similar phenotype

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129
Q

What is allelic heterogeneity?

A

the idea that different mutations in the same locus can produce the same phenotype

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130
Q

What is heteroplasmy?

A
  • the presence of both normal and mutated mitochondrial DNA

- results in variable expression in mitochondrial inherited disease

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131
Q

What is the difference between heterodisomy and isodisomy?

A

both are when an offspring receives two copies of a chromosome from one parent and none from the other

  • heterodisomy: the individual is heterozygous and this indicates a meiosis I error
  • isodisomy: the individual is homozygous and this indicates a meiosis II error
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132
Q

What might be the underlying genetic reason for an individual to have a recessive disorder when only one parent is actually a carrier?

A

it could be a case of isodisomy in which one parent contributed two copies of a chromosome and the other contributed none

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133
Q

McCune-Albright Syndrome

A
  • a mutation affecting G-protein signaling
  • this mutation would be lethal if it occurred before fertilization but individuals with mosaicism can survive it
  • presents with unilateral cafe-au-lait spots, polyostotic fibrous dysplasia, precocious puberty, and multiple endocrine abnormalities
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134
Q

What are the four assumptions of Hardy-Weinberg’s principle?

A
  • no mutation
  • natural selection is absent
  • completely random mating
  • no net migration
135
Q

What is imprinting?

A

the idea that at some loci, only one allele is active and other is inactivated by methylation

136
Q

Why is imprinting clinically important? Give two examples.

A

because when only one allele is active, a single mutation or deletion can lead to disease (e.g. Prader-Willi and Angelman syndrome)

137
Q

Describe the presentation of Prader-Willi syndrome and explain how it demonstrates the concept of imprinting.

A
  • presents with hyperplasia, obesity, intellectual disability, hypogonadism, and hypotonia
  • maternal allele is universally imprinted
  • 25% of cases, though, are due to maternal uniparental disomy in which two maternal alleles are inherited but are then both imprinted
138
Q

Describe the presentation of Angelman syndrome and explain how it demonstrates the concept of imprinting.

A
  • presents with inappropriate laughter, seizures, ataxia, and severe intellectual disability
  • paternal allele is imprinted but in 5% of cases, two paternally imprinted genes are received and no maternal allele is received
139
Q

X-linked recessive traits demonstrate what features on a hereditary map?

A

there is no male-to-male transmission and it skips generations

140
Q

What is the key feature of X-linked dominant traits on a hereditary map?

A

mothers transmit to 50% of offspring and fathers transmit to all daughters but no sons

141
Q

What are the key features of mitochondrial inheritance?

A
  • transmitted only through the mother

- heteroplasmy gives rise to variable expression in the population and within a family

142
Q

Mitochondrial Myopathies

A
  • a group of disorders secondary to failure in oxidative phosphorylation
  • muscle biopsy tends to show “ragged red fibers”
  • presents with myopathy, lactic acidosis, and CNS disease
143
Q

Where are the PKD1 and PKD2 genes?

A

they are the genes involved in ADPKD and are located on chromosome 16 and 4, respectively

144
Q

Familial Hypercholesterolemia (cause, inheritance, and presentation)

A
  • elevated LDL due to an autosomal dominant defect or absence of the LDL receptor
  • leads to severe atherosclerotic disease early in life, corneal arches, tendon xanthomas
145
Q

Li-Fraumeni syndrome is also known as what?

A

SBLA (sarcoma, breast, leukemia, and adrenal) cancer syndrome

146
Q

What is tuberous sclerosis?

A

an autosomal dominant neurocutaneous disorder with variable expression that presents with multi-organ involvement, characterized by numerous benign hamartomas

147
Q

What is the VHL gene and where is it located?

A

it is a tumor suppressor gene located on chromosome 3

148
Q

Neurofibromatosis Type I

A
  • an autosomal dominant neurocutaneous disorder with 100% penetrance and variable expression
  • due to a mutation of the NF1 gene on chromosome 17
  • presents with cafe-au-lait spots, cutaneous neurofibromas, optic gliomas, pheochromocytoma, and Lisch noduels
149
Q

Neurofibromatosis Type II

A
  • an autosomal dominant neurocutaneous disorder
  • caused by a mutation of the NF2 gene on chromosome 22
  • presents with bilateral acoustic Schwannomas, juvenile cataracts, meningiomas, and ependymomas
150
Q

Cystic Fibrosis

A
  • an autosomal recessive condition caused by a mutation of the CFTR gene on chromosome 7
  • CFTR is an ATP-gated Cl- channel that secretes Cl- into the lungs and Gi tract and reabsorbs chloride ions in the sweat glands
  • most common is a deletion of Phe508, which causes a misfiling of the protein, which is then retained in the RER and not transported to the cell membrane
  • as a result, there is a rise in intracellular chloride ions and a compensatory increase in sodium reabsorption, which increases water reabsorption; water reabsorption causes the lung and GI tract secretions to become very thick; change in sodium causes a more negative trans epithelial potential difference
  • an increase in chloride concentration in the sweat is diagnostic; can also bee seen as a contraction alkalosis and hypokalemia
  • newborn screening looks for an increase in immunoreactive trypsinogen
  • complications include recurrent pulmonary infections (S. aureus in early infarct, P. aeruginosa in adolescence); chronic bronchitis and bronchiectasis; pancreatic insufficiency with malabsorption, steatorrhea, and fat-solute vitamin deficiencies; biliary cirrhosis and liver disease; meconium ileum in newborns; infertility in men; and sub fertility in women
  • treatment involves chest physiotherapy, albuterol, aerosolized dornase alfa (a DNAse), hypertonic saline for mucus clearance, azithromycin for prophylaxis, and pancreatic enzyme replacement
151
Q

What is the most common lethal genetic disease in the Caucasian population?

A

CF

152
Q

What is the normal function of the CFTR gene product?

A

CFTR encodes an ATP-gated Cl- channel that secretes Cl- into the lungs and GI tract and reabsorbs chloride in the sweat glands

153
Q

Myotonic Type I

A
  • an autosomal dominant muscular dystrophy
  • caused by a CTG repeat expansion in the DMPK gene, coding for an abnormal myotonia protein kinase
  • presents with myotonia, muscle wasting, cataracts, testicular atrophy, frontal balding, and arrhythmia
154
Q

Fragile X Syndrome (cause, presentation, note)

A
  • an X-linked dominant condition arising from a trinucleotide repeat of the FMR1 gene that leads to methylation and diminished expression
  • presents with post-pubertal macroorchidism, long face and large jaw, large everted ears, autism, and mitral valve prolapse
  • the second most common cause of genetic intellectual disability after Down’s
155
Q

List four disease that arise from trinucleotide repeat expansion and the expansion that is involved.

A
  • Huntington Disease: CAG
  • Myotonic Dystrophy: CTG
  • Friedreich Ataxia: GAA
  • Fragile X: CGG
156
Q

What are the three most common causes of trisomy 21?

