Final Exam Flashcards

Question

Common alpha-ketoacid/aminoacid pairs in reactions with alpha-ketoglutarate/glutamate?

Answer 1

- pyruvate/alanine - oxaloacetate/aspartate

Answer 2

- Following specification of axes, patterning takes place. Patterning defines which end of undevelopmed mass of cells is head, which is tail. It segments cells to define which parts become head, thorax, abdomen etc.- Patterning along ant/post axis is determined by homeobox (HOX) genes, which are a family of transcription factors containing a special DNA binding domain called homeodomain. There are 4 HOX clusters on 4 chromosomes- Expression of each of the genes belonging to a cluster correlates with position of respective cell in embryo and with timing of expression. Each cell along axis experiences a different ratio of expression of different HOX genes. Ultimately, the pattern of HOX gene expression determines fate of a cell in segment.

Answer 3

- The individual genetic background modifies the phenotype

Answer 4

a. the importance of amino acid composition and sequence. - Collage contains 35% glycine, 11% alanine and modified amino acids known as 4-hydroxyproline and 5-hydroxylysine (previously proline and lysine, but post-translationally modified). - Collage contains the repeating sequence Gly-Pro-Hydroxyproline. Since three polypeptides (in helices) are to come together, it would be important for a smaller residue to be present at the contact points. This is the case, glycine is found here, which has R group of H. b. unusual amino acids and their molecular function. - Collagen has two unusual/modified amino acids known as 4-hydroxyproline and 5-hydroxylysine. Without proline-peptide and peptide-hydroxyproline bonds, helix and triple helix formation would not be possible. Also, strength and rigidity of the molecule would also be compromised. Therefore functional would be lost. Stability is also present in collage as a result of hydrogen bonds formed by hydroxyproline. Lastly, hydroxylysine allows for covalent linkages between helices to form via reactive aldehyde functional groups. c. the importance of vitamin-C and iron in collagen formation. - Ascorbate (vit C) is necessary to catalyze the reaction of proline to hydroxyproline via the prolyl hydroxylase enzyme. This occurs in conjunction with Fe2+ and alpha-ketoglutarate. Ascorbate is required to reduce Fe3+ to Fe2+ in the reaction and allow the enzyme to remain active. Without vit C, enzyme is inactivated and scurvy develops. - Remember hydroxylation in collage allows for normal collagen fibril formation. Without, you have collagen that lacks strength, rigidity and stability.

Answer 5

- Lead inhibits porphobilinogen synthase, causing accumulation of ALA - Lead inhibits ferrochelatase, causing accumulation of protoporphyrinogen IX - Causes symptoms similar to the porphyrias

Answer 6

- Glucose-6-Phosphate Dehydrogenase is inhibited by NAPDH. When NADPH is high, G6P can be used elsewhere.

Answer 7

- A competitive inhibitor is a reversible inhibitor. These compete with substrate to bind at the active site on the enzyme. Increasing substrate concentration will prevent inhibitor binding. Infinite concentration of substrate will abolish inhibition. Inhibitor once removed will not affect enzyme functionality. - These are the most common type of drug

Answer 8

- AD- Caused by defect in FGFR3, gain of function mutation where receptor is constitutively active, exhibits dominant negative effect. Most frequent form of dwarfirsm. Initiation of bone growth leads to short stature. New mutations occur frequently in this disease.- Mutation hotspot

Answer 9

- Tumor progenitor cells arise during development due to epigenetic changes and the action of tumor progenitor genes (TPG)- Then follows a Gatekeeper Mutation (GKM) in a tumor suppressor gene (TSM) or oncogene (ONC) to generate a benign tumor- Finally, epigenetic and genetic plasticity help evolve the benign growth into a metastatic, invasive and drug resistant tumor- Crux of matter: errors in epigenetic programming of stem cells in development lays seed(s) for cancer later in life

Answer 10

- Think of haplotypes as blocks of genetic information that are inherited together. HLA haplotypes are expressed in a codominant manner. Each parent only transmits one haplotype to the child. Certain HLA haplotypes favor or protect against diseases.- T1D: Contribution of HLA haplotypes to risk for T1D is strong, but not exclusive – only accounting for ~40% of genetic risk. Genetic variation in DR-DQ haplotypes affects risk for T1D. Some DR-DQ haplotypes increases risk and are known as susceptibility alleles. Others decrease risk and are designated protective alleles- Other immune disorders: HLA-B haplotypes determine risk for spondyloarthropathy. HLA-C haplotypes predict risk for psoriatic arthritis.

Answer 11

- Heterozygote advantage refers to positive selection of heterozygotes as a result of their genotype conferring increased fitness in a particular environment.- CFTR: protects against typhoid fever (population that benefits = European)- Beta-globin/sickle cell: protects against malaria (population that benefits = Mediterranean and African)- Beta-globin/beta-thalassemia: protects against malaria (population that benefits = Meditteranean)- HFE/hemochromatosis: protects against plague (population that benefits = European)

Answer 12

Respiratory acidosis is caused by higher levels of CO2 resulting in a decrease in blood pH. Respiratory alkalosis is caused by lower levels of CO2 resulting in an increase in blood pH.

Answer 13

- Basal transcription complex = RNA pol II with GTFs - This complex initiates transcription at low rates - High rate requires NF1 binding to CAAT box and SP-1 binding to GC-rich sequences

Answer 14

- Tumor suppressor: inhibit cell growth - Loss of function relieves growth inhibition = non-functioning brake pedal, typically recessive mutations

Answer 15

- Robertsonion translocation is movement of long and short arms of two chromosomes. Result = one chromosome composed of both the long arms the other composed of both of the short arms. The shorter derivative chromosome does not contain essential genetic information and is typically lost during cell division. Common Robertsonion translocation involves c/s 13 q and 14 q – happens at frequency of 1/1300.

Answer 16

- Every AAs used to generate pyruvate, then pyruvate into OAA via pyruvate carboxylase - In addition, aspartate and asparagine – Ox with a big ASP (ass)

Answer 17

- Vitamin B6 (pyridoxal 5’-phosphate)

Answer 18

- If pH \< pKa : acid form predominates : will act as proton donor - If pH \> pKa: basic form predominates : will act as proton acceptor

Answer 19

- 70 S ribosome inhibitor - Specifically blocks A site and prevents tRNA binding

Answer 20

Cooperative native protein structure indicates that the protein folding cannot be a random process, but instead occurs through favored pathways. This involves the rapid formation of short stable segments of secondary structure, which generate structural motifs which continue to fold into a thermodynamically stable protein structure. The seeding/nucleation model is where a misshaped protein (typically beta-sheets) induces other proteins (during folding) to change confirmation, which has a trickle down/domino effect on other proteins. Parkinson’s: alpha-synuclein is implicated, affect NT release (?) Alzheimer’s: tau and amyloid-beta are implicated, affecting microtubule (?) and neuronal plasticity (?) respectively

Answer 21

- Increased methylation silences transcription of a gene, reducing tumor suppressor expression - Decreased methylation activates transcription of a gene, increasing production of oncoprotein - Example: INK4 promoter methylation suppresses transcription, preventing p16ink4 synthesis, allowing for continued phosphorylation of Rb by cyclin-D:CDK4/6 and cell proliferation

Answer 22

- Essential fructosuria: absence of fructokinase (normally in liver), prevents uptake of fructose. Benign. Fructose can still be used by muscle or become excreted. - Hereditary fructose intolerance: deficiency in aldolase B enzyme. F1P accumulates in liver causing depletion of liver phosphate pools, preventing liver from breaking down glycogen, causing liver to be damaged by accumulation of glycogen, lack of Pi and synthesis of ATP. Pts are required to avoid fructose and sucrose (disaccharide of fructose and glucose)

Answer 23

- There are 3 kinds depending on the enzyme deficiency: Galact-1-P uridyl transferase, galactokinase or UDP-galactose epimerase. - Results in accumulation of galactose1-phosphate in liver and other tissues (CNS, kidney). Newborns present with milk intolerance and signs of liver failure, cataracts and intellectual disability. Also present with jaundice, lethargy and hepatomegaly. Diagnosis is by detection of galactose or galactose-phosphate in urine. Pts must receive a galactose-free diet (no lactose either, which is a glucose, galactose disaccharide).

Answer 24

1.) Nonhomologous End Joining during double-strand break repair2.) Unbalanced recombination between non-homologous sequences

Answer 25

- Gain of function: Mutated protein may have functions different from its wildtype variant. In this case, the few proteins with novel functions will have an effect no matter how many wildtype versions are present. This mechanism is frequently observed in signal transduction proteins.

Answer 26

- In normoxic environment, HIF-1alpha (hypoxia-inducible-factor) is hydroxylated by proline hydroxylase, leading to accumulation and destruction of itself - In hypoxic environment, HIF-1alpha associates with HIF-1beta, which regulates expression of VEGF and many other genes, allowing for angiogenesis to proceed. - Result = new blood supply delivers nutrients/oxygen, removes waste to/from tumors

Answer 27

- Translocation event moves c-myc gene from normal position on c/s #8 over to c/s #14 - Result = myc gene is now near control elements of antibody HC and continuous production of high levels of Myc occurs in B-cells. B-cells become cancerous

Answer 28

- If a large part of a population is wiped out by a catastrophic event, population has to recover from a small founder population of survivors. This bottleneck leads to amplification of rare alleles in the founder’s genotype. - Example: Samuel King immigrated to Eastern PA and founded a large family. He carried a rare recessive mutation in EVC, which cause Ellis Van Creveld syndrome (skeletal dysplasia disorder). This was propagated through founder effect. Consanguineous matings were inevitable in this genetically isolated community and children homozygous for EVC mutation were born. Carrier frequency for EVC is 12.3% in Old Order Amish community in PA, which is only 0.8% in general population

Answer 29

- Non-competitive inhibitors would perhaps make better drugs since they can inhibit enzyme activity irrespective of the substrate concentration. Would not have to worry about dosing based on substrate concentration. They are difficult to manufacture from the design perspective. Since non-competitive inhibitors bind in a location other than the active site, yet upon binding cause active site to be unable to bind substrate, how can you determine where this other site is?

Answer 30

- Pyruvate and 3-PG

Answer 31

- TFIID binds to TATA box, which distorts the DNA helix, acts as signpost and recruits remainder of factors and pol II - Transcriptional initiation complex forms

Answer 32

- Collagen disorder, generalized growth retardation, neurogenic hypotonia, oligohydramnios leads to ….- Mandibular hypoplasia leads to ….- U-shaped cleft palate and micrognathia (small jaw/chin)

Answer 33

- There are 5 isozymes of LDH and they are distributed throughout the body in different abundances. - The normal LDH isozyme profile looks at relative abundances of each LDH isozyme and indicates that LDH2 is highest. - After an MI; however, this profile changes and LDH1 (found mostly in the heart and RBCs) becomes elevated. This used to be an important diagnostic tool to determine heart attacks. If LDH5 is evelated, it is diagnostic for acute hepatitis.

Answer 34

- Glucuronic acid is a prerequisite for bilirubin excretion. - UGT, which is an enzyme that catalyzes the conjugation of bilirubin with glucuronic acid leads to buildup of bilirubin and syndromes known as Crigler-Najjar/Gilbert. - Jaundice

Answer 35

- G1/S = restriction point – checking if conditions are favorable for division - G2/M = has DNA been replicated and are conditions still favorable for division - Metaphase/anaphase transition point = are c/s all attached to mitotic spindles

Answer 36

- Binds to EC domain of Her2/Neu and is important inhibitor of tumor growth. - Mechanism? Inhibition of receptor dimerization and activation, induction of apoptosis, stimulation of antibody or complement-mediated cytotoxicity

Answer 37

- Phospholipase A1: removal of FAs from C1 of phospholipid - Phospholipase A2: removal of FAs from C2 of phospholipid, usually arachidonic acid - Phospholipase C: removal of phosphate head group from C3 of PIP2 phospholipid creating DAG and IP3

Answer 38

- Cytosine

Answer 39

- Formation of PRA is committed step of purine synthesis - PRPP + gln = PRA + glu (ez: amidophosphoribosyltransferase)

Answer 40

- Hunter’s: defect in iduronate sulfatase, accumulation of dermatan sulfate and heparan sulfate. Symptoms = skeletal abnormalities, mental retardation. X-linked recessive. - Hurler-Scheie: defect in alpha-iduronase, accumulation of dermatan sulfate and heparan sulfate. Symptoms = skeletal abnormalities, mental retardation. Autosomal recessive. - Sanfilippo’s: defect of heparan sulfate degradation. Symptoms = mild physical defects, severe mental retardation. Autosomal recessive.