A
  • 95% of cases are due to meiotic nondisjunction, which increases in probability with advanced maternal age
  • 4% of cases due to unbalanced Robertsonian translocations between chromosome 14 and 21
  • 1% from a post-fertilization mitotic error with mosaicism
157
Q

Down Syndrome

A
  • most often due to meiotic nondisjunction, which occurs with increasing probability given advanced maternal age
  • represents the most common viable chromosomal disorder and most common cause of genetic intellectual disability
  • presents with intellectual disability, flat facies, prominent epicentral folds, single palmar creases, and brushfield spots
  • can be diagnosed often in first-trimester with US showing increased nuchal translucency and hypoplastic nasal bone, low serum PAPP-A, and increased free B-hCG
  • findings in the second-trimester include low a-fetoprotein, increased B-hcG, low estriol, and increased inhibin A
  • associated with duodenal atresia, Hirschsprung disease, AV septal defects, early-onset Alzheimer’s, and ALL or AML
158
Q

Edwards Syndrome

A
  • also known as trisomy 18
  • presents with severe intellectual disability, rocker-bottom feet, micrognathia, low-set ears, clenched hands with overlapping fingers, and congenital heart disease
  • death is usually within 1 year of birth
  • in utero, PAPP-A and free B-hCG are usually low during the first trimester; second trimester shows low a-fetoprotein, low B-hCG, low estriol, and low or normal inhibin A
159
Q

Describe the in utero findings associated with Down syndrome, Edwards syndrome, and Patau syndrome.

A
  • Down: increased nuchal translucency, hypoplastic nasal bone, low serum PAPP-A, increased free B-hCG, low estriol, high inhibin A, and low a-fetoprotein
  • Edwards: low PAPP-A, low B-hCG, low a-fetoprotein, low B-hCG, low estriol, and low or normal inhibin A
  • Patau: low free B-hCG and low PAPP-A
160
Q

Patau Syndrome

A
  • also known as trisomy 13
  • in utero, free B-hCG and PAPP-A are both low
  • presents with severe intellectual disability, rocker-bottom feet, microphthalmia, microcephaly, cleft lip/palate, holoprosencephaly, polydactyly
  • death usually occurs in one year
161
Q

What is a Robertsonian translocation? How does it affect the offspring and which chromosomes are most often involved?

A
  • a chromosomal translocation in which the long arms of 2 afrocentric chromosomes (those with a centromere near their ends) fuse at the centromere
  • the short arms are generally lost leaving a one normal chromosome E, one normal chromosome F, and one fusion chromosome (instead of the original 4 normal chromosomes)
  • offspring can end up being monosomy, disomy, or trisomy depending on the gamete that is formed
  • usually involves 13, 14, 15, 21, or 22
162
Q

Cri-du-chat Syndrome (cause and presentation)

A
  • a congenital micro deletion of the short arm of chromosome 5
  • presents with microcephaly, moderate-to-severe intellectual disability, high-pitched crying/mewing, epicentral folds, and cardiac abnormalities (VSD)
163
Q

Williams Syndrome

A
  • a congenital micro deletion of the long arm of chromosome 7, which contains the elastin gene
  • presents with an “elfin” face, intellectual disability, hypercalcemia (increased sensitivity to vitD), well-developed verbal skills, extreme friendliness, and cardiovascular problems
164
Q

Which vitamins are fat soluble?

A

A, D, E, and K

165
Q

Where is Vitamin A found and what is it’s function?

A
  • found in liver and leafy vegetables
  • it is an antioxidant
  • constituent of visual pigements
  • essential for the normal differentiation of epithelial cells in specialized tissues and prevents squamous metaplasia
  • oral supplementation, in the form of isotretinoin, is used to treat severe cystic acne
166
Q

What is the result of a vitamin A deficiency?

A
  • night blindness (aka nyctalopia)
  • dry, scaly skin (aka xerosis cutis)
  • corneal degeneration (keratomalacia)
  • bitot spots on conjunctiva
  • immunosuppression
167
Q

What is the result of a vitamin A toxicity?

A
  • acute: nausea, vomiting, vertigo, and blurred vision
  • chronic: alopecia, dry skin, hepatotoxicity, enlargement of arthralgia, and pseudotumor cerebri
  • also a teratogen causing cleft palate and cardiac abnormalities
168
Q

What is isotretinoin?

A

an oral vitamin A supplement used to treat severe cystic acne, but which requires a negative pregnancy and two forms of contraception prior to its use because of it’s teratogenic effects (clef palate and cardiac problems)

169
Q

Vitamin B1 Deficiency

A
  • also known as thiamine, it is an important component of thiamine pyrophosphate, a cofactor for several dehydrogenase enzyme reactions
  • necessary for pyruvate dehydrogenase, a-ketoglutarate dehydrogenase, transketolase of the HMP shunt, and branched-chain ketoacid dehydrogenase
  • deficiency often arises from malnutrition (known as Beri Beri) or alcoholism (known as Wernicke-Korsakoff syndrome)
  • as a result of the deficiency glucose breakdown is impaired and ATP depletion worsens with glucose infusion, particularly in highly aerobic tissues like brain/heart
  • diagnose with observation of an increase in RBC transketolase activity following B1 administration
170
Q

What are dry and wet beriberi?

A
  • beriberi refers to a vitamin B1 deficiency resulting from malnutrition
  • dry presents with polyneuritis and symmetrical muscle wasting
  • wet presents with high-output cardiac failure, secondary to dilated cardiomyopathy, and edema
171
Q

Vitamin B2 Deficiency

A
  • also known as riboflavin, B2 is a component in FAD and FMN, used for redox reactions
  • presents with cheilosis (inflammation of lips, scaling, and fissures at the corners of the mouth) and corneal vascularization
172
Q

What is Vitamin B3 used for?

A
  • also known as niacin, B3 is a constituent of NAD and NADP

- derived from tryptophan, synthesis requires vitamins B2 and B6

173
Q

Niacin (vitamin B3) is used to treat what disorder?

A

dyslipidemia, specifically, it lowers VLDL and raises HDL

174
Q

Vitamin B3 Deficiency

A
  • B3 is necessary for formation of NAD and NADP and it is derived from tryptophan, using B2 and B6
  • caused by Hartnup disease (neutral amino acid transporter defect limiting tryptophan availability), carcinoid syndrome (increased tryptophan metabolism), and isoniazid (lowers B6 availability)
  • presents with glossitis and symptoms of pellagra: diarrhea, dementia with hallucinations, dermatitis along the C3/C4 dermatome (“broad collar” rash) with hyperpigmentation of sun-exposed limbs
175
Q

Hartnup Disease

A
  • an autosomal recessive deficiency of neutral amino acid transporters in the proximal renal tubular cells and on enterocytes
  • results in neutral aminoaciduria and poor absorption from the gut
  • without tryptophan, there is a deficiency of niacin, presenting with pellagra (red, rough rash following sun exposure), diarrhea, and cerebellar ataxia
  • can be treated with a high-protein diet and niacin supplementation
176
Q

How does a vitamin B3 toxicity present?

A

with facial flushing (induced by prostaglandins and avoided by taking aspirin with niacin), hyperglycemia, and hyperuricemia

177
Q

Vitamin B5 (name, function, deficiency)

A
  • also known as pantothenic acid
  • functions as an essential component of CoA and fatty acid synthase
  • deficiency presents with dermatitis, enteritis, alopecia, and adrenal insufficiency
178
Q

Vitamin B6 (name, function, deficiency)

A
  • also known as pyridoxine
  • converted to pyridoxal phosphate (PLP), a cofactor for transamination, decarboxylation reactions, and glycogen phosphorylase
  • functions in the conversion of homocysteine to cysteine and succinyl-CoA to heme
  • deficiency can be induced by isoniazid or oral contraceptives and results in convulsions, hyper-irritability, peripheral neuropathy, and sideroblastic anemia
179
Q

Vitamin B7 (name, function, deficiency)

A
  • also known as biotin
  • serves as a cofactor for carboxylation enzymes, which add 1-carbon groups
  • deficiency is rare but can be caused by antibiotic use or excessive ingestion of raw egg whites
  • presents with dermatitis, alopecia, and enteritis
180
Q

Vitamin B9 (name, source, function, deficiency)