Answer 41

- Alanine and glutamine are released in greatest quantity from muscle - BCAAs transfer their nitrogens to alpha-ketoacids (forming alanine and glutamine) and they travel to the liver where urea is formed

Answer 42

- Inflammatory disease of pancreas caused by premature activation of pancreatic digestive zymogens - Symptoms = abdominal pain, vomiting - Causes = pancreatic necrosis - Triggers = alcohol, infections, gallstones - Treatment = supportive via analgesics, fasting, elemental jejunal tube or TPN

Answer 43

- Allosteric: NTPs and dNTPs activate and inhibit (dATP inhibits) - Transcriptional

Answer 44

- Mutation in phenylalanine hydroxylase (more common) or DHBtn reductase leads to a elevation of phenylpyruvate, phenylalanine and other metabolites. - Pathology: not fully understood, but: accumulation of phenylalanine competitively inhibits the transport of other AAs across the BB barrier, which might interfere with NT synthesis. Also leads to reduced synthesis and increased degradation of myeline. Phe is also a competitive inhibitor of tyrosinase and intereferes with melanin synthesis - Symptoms: intellectual disability, recurrent seizures, hypopigmentation, eczematous skin rashes - Treatment: limiting dietary Phe (not eliminating, as it is essential), supplementation with tyrosine, treatment before child is 3 weeks of age, lifelong monitoring of plasma phenylalanine - Aspartame is a dipeptide of aspartic acid and methylated Phe derivative. Eating will cause formation of phenylalanine

Answer 45

- removal of irreversible inhibitor does not restore enzyme activity; however, removal of non-competitive inhibitor will restore enzyme activity.

Answer 46

- Unsaturated FAs: dbl bonds have to be moved around so enzymes used in beta-oxidation can recognize molecules and process them. a.) If dbl bond bw C3,4, isomerizes to trans-delta2-enoyl CoA b.) If dbl bond bw C4,5, reduced to trans-delta3-enoyl CoA, then isomerized to trans-delta2-enoyl CoA - Branched FAs: result from degradation of chlorophylls a.) requires peroxisomal alpha-oxidation, which starts with hydroxylation and ends with release of CO2

Answer 47

- Pyruvate can be oxidized to acetyl-CoA and moved into TCA or can be oxidized to lactate by lactate dehydrogenase. - When issues occur with gluconeogenic enzymes, much pyruvate can be oxidized to lactate as opposed to taking gluconeogenic pathways, leading to high levels of serum lactate and metabolic acidosis. - For example, when pyruvate carboxylase functions correctly, pyruvate is converted to oxaloacetate and is prevented from forming lactate and is now dedicate to moving through the gluconeogenesis pathway.

Answer 48

- Catecholamines (dopamine, NE, epi) - Thyroid hormones – T3/4 - Melanin

Answer 49

- ATM is activated by replication forks: when RFs are present, DNA replication is present and cell-cycle needs to be halted until this completes - ATM also activated by double-stranded breaks

Answer 50

- Myasthenia gravis: autoimmune disease characterized by muscle weakness and fatigue to the muscles involved with talking, swallowing, facial expression, chewing and eyelid movement. It is the result of self-antibodies targeting nicotinic ACh receptors at the NMJ - Cystic fibrosis: genetic disorder (pop in Caucasians) characterized by multi-organ disease, main manifestation is the accumulation of thick mucous secretions in lungs. Leading to recurrent infections. It is the result of a mutation to a chloride channel, leading to defects in fluid and electrolyte transport.

Answer 51

- Defects in complexes I-IV would result in “back up” of intermediate substrates / electron carrier molecules, including NADH. This would result in lack of NAD+, which is limited in supply. End result is that pyruvate builds up in the cell and is reduced to lactate via LDH enzyme. Lactate is an acid and therefore a lactic acidosis is occurring here. - DNP, cyanide and lack of oxygen cause the exact same thing to occur.

Answer 52

- UCP1-4. These are found in brown fat, skeletal muscle, brain and other parts of the body and function to increase body temperature.

Answer 53

- Tumor suppressor genes inhibit proliferation - Damage to both alleles must occur to allow unregulated proliferation as the genes are recessive - This is why it is called two hit model - Individuals inheriting one mutant allele of tumor suppressor gene are at increased risk for certain cancers. If somatic mutation in second allele, tumor growth will occur Retinoblastoma mutation: - Rb protein is phosphorylated by cyclin D-CDK4/6 or cyclin E-CDK2. When phosphorylated, drives cell cycle. - Inherited form: one mutant allele from parent, somatic mutation of second allele in retinal cell leads to retinoblastoma. Tumor tends to develop in infancy - Sporadic form: two separate somatic mutations in a retinal cell or its progeny produces retinal cell in which both copies of functional Rb are lost - Symptoms: Leukocoria = white pupil, represents calcified intraorbital masses

Answer 54

- HPV virus produces E6 and E7 proteins that target p53 and Rb respectively leading to ubiqutination

Answer 55

- It is an advanced thiamin (B1) deficiency that typically occurs in alcoholics. Symptoms include mental confusion, ataxia and loss of eye coordination.

Answer 56

- Malate-oxaloacetate shuttle. Oxaloacetate can be moved from the mitochondria to the cytoplasm via this shuttle and gluconeogenesis can occur.

Answer 57

- Most prevalent mitochondrial disorder. Rare at 1/50000- Caused by mutation by ND1 gene (oxphos)- LHON leads to a rapid deterioration of the optic nerve- Exhibits heteroplasmy as mitochondrial disorder

Answer 58

- HbS is an altered Hb structure where a glutamate residue in the beta chain has been substituted for valine. Glu is a acidic hydrophilic AA, which valine is a non-polar, aliphatic AA. As a result, a “sticky hydrophobic pathy” is generated in the betal chains. When in the R-form, it is shielded from water. When in the T-form; however, it is exposed to surface. When in this form, it interacts with other Hb molecules to avoid interaction in polar environment and polymerization of poly Hb is catalyzed. This distores the shape of RBCs. Cells block blood vessels and damage organs.

Answer 59

- These tissues don’t express acetoacetate:succinyl-CoA transferase to generate the intermediate: acetoacetyl-CoA that generates acetyl-CoA.

Answer 60

- Beta-alanine and beta-aminoisobutyrate - Water soluble and eliminated in urine

Answer 61

- Hypomethylation reactivates transposable elements (jumping genes) that lead to somatic recombination and genomic instability.

Answer 62

- Rare genetic disorder affecting transporter of large, neutral amino acid resulting in no absorption of these amino acids across intestinal epithelial cells, also in prox tubule of kidney causing elimination issue - Symptoms? Similar to pellagra, which is niacin deficiency – 4 D’s – diarrhea, dermatitis, dementia, death. - Treatment? Dietary supplementation with niacin

Answer 63

1.) GTP binds eIF2a 2.) GTP:eIF2a becomes bound to Met-tRNA to form ternary complex 3.) 40S:eIF3 binds ternary complex (with eIF1 and eIF1alpha) 4.) mRNA now binds small subunit and pre-initiation complex is formed (with aid of eIF-4a, eIF-4b, eIF-4f, eIF-5 and PAB) 5.) eIF-5b:GTP are added to this complex displacing hydrolyzed GDP:eIF2a and 60 S subunit is recruited and positioned with met-tRNA in P site. Elongation can now ensue

Answer 64

-His. Causes formation of salt bridge, which stabilizes T-form.

Answer 65

- Different mutations in the same gene cause different phenotypes. Mutations can be gain of function or loss of function

Answer 66

- FA synthesis begins with acetyl-CoA and then joins with malonyl CoA during round 1 - Round 2-X begins with malonyl-CoA.

Answer 67

- Function of insulin in addition to glucose metabolism is to repress ketone body production and inhibit lipolysis. - In absence as is case with T1 diabetics, large amounts of FFAs are released, ketogenesis ensues and ketoacidosis results. - Lipolysis is seen in T2 diabetics, but not as much as insulin is still available in large amounts and does have somewhat of an effect of repressing lipolysis.

Answer 68

- B12 deficiency - Folate deficiency

Answer 69

- Starvation: 1.) leads to degradation of digestive enzymes, 2.) depletes intracellular phosphate pools and 3.) depletes potassium stores - Problems: 1.) digestion is impaired and feeding leads to diarrhea and dehydration, 2.) glycolysis starting soaks up phosphate from serum leading to life-threatening hypophosphatemia and 3.) sudden insulin release (insulin moves K into cells) lowers serum potassium further - Watch electrolytes (esp. phosphate and K)

Answer 70

- Hexokinase: +: insulin; -: G6P - Glucokinase: +: insulin - Phosphoglucomutase: not regulated - UDP-glucose pyrophosphorylase: not regulated - Glycogen synthase: +: insulin; -: glucagon, epinephrine - Branching enzyme: not regulated

Answer 71

- Muscle: uptake of glucose, production of glycogen - Liver: production of glycogen, production of TAG - Adipose: uptake of glucose

Answer 72

- From serine, which is made from 3-PG

Answer 73

- Streptomycin - Neomycin - Gentamicin - Tetracycline - Chloramphenicol

Answer 74

- Imprinting is a form of DNA silencing that marks a chromosome as having come from the paternal or maternal parent. Why care? Transcriptional activities of paternal and maternal chromosomes are different.- Imprinting takes place during gametogenesis. Chromosomal regions are silenced by DNA methylation and histone deacetylation. This persists throughout the life of the individual.- Parent-of-origin imprint is erased and rewritten during gametogenesis. Female will reprogram both her chromosomes to make them look like maternal chromosomes. Male reprograms both his chromosomes to make them look like paternal chromosomes

Answer 75

- Alpha-ketoglutarate dehydrogenase complex and PDH complex.

Answer 76

- XR- Defects in p53 causes brain tumors and leukemias- Two-hit model

Answer 77

- fumarylacetoacetate hydrolase - symptoms: severe condition affecting liver, kidney and peripheral nerves, fatal at young age if untreated (liver failure) - Dietary management and nitisinone (inhibits coversion of p-hydroxyphenylpyruvate to homogentisate)

Answer 78

1.) Reversible inhibitors: removal of inhibitor fully restores enzyme activity a.) competitive: compete with and bind at substrate’s active site b.) non-competitive: binds at site other than active site forming inactive enzyme 2.) Irreversible inhibitors: removal of inhibitor does not restore enzyme activity

Answer 79

- Symptoms/signs: café au lait spots, multiple non-malignant peripheral nerve tumors (neurofibromas) and iris Lisch nodules - Result of loss of function mutation in NF1 gene (recessive) that encodes neurofibromin that normally accelerates rate of GTP hydrolysis by Ras, causing it to be in inactive form - Lack of NF1 gene function prolongs Ras signaling increases proliferation through MAP kinase pathway

Answer 80

- FAP pts inherit one defective allele from parent - Inactivation/loss of second allele occurs = - Proto-oncogene mutation, typically in Ras and loss of tumor suppressor genes typically TP53 causes adenomas - Additional mutations, gross c/smal changes, increased telomerase leads to carcinoma

Answer 81

- AR- Hypoglycemia, accumulation of glycogen

Answer 82

- inverse relationship - low Km = high S-E affinity - high Km = low S-E affinity - means some enzyme-substrates interact better than others

Answer 83

1.) Heart defects – 1/100-2002.) Pyloric stenosis – 1/3003.) Neural tube defects – 1/10004.) Orofacial clefts – 1/700-10005.) Clubfoot – 1/1000

Answer 84

- Autosomal dominant inheritance, expression at cellular level is autosomal recessive- Defects in Rb protein, leads to predisposition and / or development of cancer- Two-hit model

Answer 85

- alpha-conotoxin: produced by cone shell - alpha-cobratoxin: produced by cobra - alpha-bungarotoxin: produced by krait - tubocurarine: produced by plant These cause paralysis by blocking nicotinic ACh receptor on muscle.

Answer 86

- Ala, Ser

Answer 87

- Generation of cAMP from ATP via adenylate cyclase produces pyrophosphate (PPi). PPi is hydrolyzed into 2xPi via pyrophosphatase, which drives the formation of cAMP.

Answer 88

- s-adenosylhomocysteine is acted on by adenosylhomocysteinase, which generates adenosine and homocysteine - cystathionine beta-synthase and cystathionase are both B6 requiring enzymes

Answer 89

- Following specification of axes, patterning takes place. Patterning defines which end of undevelopmed mass of cells is head, which is tail. It segments cells to define which parts become head, thorax, abdomen etc.- Patterning along ant/post axis is determined by homeobox (HOX) genes, which are a family of transcription factors containing a special DNA binding domain called homeodomain. There are 4 HOX clusters on 4 chromosomes- Expression of each of the genes belonging to a cluster correlates with position of respective cell in embryo and with timing of expression. Each cell along axis experiences a different ratio of expression of different HOX genes. Ultimately, the pattern of HOX gene expression determines fate of a cell in segment.

Answer 90

- Lactate, - Amino acids - Glycerol

Answer 91

- Cholesterol synthesis takes place in the liver, intestine and reproductive tissues - Rate-limiting step = HMG-CoA reductase - Precursor = HMG-CoA – seen during synthesis of ketone bodies - Precursor synthesized by cytosolic HMG-CoA synthase isoform that is active in well-fed state. Mitochondrial HMG-CoA synthase isoform synthesizes the precursor when in starving/fasting state.

Answer 92

- It is an irreversible inhibitor of prostaglandin synthase and binds to the active site of the enzyme forming a covalent complex.

Answer 93

- Orotate/uracil and thymine + PRPP = XMP + PPi (ez: pyrmidine phosphoribosyltransferase) - No cytosine salvage

Answer 94

- NO produced from arginine by the enzyme nitric oxide synthase. It is a gas and diffuses readily in cell, acting locally due to short half-life and conversion into nitrates, nitrites when reacted with o2 and water. - Typical function of NO is to cause relaxation of smooth muscle. - Typical mechanims: ACh is released from nerve terminal, causes activation of NO synthase in endothelial cells, triggering conversion of arginine into NO. NO diffuses to neighbouring smooth muscle cells, binds guanylate cyclase in the cytoplasm, stimulating production of cGMP, which activates cGMP-dependent protein kinase, leading to smooth muscle relaxation. - Inactivation: NO has a short half-life as it is highly reactive with oxygen and water, produced nitrates and nitrites. In addition, cGMP is degraded by phosphodiesterasterases yielding GMP, which are not able to activate cGMP-dependent protein kinases that lead to smooth muscle relaxation.

Answer 95

- It refers to oxygen’s binding affinity of Hb being inversely related to acidity and concentration of CO2. - When CO2 concentration is high and acidic environment exists, o2 affinity for Hb is low and therefore Hb is more likely to give up o2 in tissues where this environment exists. - Causes: H+ binds to histidines foming stabilized T-form salt bridge; CO2 binds to N-terminus forming negatively charged carbamates increasing stabilization of T-form.

Answer 96

- In some autosomal dominant disease, an allele carriers has a reduced chance of reproduction, ie. reduced fitness- Therefore, reduced fitness of the carriers would lead to disappearance of the mutant alleles in populations- However, allele frequencies stay constant as new mutations appear constantly and compensate for the loss of mutant alleles- Low fitness of carriers means high percentage of new mutations- If parents are not affected by dominant disease, affected children could have inherited a new mutation- New mutations are seen in DMD, NF and achondroplasia. Genes implicated in these disorders are large, complex or contain mutation hotspots.

Answer 97

- No - Anaphase of mitosis is delayed until chromosomes attach to mitotic spindle - Correct assembly of mitotic spindle activates anaphase promoting complex (APC) - APC allows degradation of cohesin complexes, which hold sister chromatids together at centromere, sister chromatids can move to opposite poles - APC acquires different subunit and causes degradation of cyclin A or B

Answer 98

- Heme is cleaved between A and B rings by heme oxygenase, yielding biliverdin - Biliverdin reductase used NADPH to form bilirubin, which is unconjugated (aka indirect) - Becomes bound to albumin and travels to liver where it is conjugated to two UGT molecules and becomes bilirubic diglucuronide. This is form that is excreted in bile - When in gut, BDG is modified into urobiliongen by gut and then spontaneously to urobilins / stercobilins which is found in feces - Some urobilinogen is absorbed back into blood and spontaneously converted into urobilin, which is urinated out.

Answer 99

- Vitamin B12 deficiency results in deficiency in methionine synthase deficiency and therefore accumulation of N5-methyl THF and concomitant decreased in concentrations of more oxidized forms of THF, therefore Vitamin B12 leads to a functional folate deficiency - N5 N10 methylene is one of these more oxidized forms that would decrease. This is required for DNA synthesis (thymidine) - N10 formyl THF is required for purine synthesis, it is however decreased now too - Therefore lack of THF in oxidation states blocks DNA replication - Result is production of megaloblastic anemia – RBCs with large cytoplasm, but unable to divide

Answer 100

- 1.) D & L methylmalonyl-CoA (D and L methylmalonate) and 2.) N5-methyl THF - 1.) In process of converting VOMIT AAs to succinyl-CoA - 2.) In converting homocysteine and N5 methyl THF into methionine and THF respectively

Answer 101

1.) Prostaglandins - AA to PGG2 via COX1/2 - PGG2 to PGH2 via PGH synthase - PGH2 is precursor to other prostaglandins via PGD/PGE/PGF synthase enzymes 2.) Thromboxanes - PGH2 to TXA2 via thromboxane synthase - TXA2 to TXB2 via hydrolysis in blood 3.) Leukotrienes - AA to leukotrienes via lipoxygenase and other enzymes

Answer 102

- catalyze transfer of glutathione to molecules with reactive electrophiles, generating thioether linkage bw compound and cysteine of glutathione, preventing interaction with other molecules

Answer 103

- Deletion in chromosome 22 q. Frequency = 1/4000. Usually a new mutation- Malformations include: congenital heart defect, immunodeficiency, hypoparathyroidism, mental retardation, cleft palate

Answer 104

- Intracellular reducing agent: scavenging free radicals and destroying peroxides - Drug detoxification

Answer 105

- Penetrance: percentage of people with disease gene who develop symptoms- Expressivity is the severity of the symptoms

Answer 106

- Porphobilinogen synthase - Ferrochelatase

Answer 107

- Osteogenesis imperfecta-1 is caused by mutations in the collagen I genes.- OI-1 causes deformity of skeleton and predisposes bones to breakage. - Frequency = 1/10000, AD- There are 4 different classes of OI depending on the number of proalpha1 and 2 collagen chains and also if the chains are defective or not. Defect in one chain may disturb the larger structure. This is referred to as dominant negative effect.- Allele heterogeneity is also exhibited in this disease in that the severity depends on the AA exchanged. Type I have brittle bones and blue sclerae without bone deformities. Type II is perinatal lethal. Type III is progressively deforming. Type IV has bone deformities with predisposition to bone fractures.

Answer 108

- In DM pts, there is more free glucose in the cells than in other pts. This is a result of many things, including the failure of phosphorylation by hexokinase/glucokinase. This turns on aldose reductase, which uses NADPH to general sorbitol, which is used by polyol DH to form fructose, consuming NAD. As a result, antioxidant defenses that rely on NADPH are weakened and NADH is high, so glycolytic capacity is reduced. - Sorbitol also is osmotically active and draws water into cells, distorting cellular/tissue structure

Answer 109

- THF = tetrahydrofolate - Serves as a carrier of one carbon groups - Derived from folate, vitamin B9, which is found in foliage, green leafy veg, liver, eggs and beans

Answer 110

- Primary carnitine deficiency - Acyl-CoA dehydrogenase deficiency – eg. VLCAD, LCAD, MCAD and SCAD. MCAD is most common. - Refsum disease – alpha-oxidation deficiency - Peroxisome biogenesis disorders (PBD)

Answer 111

- S phase requires active cyclin A-CDK2, which is initially formed as inactive complex with inhibitor called p27kip1 - Late g1: cyclin E-CDK2 is desphosphorylated by phosphatase (Cdc25A) - cyclin E-CDK2 phosphorylates p27kip1 in complex w/ cyclin A-CDK2, cyclin A-CDK2 is activated by being freed from p27KIP2 - It promotes DNA replication by phosphorylating components of ori complexes

Answer 112

- a.) It is a severe thiamin (B1) dietary deficiency. - b.) Neuromuscular symptoms – muscle weakness, muscle atrophy, fatigue, peripheral neuropathy and lactic acidemia. - c.) Dry beri-beri which affects neuromuscular function, does not lead to fluid retention; Wet beri-beri causes peripheral edema and cardiac failure. - d.) It affects the nervous system and musculoskeletal system primarily. - e.) No, as they do not contain mitochondria, where enzymes such as PDH complex and aKGDH that participate in linking glycolysis to TCA cycle and TCA cycle function respectively. - f.) Populations that have high intake of polished rice diets.

Answer 113

- The main step to handling ethanol in the liver is through two dehydrogenases (alcohol DH and aldehyde DH), both, which produce NADH. - The other way to handle ethanol is through the higher capacity MEOS system, which as a means to process the alcohol, also oxidizes NADPH.

Answer 114

- Structural chromosomal abnormalities (rearrangements, loss and duplications) occur in approximately 0.5 % of pregnancies and 0.2 % of live births

Answer 115

- Primarily regulated by liver glutamate dehydrogenase (in mitochondria) - Regulation of glutamate DH is by cellular energy charge - High energy (high GTP, high NADH) = inhibition of enzyme - Low energy (high ADP) = activation of enzyme

Answer 116

- DNA glycosylases recognize diff types of altered bases in DNA and catalyze their hydrolytic removal - Cytosine spontaneously deaminated to uracil - Uracil DNA glycosylase removes uracil base creating AP site - AP endonuclease introduces nick - DNA phosphodiesterase removes remnant sugar and phosphate - DNA Pol and ligase fill in correct base

Answer 117

- Transcription of LDL receptor gene is upregulated in response to low cellular cholesterol - Result: more LDL receptor production and enhanced cholesterol uptake from blood Low-level transcription - SP1 (zinc-finger protein) binds to GC rich regions in LDL receptor promoter - SP1 requires CRSP protein cofactor to be activated - SP1 and CRSP help pol II and GTFS to assemble at promoter - These are all considered basal transcription factors Up-regulated transcription - Requires basal transcription factors - Also SREBP-1a enters into nucleus as triggered by low cellular cholesterol - SREBP-1a binds to SRE and recruits HAT activity plus some other proteins - Result = enhanced transcription of LDL-receptor gene

Answer 118

- FH is frequent 1/500 person disease, AD- Heterozygotes have 2-fold elevation in LDL levels as there are insufficient receptors to clear LDL from serum. Homozygotes have 4-fold evelated in LDL levels. This is an example of haploinsufficiency, allele heterogeneity- Symptoms: xanthomas

Answer 119

- Conversion of free bases and nucleosides to nucleotides - Sources are: diet, purine/pyrmidine nt degradation products

Answer 120

-Type of hemoglobinopathy. This is Hb where Fe2+ is oxidized to Fe3+ and has reduced ability to deliver o2 to tissues.

Answer 121

- X-linked dominant disorder mapped to mutations in the gene for methyl-cytosine binding protein MECP2- Mutation leads to loss of transcriptional silencing- Symptoms: autism-like symptoms, repetitive teeth grinding and hand-wringing, motor problems and characteristic gait. Onset age 6-18 months

Answer 122

- G6PD deficiency: defect that lowers the activity of PPPathway and cells have lower NADPH levels. These levels impair glutathione reduction and deprive RBCs of antioxidant protection. Affected pts are very sensitive to hydrogen peroxide, which are produced in infections (by macrophages), by drugs (eg. Primaquine that is used to treat malaria and pneumocystis pneumonia) and during consumption of fava beans (known as favism) as these cause oxidatie stress and trigger hemolytic crisis and hemolytic anemia. Most prevalent in African and Mediterranean Americans. It is x-linked recessive.