A
  • also known as folate
  • found in leafy green vegetables and absorbed in the jejunum
  • converted to THF, a co-enzyme for 1-carbon transfer/methylation reactions and critical for synthesis of nitrogenous bases in DNA an dRNA
  • deficiency is the most common vitamin deficiency in the US; seen in alcoholism and pregnancy
  • presents with macrocytic, megaloblastic anemia, hyper-segmented PMNs, glossitis, and no neurosymptoms
  • labs will show increased homocysteine and normal methylmalonic acid
181
Q

Vitamin B12

A
  • also known as cobalamin
  • found in animal products, the liver stores a very large reserve
  • functions as a cofactor for methionine synthase (converts homocysteine to methionine) and methylmalonyl-CoA mutase (converts methylmalonyl-CoA into succinyl-CoA)
  • deficiency caused by lack of intrinsic factor, malabsorption, absence of terminal ileum, or insufficient intake (veganism)
  • presents with macrocytic, megaloblastic anemia, hyper-segmented PMNs, paresthesias and subacute combined degeneration of all tracts due to abnormal myelin
  • associated with increased levels of homocysteine and methylmalonic acid levels
182
Q

Vitamin C

A
  • also known as ascorbic acid
  • functions as an anti-oxidant, facilitates iron absorption by reducing it to the ferrous state, necessary for hydroxylation of proline and lysine in collagen synthesis, necessary for DA B-hydroxylase which produces norepinephrine
  • deficiency is known as scurvy, presenting with swollen gums, bruising, petechiae, hemarthrosis, anemia, poor wound healing, perifollicular hemorrhages, and “corkscrew hair”
  • excess causes n/v/d, fatigue, and calcium oxalate nephrolithiasis; can increase risk for iron toxicity
183
Q

What are the ergocalciferol, cholecalciferol, 25-OH D3, and calcitriol forms of Vitamin D?

A
  • ergocalciferol is D2 ingested from plants
  • cholecalciferol is D3 consumed in milk and formed in sun-exposed skin
  • 25-OH D3 is the storage form
  • calcitriol is also known as 1,25-(OH2) D3 and is the active form of D3
184
Q

Vitamin E

A
  • an antioxidant that protects RBCs and membranes from free radical damage
  • deficiency results in hemolytic anemia, acanthocytosis, muscle weakness, and posterior column and spinocerebellar tract demyelination; neuro symptoms of B12 deficiency without the megaloblastic anemia, hypersegmented PMNs, or increased serum methylmalonic acid
185
Q

How is vitamin K synthesized?

A

by intestinal flora

186
Q

Which vitamins are not found in breast milk and should be supplemented in newborns?

A

vitamins D (continued oral) and K (injection at birth)

187
Q

What are the symptoms of zinc deficiency?

A

delayed wound healing, hypogonadism, diminished adult hair, dyspepsia, anosmia, and acrodermatitis enteropathica

188
Q

What is the difference between Kwashiorkor and Marasmus?

A
  • kwashiorkor is protein malnutrition resulting gin skin lesions, edema, and liver malfunction (presents as a small child with swollen abdomen)
  • marasmus is a total caloric malnutrition resulting in emaciation/muscle wasting with or without edema
189
Q

What is fomepizole and what is it used for?

A

an enzyme that inhibits alcohol dehydrogenase and is an antidote for methanol or ethylene glycol poisoning

190
Q

What is disulfiram and what is it used for?

A

it inhibits acetaldehyde dehydrogenase increasing hangover symptoms, which is beneficial in the treatment of alcoholism

191
Q

What are the three routes of ethanol metabolism? What happens to the first metabolite?

A

all lead to the formation of acetaldehyde
- via alcohol dehydrogenase using NAD in the cytosol
- via catalase using hydrogen peroxide in the peroxisome
- via CYP2E1, generating ROS, in the microsome
acetaldehyde is converted to acetate in the mitochondria

192
Q

Ethanol metabolism increases the NADH/NAD ratio. What are four other metabolic effects of this imbalance?

A
  • disfavors TCA production of NADH so acetyl-CoA is diverted to ketogenesis and lipogenesis, causing ketoacidosis and hepatosteatosis
  • pyruvate is fermented to lactate causing a lactic acidosis
  • oxaloacetate is fermented to malate, preventing gluconeogenesis (because of the need for oxaloacetate) and causing a fasting hypoglycemia
  • dihydroxyacetone phosphate is converted to glycerol-3-phosphate, which combines with fatty acids to make triglycerides, contribute to hepatosteatosis
193
Q

Why does chronic alcohol lead to hepatosteatosis?

A

because ethanol metabolism increases the NADH/NAD ratio, inhibiting TCA production of NADH, so acetyl-CoA is diverted to lipogenesis instead

194
Q

What metabolic processes occur in the mitochondria? The cytoplasm? Both?

A
  • mitochondria: B-oxidation, acetyl-CoA production, TCA cycle, oxidative phosphorylation, ketogenesis
  • cytoplasm: glycolysis, HMP shunt, and synthesis of steroids, proteins, fatty acids, cholesterol, and nucleotides
  • both: heme synthesis, urea cycle, and gluconeogensis
195
Q

What is a kinase, phosphorylase, and phosphatase?

A
  • kinase: catalyzes transfer of a phosphate group from a high-energy molecule
  • phosphorylase adds an inorganic phosphate onto a substrate without using ATP
  • phosphatase removes a phosphate group from a substrate
196
Q

What is a dehydrogenase?

A

an enzyme that catalyzes a redox reaction

197
Q

What is a mutase?

A

an enzyme that relocates a functional group within a molecules

198
Q

What is the rate determining enzyme of glycolysis? What are the positive and negative regulators of this enzyme?

A
  • phosphofructokinase-1
  • activated by AMP and F-2,6-BP
  • inhibited by ATP and citrate
199
Q

What is the rate determining enzyme of gluconeogenesis? What are the negative regulators of this enzyme?

A
  • fructose-1,6-bisphosphatase

- inhibited by AMP and fructose-2,6-bisphosphate

200
Q

What is the rate determining enzyme of the TCA cycle?

A

isocitrate dehydrogenase

201
Q

What is the rate determining enzyme of glycogenesis? What are the positive and negative regulators of this enzyme?

A
  • glycogen synthase
  • activated by glucose-6-phosphate, insulin, and cortisol
  • inhibited by epinephrine and glucagon
202
Q

What is the rate determining enzyme of glycogenolysis? What are the positive and negative regulators of this enzyme?

A
  • glycogen phosphorylase
  • activated by epinephrine, glucagon, and AMP
  • inhibited by glucose-6-phosphate, insulin, and ATP
203
Q

What is the rate determining enzyme of the HMP shunt? What are the positive and negative regulators of this enzyme?

A
  • glucose-6-phosphate dehydrogenase
  • activated by NADP+
  • inactivated by NADPH
204
Q

What is the rate determining enzyme of de novo pyrimidine synthesis? What are the positive and negative regulators of this enzyme?

A
  • carbamoyl phosphate synthetase II
  • activated by ATP and PRPP
  • inactivated by UTP
205
Q

What is the rate determining enzyme of de novo purine synthesis? What are the negative regulators of this enzyme?

A
  • glutamine-PRPP amidotransferase

- inactivated by AMP, IMP, and GMP

206
Q

What is the rate determining enzyme of the urea cycle? What is the primary positive regulator of this enzyme?

A
  • carbamoyl phosphate synthetase I

- activated by N-acetylglutamate

207
Q

What is the rate determining enzyme of fatty acid synthesis? What are the positive and negative regulators of this enzyme?