Answer 123

- Acetyl-CoA carboxylase, which converts acetyl-CoA to malonyl-CoA

Answer 124

- As a result of this deficiency -- argininosuccinicaciduria - Treat with arginine – supports continued citrulline synthesis and continuation of cycle. Argininosuccinate is water soluble and relatively non-toxic, gets eliminated from kidney as waste - Argininosuccinate carries both nitrogens

Answer 125

- R-binders in salivary enzymes bind B12 and pass it onto intrinsic factor, produced by stomach parietal cells - Absorbed in ileum through receptor mediated endocytosis - Binds to transcobalamin and is transported to tissues - Preferentially distributed to liver as vit-B12:transcobalamin complex and stored there. Kidney has some B12 stores

Answer 126

- GSD-I: aka Von Gierke’s disease: deficiency in G-6-phosphatase. Leads to hypoglycemia and increased glycogen stores in liver. This ez is only found in liver. - GSD-II: aka Pompe’s disease: deficiency in alpha-glucosidase (aka acid maltase). It is required for the degradation of glycogen, which with the deficiency, slowly accumulates in the lysosome. Over time, this process eventually kills affected cells. Death occurs by cardiac or respiratory failure. - GSD-III: aka Cori’s disease: deficiency in debranching enzyme. Glycogen granules grow large because only the non-branched, outer layers of the deposits can be degraded. Presents in early childhood or infancy with hepatomegaly, hypoglycemia and growth retardation. Can also present with muscle weakness. Some pts develop cardiomyopathy. - GSD-V: aka McArdle’s disease: deficiency in glycogen phosphorylase in muscle. Muscle is unable to use glycogen. Leads to greater than normal glycogen stores in muscles. During periods of high glucose demand, ie. exercise, patients experience muscle cramps. - GSD-VI: aka Hers disease: deficiency in glycogen phosphorylase in liver. Presents with mild to moderate hypoglycemia, mild ketosis, growth retardation and prominent hepatomegaly.

Answer 127

- RBCs: glucose, anerobic metabolism - Non-cardiac muscle: glucose-anaerobic/aerobic, FFAs - Cardiac muscle: glucose aerobically only, FFAs - Brain: glucose aerobically, ketone bodies after serious period of starvation - Adipose: glucose, TAG – FAs - Liver: FAs, glucose, AAs and lactate

Answer 128

- Hypermethylation can be reversed by this drug, which is a DNMT inhibitor. Treatment serves to allow for re-activation of silenced tumor suppressor genes

Answer 129

- 1.) Alpha receptors a.) alpha-1 subtype: Gq protein coupled = activation of PLC b.) alpha-2 subtype: Gi protein coupled = inhibition of adenylate cyclase - 2.) Beta receptors three subtypes (beta-1,2,3) are Gs protein coupled = activation of adenylate cyclase

Answer 130

- Both are defects in left/right axis formation- Situs inversus: all organs are complete mirror images in what is normally found (known a situs solitus). Usually asymptomatic- Situs ambiguous describes a more serious condition in which orientation of organs is randomized. This is usually accompanied by heart defects.

Answer 131

- Concentration of NAD to NADH are tightly monitored. Reason: NAD+ is limited in concentration. NADH must be recycled to NAD+ in order for glycolysis to continue. Lactic acid fermentation takes the electrons from NADH and places them onto pyruvate, generating lactate. This is done by lactate dehydrogenase. - Lactic acid buildup leads to lactic acidosis. Cori cycle tries to circumvent this from occurring.

Answer 132

- Ehlers-Danlos: CT disorder characterized by skin fragility, skin hyperextensibility and joint hypermobility resulting from mutations in collage proteins or proteins required for collage processed. Some benign symptoms, others complicated including bowel and arterial rupture. - Osteogenesis imperfecta: brittle bone diseases characterized by fragile bones, abnormalities in teeth, hearing losss. It can be lethal, otherwise individuals can have normal lifespan with slightly reduced bone mass.

Answer 133

- Core: Serine – Gal – GlcNAc – Gal X – Fucose - O: Serine – Gal – GlcNAc – Gal X – Fucose - A: Core – Gal X attached to GalNAc as well as Fucose - B: Core – Gal X attached to Gal as well as Fucose

Answer 134

a.) non-polar, aliphatic: hydrophobic and chained/branched, found interior aspect of proteins, uncharged Gly, Ala, Val, Leu, Ile, Met, Pro • Gly – no asymmetric carbon (2 Hs) • Pro – ring structure • Met – sulfur-containing AA b.) aromatic: hydrophobic (non-polar rings), often found interior of water-soluble proteins, uncharged Phe, Tyr, Trp • Tyr – has OH group and can be phosphorylated c.) polar, uncharged: hydrogen bond, interior/exterior of proteins Ser, Thr, Cys, Asn, Gln • Ser/Thr – have OH groups that can be phosphorylated • Cys – sulfur-containing AA, forms disulfide bridges with other thiol containing molecules (ie. cystine = 2 cysteines) d.) Ionizable side chained AA – basic/acidic: Acidic: Asp, Glu (net -1 charge at physiological pH) Basic: Lys, Arg, His\* (net +1 charge at physiological pH) \* His can be basic/uncharged as pKa = 6.0

Answer 135

- Hereditary condition due to mutations in APC (adenomatous polyposis coli) gene that encodes tumor suppressor APC. Develop 100-1000s of adenomatous polyps. 100% of untreated FAP pts developed colorectal adenocarcinomas. Prophylactic colectomy is done - APC usually functions to down-regulate WNT signaling pathway - When mutation exists, WNT signaling is activated and expression of cyclin D, Myc and other growth-promoting genes occur - Additional mutations are implicated: oncogenic forms of Ras, may impact p53 function

Answer 136

- RBCs: glucose through glycolysis to produce lactate (used in liver), G6P into PPP - Brain: glucose through glycolysis to produce acetyl-CoA (oxphos), G6P into PPP. No production of lactate - Muscle/heart: glucose through glycolysis to produce both lactate (used in liver, ? produced in heart) and acetyl-CoA (oxphos), G6P into PPP, G1P as intermediate into glycogenolysis and glycogen synthesis - Adipose tissue: same as muscle/heart, except no lactate production AND acetyl-CoA used for FA synthesis in addition to oxphos. - Liver: glucose through glycolysis to produce pyruvate (to acetyl-CoA to oxphos or FA synthesis), pyruvate to OAA (to gluconeogenesis), G6P to PPP, G1P in glycogenolysis and glycogen synthesis. \* no exit of glucose to serum unless from liver.

Answer 137

1.) Glucose: Insulin has no impact on liver, fat and muscles, as a result: - Glucose comes in, remains in serum - Liver receives AA from muscles and performs gluconeogenesis - Fat leaves adipose and enters liver, where ketone bodies are generated 2.) Lipids: insulin does not activate LPL and deactivate HSL, as a result: - Chylomicrons carrying dietary TAG stay in serum and cannot enter adipose via action of LPL - HSL is on and is performing lipolysis, TAGS are degraded into FAs, which enter circulation and travel to liver. FAs are generated in excess of what is needed to generate ketone bodies. As a result, TAGs are synthesized and packaged into VLDL, which become elevated in blood.

Answer 138

- INK4 proteins inhibit these proteins. - INK4 transcription is stimulated by growth inhibitory factors

Answer 139

- Serves to take the most reduced form of THF = N5 methyl THF back to THF form and in the process converts homocysteine to methionine - THF has no other functions in most reduced form, only when in oxidized forms does it have specific functions, including in DNA synthesis

Answer 140

- Exchange of one nt for another - Caused by replication errors, chemical mutagens, radiation, DNA damage repair - Silent: no changes to AA - Missense: change from one AA to another - Nonsense: change from AA to stop codon

Answer 141

- Use of statins - Statins inhibit the HMG-CoA reductase enzyme and prevents synthesis of mevalonic acid, a precursor molecule to farnesyl-PP, a precursor to cholesterol.

Answer 142

- a.) dehydrogenase enzymes (complexes), heme-iron proteins (aka cytochromes), iron-sulfur proteins, CoQ/ubiquinone Dehydrogenase enzymes are: Complex 1: NADH-CoQ reductase Complex 2: Succinate-CoQ reductase Complex 3: CoQH2-cytochrome c reductase Complex 4: Cytochrome c oxidase - b.) Complex 1: NADH + H+ + CoQ = NAD+ + CoQH2 Complex 2: Succinate + CoQ = Fumarate + CoQH2 Complex 3: CoQH2 + 2 cyt c (Fe3+) = CoQ + 2 cyt c (Fe2+) + 2H+ Complex 4: 4 cyt c (Fe2+) + 4H+ + o2 = 4 cyt c (Fe3+) + 2H2o - c.) see picture - d.) Protons are moved to the intermembrane space via complex I, II and IV - e.) Fatty acyl-CoA DH and glycerol-3-P DH. These both reduce CoQ and are not part of the std I-IV complexes

Answer 143

- HbA1 refers to the alpha2beta2 Hb tetramer, which is the most common form in adults, account for over 90% of total in blood - HbF is the predominant Hb tetramer present in the 2nd/3rd trimester of development. In contrast to adult Hb, HbF curve is shifted to the left indicating that at a specific o2 pressure, HbF is more saturated than adult Hb. Has higher affinity for o2 than adult Hb. This ensures that the fetus’ high metabolic o2 requirements are met. - This is due to the replacement of a histidine residue with a serine residue in the gamma chain of HbF. As a result, HbF has reduced affinity for 2,3-BPG and is left shifted.

Answer 144

a. Primary structure: the amino acid sequence of the polypeptide chain b. Secondary structure: a segment of polypeptide chain that has regular repeating structure. Results from H-bonding between the C=O and H-N groups of the polypeptide backbone. Alpha-helices and beta-pleated sheets. c. Tertiary structure: the 3D structure resulting from the interaction of various secondary structures and non-ordered regions of the polypeptide chain, results from disulfide bridges (covalent) and hydrogen bonding, ionic interactions (salt bridges) an hydrophobic forces (all non-covalent) d. Quaternary structure: protein molecules that have more than one subunit, each with tertiary structure, have overall quaternary structure. The subunits associate through same forces found in tertiary structures

Answer 145

- Beta-oxidation in peroxisomes involves preferential catabolism of LCFAs and produces hydrogen peroxide instead of FADH as seen in beta-oxidation in other tissue. Peroxisomes use oxidase enzyme

Answer 146

- Take home message: high concentrations of F26BP stimulate glycolysis; low concentrations of F26BP inhibit glycolysis - F26BP is produced by enzyme PFK2 (produces F26BP from F6P) - F26BP activates PFK1 leading to increased production of F16BP - F26BP inhibits fructose bisphosphatase leading to increased production of F16BP - Insulin stimulates PFK2 via cAMP leading to increased concentration of F26BP, which stimulates PFK1, inhibits bisphosphatase and stimulating glycolysis - Glucagon inhibits PFK2 via cAMP leading to decreased concentration of F26BP, which means that PFK1 is inhibited, bisphosphatase is stimulated and glycolysis is inhibited - AMP stimulates PFK2, causing increased concentrations of F26BP, which stimulates PFK1, inhibits bisphosphatase and stimulated glycolysis

Answer 147

- Serotonin - Melatonin - Niacin

Answer 148

- Graphically indistinguishable from a non-competitive inhibition graph.

Answer 149

- Porphyrins are conjugated systems, which absorb UV and visible light. - The light energy must be discharged upon being absorbed, so it is discharged into the tissues and generates ROS. As a result photosensitivity of skin occurs

Answer 150

- Surface of lung epithelium is covered with secretion that prevents alveolar membranes from sticking together (surfactant) - This surfactant is rich in phospholipids, particularly dipalmitoyl phosphatidylcholine (sometimes called dipalmitoyl lecithin). - This surfactant is produced at about 31 weeks gestation. - Infants born prematurely have a lecithin/sphingomyelin ratio below 2, indicating they have insufficient amounts of surfactant, which puts them at risk for respiratory distress syndrome (RDS). - Artificial surfactant mixtures treat premature infants. - Also they are given corticosteroid growth hormones to stimulate lung maturation.

Answer 151

- Methotrexate is an antifolate medication - Remember, N5-N10-methylene THF is needed to convert dUMP to dTMP

Answer 152

- Methylation of DNA occurs on cytosine residues in CpG islands- After methylation occurs, methylcytosine binding proteins bind methylcytosine.- MBPs interact with repressors of transcription leading to transcriptional block and HDACs that lead to chromatin condensation

Answer 153

- AR- Defect that impairs trafficking of CFTR chloride channel to cell surface causing pulmonary problems and pancreatic malfunction. CF pts have 2-5 times amount of NaCl in sweat. Severity varies (allele heterogeneity, modifier loci): pancreatic sufficient or insufficient- 1/2000

Answer 154

- HER2 (aka Neu): point mutation allows activation of kinase in the absence of ligand - ErbB1: deletion of ligand bind domain results in constitutive activation of kinase domain

Answer 155

- It is a shuttle mechanism to move electrons from NADH in cytoplasm to the mitochondrion. It occurs in liver and heart.