A
  • acetyl-CoA carboxylase
  • activated by insulin and citrate
  • inactivated by glucagon and palmitoyl-CoA
208
Q

What is the rate determining enzyme of fatty acid oxidation? What is the primary negative regulator of this enzyme?

A
  • carnitine acyltransferase I

- inactivated by malonyl-CoA

209
Q

What is the rate determining enzyme of ketogenesis?

A

HMG-CoA synthase

210
Q

What is the rate determining enzyme of cholesterol synthesis? What are the positive and negative regulators of this enzyme?

A
  • HMG-CoA reductase
  • activated by insulin and thyroxine
  • inactivated by glucagon and cholesterol
211
Q

Why are rate-determining steps of a metabolic process important?

A

because they are often key regulatory points

212
Q

Aerobic metabolism of glucose nets how many ATP?

A
  • 32 via the malate-aspartate shuttle in the heart and liver

- 30 via the glycerol-3-phosphate shuttle in muscle

213
Q

What is the pathogenesis of arsenic exposure and how does it present?

A
  • it causes glycolysis to produce zero net ATP because it inhibits lipoid acid, a cofactor required by pyruvate dehydrogenase
  • it presents with vomiting, rice-water stools, and garlic breath
214
Q

Describe the group carried when the following are in the activated form:

  • CoA
  • lipoamide
  • biotin
  • THF
  • S-adenosylmethionine
  • TPP
A
  • CoA carries an acyl group
  • lipoamide carries an acyl group
  • biotin carries a CO2 group
  • THF carries a 1 carbon unit
  • SAM carries methyl groups
  • TPP carries aldehydes
215
Q

NAD and FAD are derived from which vitamins?

A

B3 and B2, respectively

216
Q

NADPH is used in what four processes?

A
  • anabolic processes
  • respiratory burst
  • microsomal enzyme system
  • glutathione reductase
217
Q

What is the difference between glucokinase and hexokinase?

A
  • glucokinase is expressed in the liver and by B-islet cells; it has a low affinity (high Km) and high capacity (high Vmax), is induced by insulin, and is not inhibited by glucose-6-phosphate
  • hexokinase is expressed by most tissues constitutively, has a higher affinity (low Km) and lower capacity (low Vmax), and is inhibited by glucose-6-phosphate
  • as a result glucokinase doesn’t really turn on or function maximally until all other tissues are receiving adequate glucose
218
Q

Are hexokinase or glucokinase mutations associated with maturity-onset diabetes of the young?

A

glucokinase

219
Q

Which steps of glycolysis require ATP and which produce ATP?

A
  • hexokinase/glucokinase and PFK-1 both require ATP

- phosphoglycerate kinase (1,3-BPG –> 3-PG) and pyruvate kinase (PEP –> pyruvate) both produce ATP

220
Q

Describe the regulatory role of fructose-2,6-biphosphate.

A
  • PFK-2 and FBPase-2 are the same, bifunctional enzyme (converts between F-6-P and F-2,6-BP) whose function is reversed by PKA
  • in the fasting state, glucagon triggers an increase in cAMP, which activates PKA, leading to more FBPase-2 activity and less PFK-2 activity; the balance tips toward greater F-6-P production and less F-2,6-BP production; without F-2,6-BP, PFK-1 isn’t allosterically activated and less glycolysis occurs
  • in the fed state, insulin triggers a decrease in cAMP, which results in less PKA activity; this favors activation of PFK-2 and production of more F-2,6-BP, which allosterically activates PFK-1 and drives glycolysis forward
221
Q

What is the function of the pyruvate dehydrogenase complex? Where is it found? What cofactors does it require? What are the three major activators?

A
  • it is a mitochondrial enzyme complex linking glycolysis and the TCA cycle
  • it catalyzes the conversion of pyruvate to acetyl-CoA with the production of one NADH and CO2 molecule
  • it is composed of three enzymes requiring five cofactors: thiamine pyrophosphate (B1), lipoic acid, CoA (B5), FAD (B2), and NAD (B3)
  • it is activated by a high NAD/NADH ratio, ADP, and calcium
222
Q

Pyruvate dehydrogenase requires what cofactors?

A

TLC For Nancy

  • thiamine pyrophosphate (B1)
  • lipoic acid
  • CoA (B5)
  • FAD (B2)
  • NAD (B3)
223
Q

Pyruvate Dehydrogenase Complex Deficiency

A
  • an X-linked metabolic disorder
  • the deficiency causes a buildup of pyruvate, which is shunted to lactate ( via LDH) and alanine (via ALT)
  • presents with neurologic defects, lactic acidosis, and an elevated serum alanine starting in infancy
  • treat by increasing intake of ketogenic nutrients (high fat, lysine, or leucine content)
224
Q

Which are the only purely ketogenic amino acids?

A

lysine and leucine

225
Q

What is the Cahill cycle?

A

a method for getting regenerating glucose from pyruvate by cycling pyruvate through the liver while also transporting amino groups from skeletal muscle to the liver for disposal

  • begins with ALT transferring an amino group from an amino acid to pyruvate, forming alanine
  • alanine is transported in the blood to the liver
  • there in the liver, alanine is deaminated and pyruvate is reformed
  • the amino group is put into the urea cycle and the pyruvate undergoes gluconeogenesis
  • the glucose is then returned to skeletal muscle via the blood
226
Q

What is the Cori cycle?

A

a cycle used so that skeletal muscle can produce lactate during anaerobic periods from glucose, transport that lactate to the liver where it is reformed into glucose, and that glucose is delivered back to muscle for another cycle

  • LDH converts pyruvate to lactate
  • the lactate is transported via the blood to the liver
  • in the liver it is converted back to pyruvate and then glucose
  • the glucose is returned to the muscle via the blood
227
Q

How does the Cahill cycle compare to the Cori?

A
  • both begin with pyruvate and involve transport of those carbon units to the liver for gluconeogenesis, which provides more glucose for muscle under anaerobic conditions
  • however, because the Cahill cycle is tied to transport of ammonia group, which the liver must use ATP to dispose of, it is favored only when the body is in a state of catabolism or there is a general need to get ride of ammonia
  • they also differ in that the Cori cycle requires NADH to reduce pyruvate to lactate, which is a form of energy expenditure
  • additionally, the Cahill cycle requires an alanine aminotransferase to begin the cycle whereas the Cori cycle requires LDH
228
Q

What are the four potential fates of pyruvate in a cell?

A
  • addition of an amino group by ALT for the Cahill cycle
  • reduction by LDH to lactate for the Cori cycle
  • production of acetyl-CoA for the TCA cycle by pyruvate dehydrogenase
  • production of oxaloacetate by pyruvate carboxylase, using biotin, to replenish the TCA cycle or be used for gluconeogensis (pyruvate can’t go directly back to PEP)
229
Q

What are the products of the TCA cycle?

A

3 NADH, 1 FADH2, 2 CO2, and 1 GTP per acetyl-CoA (x2 per glucose), which equals 10 ATP per acetyl-CoA

230
Q

What happens to NADH and FADH2 produced by glycolysis and the TCA cycle?

A
  • NADH enters the mitochondria via the malate-aspartate or glycerol-3-phosphate shuttle and each generates 2.5 ATP
  • FADH2 transfers electrons directly to complex II of the electron transport chain and each generates 1.5 ATP
231
Q

What effect do rotenone, antimycin A, cyanide, CO, oligomycin, aspirin, and 2,4-dinitrophenol have on the electron transport chain?

A
  • rotenone inhibits electron transfer within complex I
  • antimycin A inhibits electron transfer within complex III
  • cyanide and CO inhibit electron transfer in complex IV
  • oligomycin inhibits complex V (ATP synthase) and so a proton gradient builds and electron transport stops
  • aspirin increases membrane permeability, reducing the proton gradient and uncoupling ATP synthase
  • 2,4-dinitrophenol increases membrane permeability, reducing the proton gradient and uncoupling ATP synthase
232
Q

How does aspirin affect the electron transport chain?

A

it increases membrane permeability, reducing the proton gradient and uncoupling ATP synthase from it

233
Q

What is 2,4-dinitrophenol?

A

a uncoupling agent that increases membrane permeability for protons and is used illicitly for weight loss

234
Q

How does the effects of 2,4-dinitrophenol and aspirin differ from that of oligomycin?

A
  • both inhibit the ETC and ATP production
  • however, aspirin and 2,4-dinitrophenol are uncoupling agents, so while ATP production is inhibited, electrons continue to flow and heat is generated instead of energy
  • oligomycin directly inhibits ATP synthase, the proton gradient builds, and electrons stop flowing without the generation of heat
235
Q

Which four enzymes of gluconeogenesis are irreversible?

A
  • pyruvate carboxylase (pyruvate to oxaloacetate)
  • PEP carbokinase (oxaloacetate to PEP)
  • F-1,6-BPase (F-1,6-BP to F-6-P)
  • G-6-Pase (G-6-P to glucose)
236
Q

Which steps of gluconeogenesis require energy units?

A

pyruvate carboxylase requires ATP and PEP carboxykinase requires GTP

237
Q

Why is muscle incapable of gluconeogenesis?

A

because it lacks glucose-6-phosphatase

238
Q

What is the primary site of gluconeogensis?

A

the liver

239
Q

Under what circumstances can fatty acids contribute to gluconeogenesis?

A
  • odd-chain FAs yield 1 propionyl-CoA molecule during metabolism, which can enter the TCA cycle as succinyl-CoA and contribute to gluconeogenesis
  • even-chain FAs only yield acetyl-CoA and cannot contribute to gluconeogenesis
240
Q

What are ketogenic amino acids? What are glucogenic amino acids?

A
  • ketogenic are those that can be degraded directly into acetyl-CoA, a precursor for ketone bodies but not glucose
  • glucogenic are those that can enter the TCA cycle at or after succinyl-CoA and be converted to oxaloacetate for gluconeogenesis
241
Q

What are the two primary products of the HMP/PPP pathway?

A
  • the oxidative part yields NADPH for anabolic reactions and ribulose-5-phosphate
  • the non-oxidative part takes ribulose-5-phosphate and forms primarily ribose-5-phosphate for nucleotide synthesis (in addition to fructose-6-phosphate and glyceraldehyde-3-phosphate)
242
Q

Essential Fructosuria

A
  • an autosomal recessive defect in fructokinase, which normally converts fructose to fructose-1-phosphate for entry into glycolysis
  • benign and asymptomatic since fructose is not trapped in cells; only sign is fructose in the blood and urine
243
Q

Which tend to be more severe, disorders of fructose metabolism or galactose metabolism?

A

those of galactose metabolism have more severe clinical presentations

244
Q

Fructose Intolerance

A
  • an autosomal recessive defect in aldolase B, which converts fructose-1-phosphate into DHAP for entry into glycolysis
  • fructose-1-phosphate accumulates and depletes phosphate, which inhibits glycogenolysis and gluconeogenesis
  • presents with hypoglycemia, jaundice, cirrhosis, and vomiting following the consumption of fruit, juice, or honey
  • urine dipstick will be negative but reducing sugar (positive copper test) can be detected in urine (non-specific)
  • treat by reducing intake of fructose and sucrose
245
Q

What is a urine dipstick test?

A

a test for glucose in urine

246
Q

What is reducing sugar in the urine a sign of?

A

it is a nonspecific test for inborn errors of carbohydrate metabolism

247
Q

Galactokinase Deficiency

A
  • an autosomal recessive deficiency of galactokinase, the enzymes that converts galactose to galactose-1-phosphate
  • galactose is instead shunted to production of galactitol by aldose reductase, which accumulates in the eye
  • relatively mild presentation with symptoms first appearing when infants begin feeding: galactosemia, galactosuria, infantile cataracts
  • may present as a failure to track objects or to develop a social smile (due to vision change)
248
Q

Classic Galactosemia

A
  • an autosomal recessive deficiency of galactose-1-phosphate uridyltransferase, which normally converts galactose-1-P to glucose-1-P
  • galactitol builds up and phosphate is depleted
  • symptoms include failure to thrive, jaundice, hepatomegaly, infantile cataracts because galactitol accumulates in the eye, and intellectual disability
  • may lead to E. coli sepsis in neonates
  • treat by excluding galactose and lactose from diet
249
Q

What is lactose a dimer of? What is sucrose a dimer of?

A
  • sucrose: glucose + fructose

- lactose: glucose + galactose

250
Q

Why are classic galactosemia and fructose intolerance more severe clinically than either galactokinase deficiency or essential fructosuria?

A

classic galactosemia and fructose intolerance are due to enzyme deficiencies that prevent further metabolism of phosphorylated compounds and therefore there is depletion of phosphoate in these disorders

251
Q

What is sorbitol?

A
  • an osmotically active alcohol of glucose formed by aldose reductase
  • traps glucose in cells and is normally converted to fructose by sorbitol dehydrogenase
252
Q

What is sorbitol and why is it clinically significant?

A
  • it is an osmotically active alcohol of glucose
  • in those with a deficiency of sorbitol dehydrogenase or in tissues such as Schwann cells, retinal cells, and kidney cells without sorbitol dehydrogenase, sorbitol causes osmotic damage
  • this is particularly true in diabetics with chronic hyperglycemia, which drives production of sorbitol in these tissues without a way of riding it
253
Q

What is aldose reductase?

A

an enzyme that converts glucose to sorbitol and galactose to galactitol, two osmotically active substances that can cause damage in tissues without sorbitol or galactitol dehydrogenase

254
Q

Why are Schwann cells, retinal cells, and the kidneys so susceptible to hyperglycemia?

A

because they express aldose reductase which converts glucose to the alcohol sorbitol, which is osmotically active, but they lack sorbitol dehydrogenase, so the substance accumulates and mediates osmotic damage

255
Q

Which cells lack sorbitol dehydrogenase?

A
  • Schwann cells
  • retinal cells
  • renal cells
256
Q

Lactase Deficiency

A
  • an insufficiency of lactase, which functions on the brush border to digest lactose into glucose and galactose
  • can be primary with an age-dependent decline after childhood due to an absence of the lactase-persistent allele; can be secondary due to a loss of the brush border to gastroenteritis or autoimmune disease; congenital deficiency is rare
  • presents with bloating, cramps, flatulence, and osmotic diarrhea
  • stool will have low pH and breath shows excess hydrogen content with a lactose hydrogen breath test
  • treatment is avoidance of dairy products or a lactase pill at meal times
257
Q

Which amino acids are essential? Divide them according to glucogenic, ketogenic, and both.

A
  • glucogenic: methionine, valine, histidine
  • ketogenic: leucine and lysine
  • both: isoleucine, phenylalanine, threonine, and tryptophan
258
Q

Which amino acids are acidic?

A

aspartic acid and glutamic acid; therefore, negatively charged at body pH

259
Q

Which amino acids are basic?

A
  • arginine is most basic

- lysine and histidine are also basic

260
Q

Draw the urea cycle.

A

FA 93

261
Q

Why is hyperammonemia a problem for metabolism?