Answer 156

- Glycolysis has 3 irreversible reactions: hexokinase, phosphofructokinase 1 and pyruvate kinase. In order for glucose to be synthesized, ie. gluconeogenesis, 4 new enzymes not seen in glycolysis are seen: Pyruvate carboxylase, PEP carboxykinase, Fructose-1,6-bisphosphatase and glucose-6-phosphatase.

Answer 157

- Cytarabine - Cyclophosphamide - Doxorubicin

Answer 158

- Uridine / cytidine + ATP = UMP / CMP + ADP (ez: uridine-cytidine kinase)

Answer 159

- AR- Fasting hypoglycemia

Answer 160

A change in amino acid sequence will lead to different interactions and therefore different folding (see 14). Different structure will confer different function. The original purpose of the protein can no longer be served. Examples of diseases where misfolded proteins are implicated: • CJD: inherited or spontaneous • Kuru: infectious • vCJD: infectious Above diseases lead to spongiform encephalopathies (neurodegeneration, brain becomes spongy) • Parkinson’s: loss of dopaminergic neurons, formation of Lewy bodies (aggregates of alpha-synuclei protein seeds more) leads to tremor, bradykinesia, postural instability • Alzheimer’s: neurological condition leading to dementia from plaque/fibrillary structures in brain containing amyloid-beta and tau proteins that seeds more

Answer 161

- Grossly evelated homocysteine (plus other metabolites of this) accumulat in body and are seen in urine - Most commonly due to cystathionine beta-synthase mutation - Symptoms: dislocation of optic lens, osteoporosis, lengthening and thinning of long bones, thromboembolism, intellectual disability - Treatment: low methionine diet with cysteine supplements, pyridoxine or betaine supplements

Answer 162

1.) ATM is activated by double-stranded breaks 2.) ATR is activated by UV light and certain DNA-damaging drugs - Both kinases stabilize p53 - P53 upregulates p21cip1 - p21 inhibits activates a kinase that prevents cdc25a and cdc25C from activating cyclin A/E-CDK2 (S phase) and cyclin A/B-CDK1 (M phase) respectively. - ATM and ATR also activate a checkpoint kinase that prevents cdc25a and cdc25C from activating cdc25a and cdc25C from activating cyclin A/E-CDK2 (S phase) and cyclin A/B-CDK1 (M phase) respectively

Answer 163

1.) chromatin remodeling complexes: use ATP to change nucleosome structure temporarily to allow or inhibit transcription 2.) HATs: acetylate lysine residues in histones, reduce net pos charge of protein, weakens histone:DNA interaction, facilitates transcription 3.) HDACs: remove acetyl groups from histone, increasing net pos charge of protein, strengthens histone:DNA interaction, inhibits transcription 4.) DNA methylation: methyl groups added to cytosine, found in silent regions of genome, binds proteins that recruit HDACs to DNA, promoting condensation and inhibiting transcription

Answer 164

- Binds to IR in PM of target cells - IR = kinase, phosphorylates itself then IRS - Phosphorylation cascade ensues, but at level of enzymes, dephosphorylation occurs via phosphatase - Cell undergoes dramatic changes in protein activation, protein localization and gene transcription

Answer 165

- Pyruvate carboxylase: +: acetyl-CoA; -: insulin - PEP carboxykinase: +: glucagon via cAMP; -: insulin, AMP - Fructose-1,6-bisphosphatase: +: citrate; -: F26BP, AMP (main regulated step) - Glucose-6-phosphatase: +: glucagon; -: insulin

Answer 166

- PPP via G6PD - Conversion of malate to pyruvate via malic enzyme

Answer 167

- Impairment of Shh signaling secondly to defect in cholesterol biosynthesis. - This is an autosomal recessive disorder affecting 1/20-50K- Leads to multiple severe congenital malformations

Answer 168

- glutamine

Answer 169

- 5-fluorouracil - Methotrexate

Answer 170

- Midline defects such as holoprosencephaly = failed or incomplete separation of forebrain early in gestation

Answer 171

1.) Synthesis of uridine nucleotides (three\* enzymes below are part of CAD multifunctional protein) - Gln + bicarb + ATP = carbomyl phosphate + ADP + glu (ez: \*carbomyl phosphate synthetase II) - Carbomyl phosphate + Asp = N-carbamoyl aspartate + Pi (ez: \*asp transcarbamoylase) - N-carbamoyl aspartate = dihydroorotate (ez: \*dihydroorotase) - Dihydroorotate + NAD = orotate + NADH (ez: dihydroorotate DH) - Orotate + PRPP = OMP + Pi (ez: ^orotate phosphoribosyltransferase) - OMP = UMP + Co2 (ez: ^OMP decarboxylase) Notes: three beginning ezs are part of \*CAD multifunctional enzyme, last two are part of ^UMP synthase multifunctional enzyme 2.) Synthesis of cytosine nucleotides - UMP is converted to UTP via nucleoside-5-monophosphate kinases and nucleoside diphosphate kinases - UTP + glut + ATP = CTP + gln + ADP + Pi (ez: CTP synthase) 3.) Synthesis thymine nucleotides - Note: TMP, TDP or TTP are never synthesized (never get ribose forms), only make dTMP, dTDP and dTTP - dUMP + N5,N10-methylene THF = dTMP + THF

Answer 172

- RNA pol I, some Pol III

Answer 173

1.) CPS I: - Found in mitochondria of liver, synthesizes carbomyl phosphate for urea cycle - Substrates: bicarb, 2ATP, ammonium; Products: carbomyl phosphate, ADP, phosphate 2.) CPS II: - Found in cytosol of liver, synthesizes UMP - Substrates: bicarb, 2ATP, gln; Products: carbomyl phosphate, ADP, glu

Answer 174

- v = (Vmax [S])/(Km + [S]) - v = rate of ez catalyzed reaction - Vmax = maximum reaction rate (reached when every ez molecule is bound to substrate). Depends only on ez concention. - [S] = substrate concentration - Km = Michaelis-Menten constant (k2+k3)/k1 – it is the substrate concentration at which v=Vmax / 2 . Km is independent of enzyme concentration, reflects physical properties of enzyme.

Answer 175

- B.) NE (remember, tyrosine in thyroglobulin molecule, not free tyrosine)

Answer 176

- A non-competitive inhibitor is a reversible inhibitor. These bind at sites on the enzyme other than the active site, forming inactive enzymes (E-I form or E-S-I). Increasing the concentration of the substrate does not influence inhibitor binding. It is reversible if the inhibitor can be removed. Enzyme will work after inhibitor removal.

Answer 177

- use of ATP: hexokinase (produce G6P from glucose) and phosphofructokinase (produce F16BP from F6P) - produce ATP: phosphoglycerate kinase (produce 3PG from 13BPG) and pyruvate kinase (produce pyruvate from phosphoenolpyruvate) - produce NADH: glyceraldehyde phosphate DH (produce 13BPG from dihydroxyacetonephosphate) - net ATP: 2 - net NADH: 1

Answer 178

- converted into dolichol-PP for protein glycosylation - converted into coQ for electron transport - used for prenylation (post-translational) of proteins which influence water solubility of proteins

Answer 179

- a.) lactate, oxaloacetate, acetyl-CoA and alanine - b.) PDH complex - c.) pyruvate carboxylase - d.) pyruvate carboxylase is allosterically activated by acetyl-CoA. When there is sufficient amount of acetyl-CoA and therefore little need to divert more pyruvate into acetyl-CoA, pyruvate carboxylase converts pyruvate to oxaloacetate.

Answer 180

- C.) melanin

Answer 181

- Twin and adoption studies (MZ vs DZ twins)- Concordant trait = trait shared by both twins- Discordant trait = trait not shared by both twins- Diseases with significant genetic component will show higher concordance rate in MZ twins than in DZ twins using crude measure known as heritability H2- H2 = (concordance MZ – concordance DZ) x 2- High heritability = trait is determined predominantly by genetic factors

Answer 182

- To acetyl-CoA: Leucine, Lysine, Phe, Tyr, Trp, Iso - To fumarate: Trp, Tyr, Phe

Answer 183

- Proteoglycans of the ECM - H-antigen on surface of RBCs (predictable)

Answer 184

- Glycogen phosphorylase: +: glucagon, epinephrine; -: insulin - Glucose-6-phosphatase: +: glucagon, epinephrine; -: insulin - Debranching enzyme: not regulated

Answer 185

- N-linked: starts in ER before protein folding is complete, adds sugars to Asn residues in protein in predictable fashion, modification of this can occur in Golgi - O-linked: starts in Golgi after protein folding is complete, adds sugars to serine or threonine residues, but not in predictable fashion

Answer 186

- Pts present with cleft palate, micrognathia (small jaw), down slanting palpebral fissures and malar hypoplasia (underdeveloped zygoma). - This is an AD disorder. Individuals have high risk for complications relating to this disorder – eg. Cardiovascular.

Answer 187

- In over 50% of birth defects, no cause can be identified, remaining are:- Genetics: 50% have complex inheritance, 25% caused by chromosomal defects, 20% caused by single-gene mutations- Non-genetic factors such as maternal medication and infections = 5%

Answer 188

- Inhibits ribonucleotide reductase and prevents dNTP synthesis, blocking cell division

Answer 189

- a.) Vitamin B1. Required for PDH and alpha-KGDH enzymes to function. - b.) Primarily affects alcoholics, elderly and low income groups who are more likely to have poor diets. - c.) loss of appetite, constipation, nausea, fatigue, depression, peripheral neuropathy - d.) Wernicke-Korsakoff = advanced deficiency frequently seen in alcoholics: mental confusion, ataxia, loss of eye coordination Beri-Beri = severe deficiency seen in populations that heavily rely on polished rice diets: neuromuscular symptoms – muscle weakness, muscle atrophy, fatigue, peripheral neuropathy, lactic acidemia

Answer 190

- Mutations to glutamate dehydrogenase enzyme rendering it insensitive to inhibition by GTP. - As a result, increased AA catabolism occurs in environment that is high energy - Leads to elevated levels of ATP and hyperammonemia - Increased ATP in beta-cell promotes insulin releases, resulting in hypoglycemia - Less active urea cycle with more ammonia production = hyperammonemia

Answer 191

- In this disorder, RBCs are deprived of ATP (only get 1 ATP instead of 2 from glycolysis), which leads to lysis of the cells (chronic hemolytic anemia) because the membrane potential cannot be maintained. These patients present at pale, jaundiced, fatigued, SOB, tachycardic. They have splenomegaly, excess of iron in blood and have gallstones. Severe cases require pts to have regular blood transfusions.

Answer 192

- Adenosine

Answer 193

- Proteins directed to lysosome require phosphomannose

Answer 194

- Glutamine produced in peripheral tissues enters the bloodstream and is absorbed by the kidneys, liver and gut - Amide group is hydrolyzed by glutaminase and produces glutamate and ammonium ion - Kidney excretes NH4+ directly and liver produces urea in urea cycle. Glutamine is nutrient in gut, ammonium enters hepatic portal and metabolized by liver

Answer 195

- APC causes degradation of cyclin A and B, which shuts off CDK1 activity and stops mitotic events from occurring - Desphosphorylation of cyclin-CDK targets by Cdc14 returns proteins to their interphase state: promotes decondensation of chromatin, disassembly of mitotic spindle, reassembly of nuclear membrane, cytokinesis) - APC becomes inactivated and Rb is dephosphorylated

Answer 196

- It is an anaplerotic reaction to regenerate oxaloacetate when levels are low. - Pyruvate + ATP + HCO3 = oxaloacetate + ADP + Pi + H+ (ez: pyruvate carboxylase, coenzyme: biotin) - Acetyl-CoA. When there is sufficient amount of acetyl-CoA and therefore little need to divert more pyruvate into acetyl-CoA, pyruvate carboxylase converts pyruvate to oxaloacetate.