A

because it depletes a-ketoglutarate, thus inhibiting the TCA cycle

262
Q

What are the symptoms of hyperammonemia and give four mechanisms for treatment?

A
  • symptoms include tremor (asterixis), slurring of speech, somnolence, vomiting, cerebral edema, and blurring of vision
  • treat by reducing protein in diet, using lactulose to acidify GI tract and trap ammonia for excretion, using rifaximin to reduce colonic ammoniagenic bacteria, and give benzoate, phenyl acetate, or phenyl butyrate to bind ammonia and enhance excretion
263
Q

N-acetylglutamate Synthase Deficiency

A
  • a deficiency in the enzyme that produces the required cofactor for carbamoyl phosphate synthetase I of the urea pathway
  • causes hyperammonemia
  • presenting in neonates as poorly regulated respiration and body temperature, poor feeding, developmental delay, and intellectual disability
  • treat by reducing dietary protein, lactulose to acidy GI tract and enhance excretion, giving rifaximin to reduce colonic ammoniagenic bacteria, and benzoate, phenyl acetate, or phenyl butyrate to bind ammonia and enhance excretion
264
Q

Ornithine Transcarbamylase Deficiency

A
  • an X-linked recessive deficiency which interferes with the body’s ability to eliminate ammonia
  • usually presents in the first few days of life with tremor (asterixis), slurring of speech, somnolence, vomiting, cerebral edema, and blurring of vision
  • labs find elevated orotic acid in blood and urine (because excess carbamoyl phosphate is converted to orotic acid) and low BUN
  • the most common urea cycle disorder
265
Q

List the phenylalanine derivatives.

A
  • Phe to tyrosine
  • tyrosine to throxyine (used) and dopa
  • dopa to melanin (used) and DA
  • DA to NE to Epi
266
Q

List the tryptophan derivatives.

A
  • converted to niacin for NAD/NADP

- converted to serotonin and melatonin

267
Q

Histidine is a precursor for what product?

A

histamine

268
Q

Glycine is a precursor for what important products?

A

porphyrin and heme

269
Q

Glutamate is a precursor for what important products?

A

GABA and glutathione

270
Q

Arginine is a precursor for what important products?

A

creatine, urea, and nitric oxide

271
Q

Phenylketonuria

A
  • an autosomal recessive metabolic disorder arising from diminished phenylalanine hydroxylase activity or lack of the tetrahydrobiopterin cofactor
  • inability to convert phenylalanine to tyrosine and to synthesize the catecholamines derived from it
  • presents with intellectual disability, growth retardation, seizures, fair skin (less melanin from DOPA), eczema, and a musty body odor
  • screened for 2-3 post-birth because maternal enzyme makes child normal at birth
  • labs find excess of phenylketones (phenylacetate, phenyllactate, and phenylpyruvate) in urine
  • treat with a diet low in phenylalanine (avoid the sweetener aspartame) and high in tyrosine plus tetrahydrobiopterin supplementation
272
Q

Maternal Phenylketonuria

A
  • a form of PKU arising form lack of proper dietary therapy during pregnancy (not a genetic defect)
  • presents with microcephaly, intellectual disability, growth retardation, and congenital heart defects at birth
273
Q

Maple Syrup Urine Disease

A
  • an autosomal recessive metabolic disorder caused by reduced branched-chain alpha-ketoacid dehydrogenase activity
  • this enzyme deficiency blocks degradation of branched amino acids (isoleucine, leucine, and valine)
  • presents with vomiting, poor feeding, urine which smells like maple syrup or burnt sugar, severe CNS defects or intellectual disability
  • will find elevated alpha-ketoacids of these branched amino acids in blood, especially of leucine
  • treat with a restriction of branched amino acids in diet and thiamine supplementation (cofactor for deficient enzyme)
274
Q

Albinism results from a mutation of what enzyme?

A

mutation of tyrosinase, the enzyme that converts DOPA to melanin

275
Q

Alkaptonuria

A
  • an autosomal recessive deficiency of homogentisate oxidase in the degradative pathway of tyrosine to fumarate
  • pigment-forming homogentisic acid accumulates in tissue, which presents as bluish-black connective tissue and sclerae as well as urine that turns black with prolonged exposure to air
  • may also cause debilitating arthralgia since homogentisate is toxic to cartilage
276
Q

Homocysteinuria

A
  • a group of autosomal recessive conditions that all result in excess homocysteine
  • can be caused by a cystathionine synthase deficiency, decreased affinity of cystathionine synthase for pyridoxal phosphate, or a methionine synthase deficiency
  • presents with homocysteinuria, intellectual disability, osteoporosis, marfanoid habits, kyphosis, lens subluxation (down and inward), thrombosis, and atherosclerosis
  • treat cystathionine synthase deficiency with a diet low in methionine
277
Q

Cystathionine Synthase Deficiency

A
  • an autosomal recessive cause of homocystinuria due to a deficiency of the enzyme or poor affinity of the enzyme for it’s necessary cofactor, pyridoxal phosphate (B6)
  • homocysteine will be converted to methionine instead of to cystathionine and then cysteine
  • presents with homocysteinuria, intellectual disability, osteoporosis, marfanoid habits, kyphosis, lens subluxation (down and inward), thrombosis, and atherosclerosis
  • treated with a diet low in methionine but high in cysteine, B12, and folate if due to enzyme deficiency
  • treated with B6 and cysteine supplementation if due to poor affinity for the cofactor
278
Q

List three possible causes for homocystinuria.

A

all are autosomal recessive:

  • cystathinoine synthase deficiency
  • poor affinity of cystathionine synthase for pyridoxal phosphate (B6), a necessary cofactor
  • methionine synthase deficiency
279
Q

Describe homocysteine metabolism.

A
  • can be converted to methionine by methionine synthase using the cofactor B12
  • can be converted to cystathionine by cystathionine synthase, using serine and the cofactor B6, which is then converted to cysteine
280
Q

Methionine Synthase Deficiency

A
  • an autosomal recessive cause of homocystinuria due to a deficiency of the enzyme
  • homocysteine will be converted to cystathionine and then cysteine instead of to methionine
  • presents with homocysteinuria, intellectual disability, osteoporosis, marfanoid habits, kyphosis, lens subluxation (down and inward), thrombosis, and atherosclerosis
  • treat with methionine supplementation
281
Q

Cystinuria

A
  • an autosomal recessive defect of the PCT and intestinal amino acid transporter, which prevents reabsorption of cysteine, ornithine, lysine, and arginine (COLA)
  • excess cystine in the urine can lead to recurrent precipitation of hexagonal cystine stones (2 cysteine connected by a disulfide bone form cystine)
  • the urinary cyanide-nitroprusside test is diagnostic
  • treat with urinary alkalization, chelating agents, and good hydration
282
Q

Describe how glucagon, epinephrine, and insulin regulate glycogen metabolism.

A
  • glucagon binds a receptor in the liver and activates AC, causing a rise in cAMP, which activates PKA
  • PKA activates glycogen phosphorylase kinase, which phosphorylates glycogen phosphorylase, the enzyme responsible for liberating glycogen for gluconeogenesis
  • similarly, epinephrine binds a/B receptors, causing an influx in calcium and activation of AC, respectively, which both activate glycogen phosphorylase and lead to activation of glycogen phosphorylase
  • insulin, on the other hand, activates a tyrosine kinase dimer receptor and phosphorylates glycogen synthase, favoring production of glycogen
283
Q

Name the two kinds of bonds present in glycogen.

A
  • linkages consist of a-(1,4) bonds

- branches consist of a-(1,6) bonds

284
Q

Describe the steps necessary for storing glucose as glycogen.

A
  • glucose to glucose-6-P by glucokinase in hepatocytes
  • glucose-6-P to glucose-1-P
  • glucose-1-P to UDP-glucose by UDP-glucose pyrophosphorylase
  • UDP-glucose to glycogen by glycogen synthase
  • branches are formed by the branching enzyme
285
Q

What is a-1,4-glucosidase?

A
  • a lysosomal enzyme, which degrades a small amount of glycogen
  • not the primary pathway for glycogen degradation
286
Q

Describe the steps necessary for converting glycogen back to glucose.

A
  • glycogen phosphorylase liberates glucose-1-phosphate residues from branched glycogen until 4 glucose units remain
  • then 4-a-D-glucanotransferase (aka debranching enzyme) moves three molecules of glucose-1-P from the branch to the linkage
  • then a-1,6-glucosidase (aka deb ranching enzyme) cleaves off the last residue, freeing glucose
287
Q

What is “limit dextrin”?

A

a term used to refer to the one to four residues remaining on a branch of glycogen after glycogen phosphorylase has shortened it as far as it can

288
Q

What sort of stain should be used to identify glycogen?

A

PAS

289
Q

List the four glycogen storage diseases.

A

Very Poor Carbohydrate Metabolism

  • Von Gierke disease
  • Pompe disease
  • Cori disease
  • McArdle disease
290
Q

Von Gierke Disease

A
  • also known as type I glycogen storage disease
  • arises from a deficiency of glucose-6-phosphatase, the final enzyme necessary for converting glycogen to glucose
  • interferes with both gluconeogenesis and glycogenolysis
  • presents with severe fasting hypoglycemia; an increase in glycogen within the liver; high blood lactate, triglycerides, and uric acid; and hepatomegaly
  • treat with frequent oral glucose and avoidance of fructose or galactose
291
Q

Pompe Disease

A
  • also known as type II glycogen storage disease
  • arises from a defect of lysosomal a-1,4-glucosidase and a-1,6-glucosidase (the final debranching enzyme)
  • presents with cardiomegaly, hypertrophic cardiomyopathy, exercise intolerance, and early death (“Pompe trashes the pump”)
292
Q

Cori Disease

A
  • also known as type III glycogen storage disease
  • due to a defect of a-1,6,glucosidase (debranching enzyme)
  • gluconeogenesis is intact so it’s milder than Von Gierke and has normal lactate levels
  • instead, there is an accumulation of limit dextrin-like structures in the cytosol
293
Q

McArdle Disease

A
  • also known as type IV glycogen storage disease
  • due to a deficiency of skeletal muscle glycogen phosphorylase (aka myophosphorylase)
  • blood glucose levels are typically unaffected but there is an increase in glycogen within muscle that cannot be broken down
  • this leads to painful muscle cramps, myoglobinuria with strenuous exercise, and arrhythmia from electrolyte abnormalities
  • “second-wind” phenomenon is a classic finding and exercise tolerance rises after about 10 minutes since there is an increase in muscular blood flow
294
Q

Fabry Disease

A
  • an X-linked recessive lysosomal storage disease
  • deficiency of a-galactosidase A
  • ceramics trihexoside accumulates in lysosomes
  • an early triad of episodic peripheral neuropathy, angiokeratomas, and hypohidrosis
  • a later stage with progressive renal failure and cardiovascular disease
295
Q

Gaucher Disease

A
  • an autosomal recessive lysosomal storage disorder
  • deficiency of glucocerebrosidase
  • glucocerebroside accumulates in lysosomes
  • presents with hepatosplenomegaly, pancytopenia, osteoporosis, and avascular necrosis of the femur
  • histology finds Gaucher cells, lipid-laden macrophages resembling crumpled tissue paper
296
Q

Niemann-Pick Disease

A
  • an autosomal recessive lysosomal storage disorder
  • deficiency of sphingomyelinase
  • accumulation of sphingomyelin
  • presents with neurodegeneration, hepatosplenomegaly, foam cells, and a cherry red spot on the macula
297
Q

Tay-Sachs Disease

A
  • an autosomal recessive lysosomal storage disease
  • caused by a deficiency of hexosaminidase A, which converts GM2 to GM3
  • GM2 ganglioside accumulates in lysosomes
  • presents with progressive neurodegeneration, developmental delay, a “cherry red” spot on the macula, lysosomes with onion skin, and no hepatosplenomegaly
298
Q

Krabbe Disease

A
  • an autosomal recessive lysosomal storage disease
  • caused by a deficiency of galactocerebrosidase, which converts galactocerebrosidase to ceramide
  • galactocerebroside and psychosine accumulate
  • presents with peripheral neuropathy, developmental delay, optic atrophy, and globoid cells
299
Q

Metachromatic Leukodystrophy

A
  • an autosomal recessive lysosomal storage disease
  • deficiency of arylsulfatase A
  • accumulation of cerebroside sulfate
  • presents with central and peripheral demyelination with ataxia and dementia
300
Q

Most lysosomal storage diseases have what mode of inheritance? What are the exceptions?

A
  • most are autosomal recessive

- Fabry disease and Hunter syndrome are the exceptions, which are X-linked recessive

301
Q

Compare and contrast Riemann-Pick disease and Tay-Sachs disease.

A
  • both are autosomal recessive lysosomal storage diseases
  • both present with progressive neurodegeneration and a cherry-red spot on the macula
  • but Niemann-Pick is due to a sphingomyelinase deficiency and presents with foam cells as well as hepatosplenomegaly
  • whereas Tay-Sachs presents with lysosomes with onion skin and no hepatosplenomegaly
302
Q

Hurler Syndrome

A
  • an autosomal recessive lysosomal storage disease
  • caused by a deficiency of a-L-iduronidase
  • heparan sulfate and dermatan sulfate accumulate in lysosomes
  • presents with developmental delay, gargoylism, airway obstruction, corneal clouding, and hepatosplenomegaly
303
Q

Hunter Syndrome

A
  • an X-linked recessive lysosomal storage disease
  • caused by a deficiency of iduronate sulfatase
  • heparan sulfate and dermatan sulfate accumulate in lysosomes
  • presentation is like a mild Hurler syndrome (developmental delay, gargoylism, airway obstruction, and hepatosplenomegaly) plus aggressive behavior and without corneal clouding
304
Q

Compare and contrast Hurler and Hunter syndromes.

A
  • both are lysosomal storage diseases that cause the accumulation of heparan sulfate and dermatan sulfate
  • Hurler is autosomal recessive while Hunter is X-linked recessive
  • Hunter has a milder presentation than Hurler and has the addition of aggressive behavior without corneal clouding
305
Q

What are the three primary sites for fatty acid synthesis?

A

the liver, lactating mammary glands, and adipose tissue

306
Q

Systemic Primary Carnitine Deficiency

A
  • an inherited defect in the carnitine shuttle, which is required for degradation of fatty acids
  • specifically, it transports fatty acyl-CoA into the mitochondria for further processing
  • LCFAs accumulate in the cytosol and are toxic
  • presents with weakness, hypotonia, and hypoketotic hypoglycemia
307
Q

Describe fatty acid synthesis.

A
  • citrate from the mitochondria is transported into the cytosol via the citrate shuttle
  • acetyl-CoA is formed by ATP citrate lyase
  • this is converted to malonyl-CoA with the addition of CO2 (using biotin)
308
Q

Describe fatty acid degradation.