Answer 197

- AAs that cannot be synthesized - Pvt Tim Hall = mnemonic - Phe, Val, Thr, Try, Iso, Met, His, Arg, Leu, Lyc - Special case = Arg – can be synthesized, not sufficiently to keep up with needs

Answer 198

1.) EF-1-GTP charges tRNA molecule (EF1-GDP = product). AA-tRNA moves into A site 2.) Peptide bond formation occurs 3.) EF-2-GTP hydrolysis allows ribosomal complex to move one codon down with mRNA-peptidyl-complex now occupying the P site and the A site is empty. Uncharged tRNA leaves through E site 4.) Ribosome is now ready to repeat the cycle 5.) Once the stop codon is moved into the A site, eRF bound to GTP is hydrolyzed and the ribosomal complex dissociates

Answer 199

- Pre-hepatic jaundice: hemolysis. More unconjugated bili in blood than liver can deal with. Moves into tissue membranes. No change to urine or feces color - Hepatic/hepatocellular jaundice: liver disease prevents conversion of unconjugatd bilirubin into bilirubin diglucuronide. Unconjugated bilirubin moves into other tissue membranes. Urine is pale, feces is pale - Post-hepatic/cholestatic jaundice: obstruction of liver exits allows for some processing of unconjugated to conjugated bilirubin, but prevents conjugated form from moving out (into gut). Conjugated form can move into blood and embed into tissue membranes with unconjugated. Also moves to kidney where it causes orange color in urine. Feces are pale

Answer 200

- Genetic drift (non-small populations)- Selection (fitness is unequal in offspring)- Assortative mating (mating is non-random)- Population bottlenecks/founder effect

Answer 201

- 70 S ribosome inhibitor - Specifically causes mistranslation of codons

Answer 202

- AR and AD collagen disorder- Dominant forms of EDS are caused by mutations in the collage genes. Misfolded collagen molecules exert a dominant negative effect- Other forms of EDS are caused by mutations in enzymes required or the processing of collage molecules. As typical for enzyme defects, these mutations show a recessive mode of inheritance.

Answer 203

- RNA Pol III

Answer 204

- Liver: stimulates degradation of glycogen, stimulates gluconeogenesis from AA sources, stimulates energy production from AA sources - Adipose: stimulates lipolysis

Answer 205

- PRPP consumed by HGPRtase and APRtase - Less available for amidophosphoribosyltransfer, therefore less PRA formed therefore less de novo synthesis

Answer 206

- Lack of intrinsic factor secreted by parietal cells of stomach

Answer 207

- It refers to oxygen’s binding affinity of Hb being inversely related to acidity and concentration of CO2. - When CO2 concentration is high and acidic environment exists, o2 affinity for Hb is low and therefore Hb is more likely to give up o2 in tissues where this environment exists. - Causes: H+ binds to histidines foming stabilized T-form salt bridge; CO2 binds to N-terminus forming negatively charged carbamates increasing stabilization of T-form.

Answer 208

1.) Alignment out of registration, unequal crossover 2.) Strand slippage in replication as a result of repetitive sequences 3.) Intercalating agents causes slip bw stacked base pairs of DNA that distort helix and cause insertions or deletions

Answer 209

- Core proteins are manufactured in ER - Transferred to Golgi where glycosyltransferases add disaccharides to them. - Sulfotransferases add sulfate groups to them (can be unpredictable) - Exported in membrane-bound vesicle, finds linker and attached to polysaccharide backbone

Answer 210

- MSH2 or MLH1 code for DNA mismatch repair. Mutations lead to HNPCC: hereditary nonpolyposis colorectal carcinoma - BRCA1 or BRCA2 gene code for machinery involved in homologous recombination. Mutations lead to increased risk of breast/ovarian and cancer development. Unable to repair of double-stranded DNA breaks.

Answer 211

1. Origin recognition complex proteins bind to origins – ORC activated s phase, then inactivated until after mitosis 2. DNA helicase unwind the double helix 3. SSBPs bind DNA and prevent reformation of double helix 4. Tension in DNA acted on by topoisomerase I, which cuts phosphodiester bond of one strand and allows strand to rotate, religation occurs 5. Primase activity of DNA pol alpha uses exposes SS DNA region as template to synthesize a short complimentary stretch of RNA, provides 3’ OH 6. DNA pol alpha is replaced by delta or epsilon 7. Protein complex known as sliding clamp is loaded onto DNA, facilitates pol activity 8. DNA pol replicates continuously on leading strand, discontinuously (delta) on lagging strand 9. RNase activity removes primer, DNA pol possibly delta fills in gap left by primer removal 10. DNA ligase joins Okazaki fragments

Answer 212

-Fe3+ is the predominant form and there are no enzymes to oxidize back to Fe2+

Answer 213

- alpha-ketoglutarate and oxaloacetate

Answer 214

De-novo DNA methylation- Methylation is introduced into an unmethylated strand of DNA by DNA methyltransferases DNMT3a and bMaintenance- Pattern of DNA methylation is maintained through mitosis by DNA methyltransferase DNMT1- During S-phase, DNA pol synthesizes a non-methylated strand from the methylated template strand- New double-strand consists of a methylated and non-methylated strands transiently. DNMT1 methylates the non-methylated strand based on what is seen on the template

Answer 215

- oxidized form: N10-formyl THF - reduced form: N5-methyl THF - THF can carry and move single carbon molecules around the body. - Major one carbon pool source = serine via 3-PG - Minor sources = formaldehyde (from methanol), formate (from tryptophan), histidine - Accumulated THF form: N5-methyl THF

Answer 216

- Nascent HDL associates with apoE,C and A in hepatocytes.

Answer 217

The value of the pKa can help determine which forms of the acid will be dominant at a certain pH. When the pH=pKa the concentrations of acid and base are equal. When pHpKa the base form dominates.

Answer 218

- Anterior/posterior axis. This is defined by the primitive streak, which is defined by the position of the entry of the sperm into the egg. Node is the anterior end of the streak and the groove is the primitive streak and serves as the anterior/posterior axis.

Answer 219

- Glycogen phosphorylase is inactivated - Glycogen synthase is activated

Answer 220

Protein restriction (not elimination d/t essential AA req or supply AA via alpha-ketoacids) Hemodialysis (removes excess ammonia) Phenylbutyrate (metabolite binds glutamine in water soluble form, which is excreted by kidneys) and benzoate (metabolite binds glycine in water soluble form, which is excreted by kidneys) Mannitol (promotes diuresis)

Answer 221

- AR- Sucrose/glucose polymer intolerance

Answer 222

- 2-3% of children are born with a recognizable birth defect- 20% of total mortality, birth defects are most common cause of infant death in US- Another 20% of infant deaths are caused by prematurity, which also can be considered a failure of normal development

Answer 223

- Zellweger syndrome is a disorder of failure to produce functional peroxisomes and therefore failure to produce plasmalogens. Results in defective myelination, which leads to hypotonia, severe intellectual disability and is generally fatal in few few months of life. Infants present with poor weight gain, weak suck, hypotonia, high foreheads, flat broad nasal bridges and underdeveloped jaws.

Answer 224

- Gs – stimulation of cAMP via adenylate cyclase - Gi – inhibition of cAMP via adenylate cyclase - Gq – stimulation of IP3/DAG via PLC

Answer 225

- Cyanide inhibits cytochrome oxidase (complex IV) by binding Fe3+ and preventing reduction to Fe2+. It is fast acting and lethal. Causes lactic acidosis. Treatment: nitrites (oxidize Hb so cyanide binds to Hb instead of cytochrome oxidase) and Na thiosulfate (converts cyanide to non toxic SCN- form).

Answer 226

- Glucose enters glycolysis with pyruvate as end product - Pyruvate is converted into alanine via ALT and sent into bloodstream - Alanine is taken up by liver and converted back into pyruvate by ALT - Pyruvate is converted into glucose via gluconeogenesis

Answer 227

- tyrosine aminotransferase - Symptoms: keratitis, photophobia, skin lesions on palms and soles, intellectual disability

Answer 228

- Many lipids in body are not saturated. - Desaturation of FAs occur in endoplasmic reticulum as shown here:

Answer 229

- High F26BP concentrations: glycolysis is stimulated, gluconeogenesis is inhibited - Low F26BP concentrations: glycolysis is inhibited; gluconeogenesis is stimulated

Answer 230

- BCAA = LIV mnemonic = leu, iso, val - Metabolism: muscle has high levels of BCAT (branched-chain AA aminotransferase), which forms branched-chain alpha-ketoacids that are released into blood. BCKDH (branched-chain alpha-ketoacid DH) complex decarboxylates these BCAA in liver - Valine (see picture) - Isoleucine produces acetyl-CoA and propionyl-CoA, it is ketogenic and glucogenic AA - Leucine produces acetyl-CoA and acetoacetate, it is ketogenic AA only

Answer 231

- Group of immune disorders impacting B and T cell proliferation - ~15% of cases due to adenosine deaminase (in degradation of AMP) where adenine metabolites build up - Model: accumulation of dATP inhibits ribonucleotide reductase blocking DNA replication and preventing proliferation OR adenine metabolites are toxic to lymphocytes

Answer 232

- Only make deoxyribose nucleotide forms

Answer 233

- SGLT1: found in small intestine, responsible for actively transporting glucose from lumen into intestinal epithelia. - GLUT1: found in all tissues, responsible for basal glucose uptake - GLUT2: found in liver, intestine and beta-cells of pancreas. In liver: removes glucose from blood. In intestine: releases glucose from epithelia into blood. In pancreas: regulates secretion of insulin. Also able to move fructose. - GLUT3: found in all tissues, responsible for basal glucose uptake - GLUT4: found in muscle and adipose tissue. Increases with endurance training, induced by insulin. - GLUT5: found in small intestine, responsible for uptake of fructose into epithelial cells and movement into blood serum.

Answer 234

- Hypoxanthine + o2 = xanthine + H2o2 (ez: xanthine oxidase) - Guanine + H2o = xanthine + NH4+ (ez: guanine deaminase) - Xanthine + o2 = uric acid + H2o2 (ez: xanthine oxidase) - Uric acid eliminated in urine

Answer 235

- Used to treat mycobacterial infections such as TB and leprosy - It is a specific inhibitor of RNA pol found in many types of bacteria, but euk Pol II is not sensitive to it

Answer 236

- XR- Sensitivity to H2o2 generating agents and fava beans

Answer 237

- SLE is caused by epigenetic changes in T-cells- This is an autoimmune disease with incidence = 1/2000 affecting females 8-10 times more than males- In this condition, antibodies against nuclear components are produced.- Global hypomethylation of the T-cell genome is seen in these patients- DNMT inhibitor treatment on T-cells causes SLE-like phenotypes

Answer 238

- AR- Hemolysis

Answer 239

Hemoglobin is comprised of two alpha-globulin subunits and two beta-globulin subunits. Each has an iron containing heme prosthetic group. The hemoglobin forms by association of two alpha-beta-dimers which interact through H-bonds and salt bridges. Each subunit resembles that of myoglobin. Myoglobin has high affinity for o2 at low partial pressures of oxygen (hyperbolic o2 binding curve), whereas hemoglobin has a lower affinity for oxygen at lower partial pressures and its affinity increases as partial pressures increase and a conformational change takes place (sigmoid binding curve), changing affinity of each heme group that is to be “loaded.”

Answer 240

- From Phe and Met, which are both essential AAs

Answer 241

- Nalidixic acid and ciprofloxacin act on bacterial topoisomerase II enzymes and function as antibiotics - Doxorubicin acts on human topoisomerase II and is used as an anticancer agent

Answer 242

- 2 F6P and 1 glyceraldehyde-3-phosphate - These are intermediates in the glycolytic / gluconeogenic pathways and can be synthesized from pentoses depending on the need of the cell.

Answer 243

- Boundary elements aka chromatin barriers serve to separate active and inactive genomic regions

Answer 244

- RET gene encodes tyrosine kinase receptor located in the plasma membrane. Both mutations below are autosomal dominant.- Loss of function mutation in RET gene causes Hirschprung disease. Receptor has inability to respond to stimulus. In this disease, there is impaired development of neurons that populate the colon giving rise to aganglionic colon.- Gain of function mutation in RET gene causes Multiple Endocrine Neoplasia (MEN). Receptor renders signaling molecule constitutively active. Proliferation of neuroendocrine cells occur.

Answer 245

L starting AAs – leucine, lysine

Answer 246

- Type 2 diabetics are insulin insensitive - As a result of insulin signaling stating to the body that glucose is in abundance and should be taken up, fatty acids are still being released from adipose tissue and the liver has to repackage large amounts of these, which in turn means that LDL levels are high.