A
  • fatty acids + CoA are combined to form fatty acyl-CoA
  • they are transported into the mitochondria via the carnitine shuttle in a reaction inhibited by malonyl-CoA (an intermediate in FA synthesis)
  • in the mitochondria it undergoes beta-oxidation and acetyl-CoA is formed
  • this can be converted to ketone bodies or enter the TCA cycle
309
Q

Medium Chain Acyl-CoA Dehydrogenase Deficiency

A
  • an autosomal recessvie disorder of fatty acid oxidation
  • the inability to break down fatty acids into acetyl-CoA leads to accumulation of 8- to 10-carbon fatty acyl carnitines in the blood and hypoketotic hypoglycemia
  • presents in infancy with vomiting, lethargy, seizures, coma, and liver dysfunction
  • minor illnesses in the setting of this disease can lead to sudden death
  • treat by avoiding fasting
310
Q

Describe ketone formation and where it occurs.

A
  • in the liver, fatty acids and amino acids are broken down into units of acetyl-CoA, which are converted to HMG-CoA
  • HMG-CoA can be converted to acetoacetate and then onto B-hydroxybutyrate, which are both ketone bodies
  • extrahepatic tissues converted B-hydroxyburtyrate back into acetoactate
  • this is then attached to CoA using the TCA cycle and formed back into acetyl-CoA
  • acetyl-CoA can enters the TCA cycle itself for energy production
311
Q

List the three ketone bodes. Which of these can be detected via urine screening?

A
  • acetone
  • acetoacetate can be detected in urine
  • B-hydroxybutyrate
312
Q

Under what circumstances are ketone bodies formed?

A
  • in prolonged starvation and diabetic ketoacidosis, oxaloacetate is depleted for gluconeogenesis
  • certain tissues can’t process fatty acids and other more complex nutrients, so acetyl-CoA from free fatty acids is shunted toward the production of ketone bodies
  • this process is also necessary in alcoholics who have excess NADH, which shunts oxaloacetate to malate and also impairs gluconeogenesis
313
Q

How is acetone formed during diabetic ketoacidosis, prolonged starvation, and chronic alcohol use? What happens to it?

A
  • acetone is a ketone body formed in these situations
  • it is formed from acetoacetate while in the blood
  • this is expired by the lungs and gives the breath a fruity smell
314
Q

How many calories are in 1g of protein, carbohydrate, fat, or alcohol?

A
  • protein: 4 calories
  • carbohydrate: 4 calories
  • fat: 9 calories
  • alcohol: 7 calories
315
Q

During periods of starvation and fasting, the bodies priority is what?

A

deliver sufficienct glucose to the brain and RBCs while preserving protein for as long as possible

316
Q

Describe the changes in metabolic fuel use that occur given longer periods of starvation.

A
  • between meals, most energy comes from hepatic glycogenolysis under the direction of glucagon and epinephrine and some comes from hepatic gluconeogenesis and release of FFAs by adipose
  • after 1-3 days of starvation, there is a greater reliance on FFAs since glycogen stores are depleted after 24 hours of starvation; hepatic gluconeogenesis increases using peripheral tissue lactate and alanine as well as adipose tissue glycerol and propionyl-CoA from odd-chain FFAs
  • after 3 days, adipose stores are the primary source of energy with ketone bodies being the main energy source for the brain
  • onece adipose is depleted, protein catabolism begins
317
Q

How long after starvation until glycogen reserves are depleted?

A

just 24 hours

318
Q

What is the rate limiting step of cholesterol synthesis and what induces this enzyme?

A

HMG-CoA catalyzes the rate limiting step, converting HMG-CoA to mevalonate, and is induced by insulin

319
Q

How do statins work?

A

they competitively inhibit HMG-CoA reductase to limit cholesterol synthesis

320
Q

What is the function of pancreatic, lipoprotein, hepatic TG, and hormone-sensitive lipase?

A
  • pancreatic lipase is responsible for the degradation of dietary triglycerides in the small intestine
  • lipoprotein lipase can be found on vascular endothelial surfaces and is responsable for degradation of triglycerides circulating in chylomicrons and VLDLs
  • hepatic TG lipase is responsible for the degradation of triglycerides remaining in IDL (remnant of VLDL)
  • hormone-sensitive lipase: degradation of triglycerides stored in adipocytes
321
Q

What is the function of lecithin-cholesterol acyltransferase? What is the function of cholesterol ester transfer protein?

A
  • LCAT catalyzes the esterification of plasma cholesterol, transforming nascent HDL into mature HDL
  • CETP mediates the transfer of cholesterol esters from HDL to other lipoprotein particles such as VLDL, IDL, and LDL
322
Q

What is the function of ApoE and in which lipoproteins can it be found?

A
  • mediates remnant uptake

- found in chylomicrons, chylomicron remnants, VLDL, IDL, and HDL (just not LDL)

323
Q

What is the function of ApoA-I and in which lipoproteins can it be found?

A
  • responsible for activating LCAT, which esterifies plasma cholesterol
  • found in chylomicrons and HDL
324
Q

What is the function of ApoC-II and in which lipoproteins can it be found?

A
  • serves as a cofactor for lipoprotein lipase, the enzyme found on vascular endothelial surfaces that degrades triglycerides circulating in chylomicrons and VLDLs
  • found in chylomicrons, VLDL, and HDL
325
Q

What is the function of ApoB-48 and in which lipoproteins can it be found?

A
  • mediates chylomicron secretion

- found in chylomicrons and chylomicron remnants

326
Q

What is the function of ApoB-100 and in which lipoproteins can it be found?

A
  • binds the LDL receptor

- found in VLDL, IDL, and LDL

327
Q

What is the purpose of chylomicrons?

A
  • they are secreted by intestinal epithelial cells and deliver dietary triglycerides to peripheral tissues
  • they delivery cholesterol to the liver in the form of chylomicron remnants, which are mostly depleted of their triglycerides
328
Q

What is the purpose of VLDL?

A

they are secreted by the liver and deliver hepatic triglycerides to peripheral tissues

329
Q

What is the purpose of IDL?

A

it is formed from the degradation of VLDL and is responsible for delivering the remaining triglycerides and cholesterol to the liver

330
Q

What is the purpose of LDL?

A
  • formed by hepatic lipase modification of IDL in the liver and peripheral tissues
  • delivers hepatic cholesterol to peripheral tissues
  • taken up by target cells via receptor-mediated endocytosis
331
Q

What is the purpose of HDL?

A
  • secreted from both the liver and intestine
  • they mediate reverse cholesterol transport from the periphery to the liver (scavenger) and act as a repository for apolipoproteins C and E, which are needed for chylomicron and VLDL metabolism
  • their synthesis is increased by alcohol
332
Q

Hyperchylomicronemia

A
  • an autosomal recessive familial dyslipidemia
  • caused by a lipoprotein lipase or apolipoprotein C-II deficiency
  • labs will find high chylomicrons, triglycerides, and cholesterol in the blood
  • presents with pancreatitis, hepatosplenomegaly, and eruptive or pruritic xanthomas
  • does not increase the risk for atherosclerosis
333
Q

Familial Hypercholesterolemia

A
  • an autosomal dominant familial dyslipidemia
  • caused by the absence or defective nature of LDL receptors
  • labs find high LDL and cholesterol (heterozygous have cholesterol near 300 while homozygotes have nearly 700 mg/dL)
  • presents with accelerated atherosclerosis (MI before age 20 in some cases), tendon xanthomas, and corneal arcus
334
Q

Hypertriglyceridemia

A
  • an autosomal dominant familial dyslipidemia
  • caused by hepatic overproduction of VLDL
  • labs find high VLDL and triglycerides
  • hypertriglyceridemia can cause an acute pancreatitis

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