Answer 247

- Glu, Cys and Gly - Made in liver (not on ribosomes) - Contains non-regular peptide bond called gamma-glutamyl linkage that is stable and resistant against proteases

Answer 248

- Congenital chaperone defects cause protein folding disorder

Answer 249

- When changes to substrate concentration occur, enzyme is sensitive enough to decrease reaction rate or increase reaction rate.

Answer 250

- alanine aminotransferase - synthesizes alanine and alpha-ketoglutarate from pyruvate and glutamate

Answer 251

- Development of CNS begins from neural tube. Neuronal stem cells on ventricular side of neural tube divide and generate neuronal precursor cells- These precursor cells have to migrate outward from the ventricle along a scaffold of glial cells, which occurs in waves- Mutation / deletion of LIS1 gene interferes with orderly pattern of migration. Result = cerebral cortex is thickened and lacks defined cell layers. Lissencephaly = smooth brain. Individuals suffer from severe mental retardation.

Answer 252

- a.) oxidoreductases: class I: catalyze redox reactions, involve electron acceptors / donors incl. oxidases, oxygenases, reductases, dehydrogenases - b.) transferases: class II: transfer groups (carboxyl, amino, glucosyl, phosphoryl, methyl etc.) from one substrate to another without the input of energy incl. kinases, aminotransferases, carboxylases, methyltransferases - c.) hydrolases: class III: cleave bonds by addition of water incl. glucosidases, ATPases, phosphatases, peptidases, lipases - d.) lyases: class IV: break bonds without addition of water or oxidative cleavage - e.) isomerases: class V: change steoreochemistry of optical or geometric isomers incl. epimerases, mutases, racemases - f.) ligases: class VI: catalyze formation of bonds via input of energy (usually via hydrolysis of XTP), not via transfer to bond incl. ligases, synthases, synthetases, carboxylases

Answer 253

- Irreversible inhibitors chemically modify and inactivate enzymes by forming covalent complexes at the active site residues. Aspirin is an example and it is a prostaglandin synthase inhibitor.

Answer 254

- Genetic defect in BCKDH that leads to accumulation of BC alpha-ketoacids in body - Symptoms: poor feeding, vomiting, slow/irregular breathing, ketoacidosis, hypoglycemia and neurological dysfunction - High incidence in old order menonite - Result: fatal in one week unless treatment - Treatment: reduced BCAA in diet and monitoring of serum BCAA levels

Answer 255

- Thyroid hormone becomes bound to receptors that are constitutively in the nucleus and are bound to DNA elements of genes that respond to it - THR (receptor) when not bound to thyroid hormone is dimerized with RXR (retinoid X receptor) - This dimer recruits HDAC, which condenses chromatin and inhibits transcription - Binding of thyroid hormone triggers conformation change in THR, HDAC is released and HAT binds in its place, leads to relaxation of chromatin and enhancement of transcription - Response: stimulated metabolic rate in most tissues

Answer 256

- Deficiency in niacin, leading to diarrhea, dementia, dermatitis and death.

Answer 257

- Inhibits synthesis of triacylglycerol

Answer 258

-Scurvy is the result of vit C deficiency. Blood vessels, tendons and skin become fragile. Symptoms include malaise, lethargy, easy bruising, dry skin, loosening of teeth, sleep disturbances and leg pain.

Answer 259

- Epinephrine (function: glycogenolysis in muscle, fat hydrolysis in adipose, increased HR and FOC) - Glucagon (function: glycogenolysis in liver, fat hydrolysis in adipose) - AVP/ADH/vasopressin (function: water re-absorption in kidney)

Answer 260

- Bile contains cholesterol, bile salts and phospholipids. These aid in emulsification of dietary fats. Cholesterol is prone to precipitating in gallbladder and duct works as its water solubility is low. When in high concentration, it particularly precipitates out causing formation of cholesterol stones known as gallstones, which can obstruct the gallbladder and ducts causing painful backup of bile of pancreatic enzymes.

Answer 261

-His. Causes stabilization of T-form.

Answer 262

- protein produced by C. diphtheriae that inactivates EF-2 by ADP ribosylation, preventing elongation

Answer 263

- Nucleoside 5 monophophate kinases: XMP + XTP = 2 XDP - Nucleoside disphosphate kinases: XDP + XTP = XTP + XDP

Answer 264

- 70 S ribosome inhibitor - Specifically binds to small subunit (30 S) and inhibits initiation and causes mistranslation of codons

Answer 265

- Beta-aminoisobutyrate - Found in urine of cancer pts undergoing radiation or chemotherapy

Answer 266

- Pyloric stenosis is more common in male birth 1/200 than in female birth 1/1000. Accordingly, in pyloric stenosis, there is a lower threshold for males (males need few contributing alleles) and a higher threshold for females (females need more contributing alleles).- When assessing recurrence risk then: affected female proband has more contributing alleles than affected male proband and therefore has higher risk of having an affected sibling than does a male proband. Also her risk of having an affected brother is higher than her having an affected sister because a brother would only need fewer contributing alleles to develop a disease.- Affected male proband has higher recurrence risk for having a brother than a sister with pyloric stenosis.

Answer 267

- Niacin (aka B3): part of structure of NAD+ (oxidized and reduced) and NADP+ (oxidized and reduced). - Riboflavin (aka B2): part of structure of FAD and FMN (reduced and oxidized forms).

Answer 268

- Viagra is a phosphodiesterase inhibitor and prevents deactivation of cGMP, allowing their levels to remain elevated for longer. cGMP is what binds to cGMP-dependent protein kinases that cause smooth muscle to relaxed. As a result, increase in blood flow to the penis is prolonged, treating erectile dysfunction.

Answer 269

1.) Ellis van Creveld Syndrome: Old Order Amish of Lancaster County2.) Tay-Sachs Disease (ganglioside storage disease): Ashkenazi Jews3.) Tyrosinema: French Canadians in Quebec

Answer 270

- 70 S ribosome inhibitor - Specifically causes mistranslation of codons

Answer 271

1.) 1-4 weeks (blastogenesis): abnormalities during this period produces multiple major abnormaities in entire embryonic regions. Example = VACTERL2.) 5-8 weeks (organogenesis): abnormalities during this period affects specific organs and produces single major anomalies. Example = congenital heart defects3.) 9+ weeks: major organs have formed, abnormalities here will have mild effects on the individual. Example = single palmar crease

Answer 272

- Adenosine + ATP = AMP + ADP (ez: adenosine kinase) - No salvage of guanosine

Answer 273

-N-terminus. Causes formation of carbamate, forms salt bridge which stabilizes T-form.

Answer 274

- Risk for general population = 0.5% risk- If second degree relative affected = 0.7-2% risk- If first degree relative affected = 3-4% risk- If two first degree relatives affected = 5-8% risk- Three first degree relatives affected = 9-12% risk- Identical twin = 20-30% risk

Answer 275

- AR- IEM, Defect in Phe hydroxylase, Phe accumulates and damages the CNS. With many other IEM, screened for at birth- 1/2900

Answer 276

- promotion of SM contraction - anaphylaxis

Answer 277

- Glutamate - Decarboxylation of glutamate forms GABA - Requires pyridoxal phosphate - Neurotransmitter

Answer 278

- Hypoxanthine + guanine + PRPP = IMP / GMP (ez: HGPRtase) - Adenine + PRPP = AMP (ez: APRtase)

Answer 279

- BDG (conjugated bilirubin) moves into gut in bile. It is converted to bilirubin and urobilinogen by bacteria. - Urobilinogen can be further converted into urobilins and stercobilins in gut and gives color to feces - Urobilinogen can also be absorbed into blood and converted to urobilin in blood stream, being moved to and excreted from kidneys.

Answer 280

- PRPP = 5 phosphoribosyl 1 pyrophosphate - Ribose 5 phosphate + ATP = PRPP (ez: PRPP synthetase) - PRPP + gln = PRA (phosphoribosylamine) + PPi (ez: amidophosphoribosyltransferase) - 9 step process to convert PRA to IMP (4 reactions require ATP, C and N donated from gly, gln, asp, CO2 and N10-formyl THF). IMP = inosine monophosphate - IMP precursor for AMP and GMP via following rxns: - IMP + Asp + GTP = adenylosuccinate + GDP + Pi (ez: adenylosuccinate synthetase) - Adenylosuccinate = AMP + fumarate (ez: adenylosuccinase) - IMP + NAD = xanthosine5monophosphate (ez: IMP dehydrogenase) - XMP + Gln + ATP = GMP + glu + AMP (ez: GMP synthase) - Specific Nucleoside monophosphate kinases (convert XMP to XDP) and diphosphate kinases (XDP to XTP)

Answer 281

- phenylalanine hydroxylase - Symptoms: intellectual disability, recurrent seizures, hypopigmentation, eczematous skin rashes

Answer 282

- Dolichol phosphate in ER membrane acts as site for oligosaccharide in ER - Glycosyltransferase adds two GlcNAcs to dolichol - Glycosyltransferase adds five mannose - Dolichol phosphate linked to above CHOs reorientates from cytoplasm into ER lumen - 4 more mannoses are added onto oligosaccharide using dolicholphosphomannose - 3 glucoses are added to mannose forming universal oligosaccharide containing 14 sugars - Highly specific modification of universal oligosaccharide occurs in Golgi apparatus by addition or removal of CHOs, yielding high mannose type or complex type (sialic acid, fucose, N-acetyl glucosamine, N-acetyl-galactosamine, galactose)

Answer 283

1.) Masculinization of female babies: normal ovaries, but ambiguous or male genitalia- Congenital adrenal hyperplasia (most common, defect in 21-hydroxylase involved in cortisol biosynthesis results in block in cortisol synthesis with intermediates being shunted into androgen synthesis pathway). As result: females have high levels of androgens and develop ambiguous or male genitalia2.) Feminization of male babies: failure to develop unambiguous male genitalia- Defect in testes development during embryogenesis- Problem in androgen biosynthesis by testes (eg. Issue with steroid 5 alpha reductase) - Deficiency in androgren receptor production or signaling by target cells (androgen insensitivity)

Answer 284

- Completion of DNA replication activates protein phosphatase (cdc25C) - Protein phosphatase dephosphorylates a particular tyrosine residue in CDK1, which activates cyclin A or B-CDK1 complexes - Cyclin A or B-CDK1 complexes phosphorylate many proteins that participate in early mitotic events including chromosome condensation, assembly of mitotic spindle and breakdown of nuclear membrane

Answer 285

- Newly synthesized DNA contains nicks, which distinguishes parental and daughter strands - Base mismatch distort DNA helical structure - Repair enzymes recognize distortion and remove mismatched base, excise nucleotides back to nearest nick - Gap fill by DNA pol using parental DNA strand as template

Answer 286

1.) Recessive inheritance: one normal allele prevents disease, recessive inheritance is mostly observed in defects of enzymes/proteins involved in transport and storage, loss of one functional allele can be compromised2.) Dominant inheritance: mostly observed in defects of structural proteins, proteins involved in growth, differentiation and development and receptor/signaling proteins

Answer 287

- It is a pesticide and poison that uncouples ETC/ox-phos. It causes sweating, flushing, nausea, inc RR, tachycardia, fever, coma, death in 1-2 days. Treatment with ice baths, oxygen and fluid/electrolyte replacement.

Answer 288

- Ribonucleotides must be in diphosphate form - Enzymes needed : ribonucleotide reductase and thioredoxin reductase. - Cofactors: thioredoxin - Thioredoxin reductase uses NADPH to generate reduced thioredoxin for another rxn to occur

Answer 289

- Beriberi: result of thiamine deficiency that in addition to affecting PDH and alphaKGDH, also affects the transketolase reactions of the non-oxidative phase of the PPPathway preventing rearrangement of carbon structures and leading to an imbalance in the CHO pool. Prevalent in low income communities, but most especially in alcoholic patients. Alcoholism reduces thiamine uptake and storage.

Answer 290

- Polyadenylation = addition of 100s of adenine residues to end of mRNA moledule - Stop pt for transcription is specified by a consensus seq in DNA known as polyadenylation signal, which is transcribed into pre-mRNA - This signal is recognized by specific protein factors - This tail is important for RNA stability

Answer 291

- Helicases and nucleases work together to peel off region containing thymidine dimer lesion - DNA Pol and DNA ligase fill in gap

Answer 292

1.) Cytarabine is an analogue of cytidine, contains arabinose in place of ribose. Converted to cytarabine triphosphate. Competes with dNTPs for binding to DNA polymerase 2.) Cyclophosphamide is converted to phosphoramide mustard by liver. It is a bi-functional alkylating agent that forms inter and intra strand DNA crosslinks that block replication and can trigger apoptosis 3.) Doxorubicin form tripartite complex with DNA and topo II. Topo II introduces D-S breaks in DNA. Binding doxorubicin prevents re-ligation of D-S breaks. Breaks accumulate and trigger apoptosis

Answer 293

TIPhe = try, trp, tyr, iso and phe

Answer 294

- No intact template / parental strand to direct repair - Nonhomologous end-joining: broken ends processed, loss of nucleotides at breakpoint, brought together, ligated, ends with permanent change in DNA sequence - Homologous end-joining: repair of damaged chromosome using information contained in undamaged, homologous chromosomes, allows repair of d-s breaks without loss of information

Answer 295

- Assortative mating is the selection of partners based on specific genetic traits.- It disturbs the equilibrium distribution of alleles, specifically, the mating of genetically similar individuals increases the degree of homozygosity in a population. The allele frequencies in the gene pool don’t change, only change is increase in homozygote frequency.

Answer 296

- Surface mannose residues are not phosphorylated and therefore lysosomal proteins don’t reach the correct compartment and appear in serum - Result: lysosomal degradation of proteins and CHOs is impaired, inclusion bodies are seen in lysosomes making them appear dense

Answer 297

- HSL=hormone sensitive lipase - In adipose tissue, HSL releases FFAs into blood by cleaving TAGs into glycerol and FAs - Inhibited by insulin

Answer 298

- Phosphorylation of Rb in Rb:E2F by cyclin D:CDK4/6 causes dissociation of Rb from E2F - E2F is a transcriptional activator of cyclin E:CDK2 - In the absence of growth factors, Rb phosphorylation can still occur independent of cyclin D:CDK4/6 and cell cycle can progress

Answer 299

- Isolated anomalies: single problem that can be sporadic or multifactorial in order that just affects a single body region. Ex: cleft palate. Major anomalies = anomalies requiring surgical or cosmetic consequences. Minor anomalies = little impact on well-being of pt – can give diagnostic clues about presence of a syndrome.- Sequences: cascade of events, starting from isolated anomaly and leading to multiple malformations- Syndromes: affect several body regions and often display chromosomal or Mendelian inheritance.

Answer 300

- Conformation: eg. Misfolding results in hydrophobic domains being placed on surface and leads to degradation - N-terminus: Ser/Met proteins are more stable than Arg/Lys proteins - Other sequences: eg. PEST sequences shorten lifespan

Answer 301

- It is a shuttle mechanism to move electrons from NADH in cytoplasm into the mitochondrion. It occurs in brain and muscle.

Answer 302

- Ran-GTP bound to importin = inactivated Importin - Ran hydrolyzes GTP to GDP and importin dissociates, Ran-GDP moves into nucleus - Importin binds cargo and moves through nuclear pore complexes into nucleus - Ran-GDP in nucleus binds GTP and dislocates GDP - Importin dissociates from cargo in nucleus and associates with Ran-GTP moves out to cytoplasm

Answer 303

-Fe2+, ascorbate and alpha-ketoglutarate in addition to enzyme.

Answer 304

Renal failure, methanol poisoning, DKA

Answer 305

- Both toxins catalyze ADP-ribosylation, which is the attachment of ADP-ribose to specific residues. - Cholera toxin catalyzes this reaction in Gs alpha subunit proteins, causing subunit to remain in active state, leading to high adenylate cyclase and cAMP levels. - Pertussis toxin catalyzes this reaction in Gi alpha subunit proteins, causing subunit to remain in inactive state, leading to high adenylate cyclase and cAMP levels.

Answer 306

- Enhancer (way upstream) - Gene-specific elements: DNA sequences unique to particular genes or groups of genes - CAAT box or GC-rich region: may be present - TATA box: almost invariably found in genes transcribed by Pol II - Gene

Answer 307

- De-acetylated histones are methylated and bind HP1 proteins- HP1 proteins bind histone methylase- This binding results in methylation of histones spreadings along chromosomes until boundary elements are reached.

Answer 308

- Points of regulation are at 1.) recognition of start codon and 2.) activity of initiation factors 1.) Recognition of start codon: bind of regulatory protein in 5’ UTR can mask start codon 2.) eIF-2a can be inactivated by phosphorylation

Answer 309

- T-form refers to the tight form of Hb and occurs when Hb is deoxygenated. In this form, Hb does not have high affinity for o2. At the tissue level where low pH, high CO2 and high 2,3-BPG are present, the tight form is favored and o2 is offloaded. - R-form refers to relaxed form of Hb when it has a high affinity for o2 molecules. This occurs in alveoli where high pH, low CO2 and low 2,3-BPG are present.

Answer 310

- cAMP signaling pathway, which leads to glycogenolysis.

Answer 311

- Deletion in chromosome 5 p. Usually a new mutation- Facial changes: microcephaly, hypertelorism (wide set eyes), micrognathia (undersized jaw). Brain/CNS changes: severe mental retardation. Cardiovascular: heart defects. Characteristic cat-like cry.

Answer 312

- As a result of this deficiency – citrullinemia - Treat with arginine and phenylbutyrate supplements - Cirtruline can be cleared directly, but only carries single nitrogen

Answer 313

- Adenylate cyclase is activated by Gs proteins. Deactivated when Gs proteins are inactivated by their GTPase or when Gi proteins bind adenylate cyclase.

Answer 314

- 70 S ribosome inhibitor - Specifically prevents peptidyl bond formation

Answer 315

- AIP: acute intermittent porphyria: deficiency in PBG deaminase, causes build up of PBG and ALA. Give urine a dark red color. Life threatening and causes episodes of confusion and sharp abdominal pain - PCT: porphyria cutanea tarda: deficiency in uroporphyrinogen decarboxylase, leads to buildup of porphyrins (detected in urine). Porphyrins able to absorb visible and UV light. As a result, light energy is builtup and discharged into tissue and generates ROS. As a consequence, PCT causes photosensitivity of skin and leads to blistering of sun-exposed areas.

Answer 316

- Genetic drift is the change in allele frequency within a population due to random sampling/statistical variation. This occurs in small populations. - Example: 10 couples stranded on deserted island. One of males is heterozygous carrier of CFTR mutation. Allele frequency is 1/40 (2.5%). Time goes by and couples have average of 2 children. By chance, none of children have inherited mutation from father. By genetic drift, CFTR allele is now completely lost from this island’s population.

Answer 317

- Transamination via aminotransferase enzyme (ALT / AST) - Deamidation of glutamine via glutaminase

Answer 318

- Example: acetaminophen. - UGT catalyzes conjugation of UDP-glucuronate with acetaminophen, making it water soluble, allowing it to be excreted in urine

Answer 319

- Acidic pH of stomach denatures proteins - Pepsinogen is secreted by the stomach - It autoinhibits it’s active site, becomes altered in acidic environment and cleaves itself into pepsin - Pepsin’s active site contains aspartic acid residues. - It is a endopeptidase and cleaves internal peptide bonds, prefers bonds formed between AA groups of aromatic and hydrophobic amino acids - Chyme enters duodenum, stimulates release of secretin and CCK by intestinal mucosa - Secretin: stimulates acinar cells in pancreas = alkaline fluid released (bicarb rich), which neutralizes chym - CCK: stimulates release of bile and release of pancreatic digestive zymogens (trypsinogen, chymotrypsinogen, proelastase, procarboxypeptidases) - Enteropeptidase present on wall of intestinal mucosa cleaves trypsinogen to trypsin - Trypsin cleaves remaining pancreatic zymogens into active forms (chymotrypsin, elastase, carboxypeptidases)

Answer 320

- Methylguanosine is added to the 5’ end of pre-RNA - This distinguishes mRNA from other types of RNA - Required for subsequent processing steps - Protects against degradation - Important for initiation of translation

Answer 321

- PRPP consumptions means less PRPP available to stimulate CPS II, orotate phosphoribosyltransferase, therefore de novo pyrmidine synthesis is decreased

Answer 322

- Conversion of HMG-CoA to Acetoacetate via HMG-CoA lyase, which produces and acetyl-CoA. Procession through this step will commit the pathway to forming ketone bodies.

Answer 323

- Ribose-5-phosphate, 2 NADPH and CO2

Answer 324

- Mnemonic: Some Good Children are Pyrates - Serine, Glycine, Cysteine, Alanine = Pyruvate

Answer 325

- Mutations in different genes cause the same phenotype

Answer 326

Deoxygenated Hb is in a T-form (tight) with low o2 affinity. A valine reside partially blocks the o2 binding site in the beta subunits. When o2 concentration increases (ie. in lungs), o2 is forced by mere concentration onto alpha subunits. A conformational change occurs as a result of this binding and the valine residues are rotated out of the o2 binding site in the beta subunits. The Hb molecule is now in a high o2 affinity form known as the R-form (relaxed). The importance of this is considered when looking at the physiological range when o2 is loaded / unloaded from Hb.

Answer 327

- An irreversible inhibitor is one that forms covalent complexes with active site residues in enzymes, chemically modifying and therefore inactivating an enzyme. No change occurs with increased substrate concentration, nor removal of inhibitor.

Answer 328

- Outer leaflet is rich in PC and sphingomyelin (both have choline) - Inner leaflet is rich in PE and PS - Stress activates enzymes known as flippases that flips lipids between leaflets - Eg. When PS appears in outer leaflet of RBCs, RBCs are destroyed by macrophages.

Answer 329

- Selection works against or in favor of certain genotypes. Over time, selection will reduce number of detrimental mutant alleles in a population. However, frequency of mutant alleles will stabilize at a low level. In this state of equilibrium, loss of mutant alleles by negative selection will be equal to spontaneous occurrence of new mutant alleles

Answer 330

- Inability to convert phenylalanine to tyrosine due to mutation often at 5’ splice donor site in phenylalanine hydroxylase gene - Results in defective splicing, protein produced lacks one exon and is rapidly degraded

Answer 331

- Autosomal dominant disorder resulting from defects in LDL receptor. As a result, serum lipid concentrations are elevated and result in high levels of LDL in the blood serum. As a result of the overflow pathway into macrophages, atherosclerotic changes in blood vessels occur leading to higher incidences of CVD in the 3rd and 4th decades of life. - These individuals present with xanthomas (deposition of lipis) to joints and tendons. Lab studies indicate elevelated cholesterol and triglyceride levels.

Answer 332

- substrates: o2, THBtn, phenylalanine - products: tyrosine, H2o and DHBtn - cofactors: DHBtn reductase, which requires NADH

Answer 333

- In development, cells must respond to environmental clues by changing their shape and polarity, which involves rearranging cytoskeleton and polarizing secretion of proteins to apical or basal surfaces of cell- Kidney: Epithelial cells need to sense fluid flow in kidney tubule. Detection of fluid stream leads to stopping of cell proliferation and correct polarization of cell. This occurs by relocating erb-b2/EGFR to basal surface. In polycystic ovary disease, mutations to two genes polycystin 1 and 2 render a cell incapable of sensing fluid flow. As a result, cell proliferation doesn’t stop, development of polarity doesn’t occur (erb-b2/EGFR) remains on the apical surface and kidney develop cysts.

Answer 334

- Galactose + ATP =(ez: galactokinase) Galactose-1-P

Answer 335

- Rare inherited disorder resulting from mutations in gene that encodes ATM kinase - Symptoms: difficulty in coordinating movement (ataxia) and appearance in small, widened blood vessels on skin (telangiectasia) - Pts susceptible to infections and at increased risk of leukemias and lymphomas. They are highly sensitive to radiation exposure.

Answer 336

- Way for generating pentoses and NADPH - Pentoses are used for synthesis of: DNA, RNA, ATP, NADH, FADH, Coenzyme A - NADPH are used for synthesis of: FAs, cholesterol, NTs, nucleotides and reduction of oxidized glutathione and P450 monooxygenases

Answer 337

- Haploinsufficiency: half of gene dosage might not be sufficient for a cell to carry out its function. Many structural proteins are needed in quantities too large to be supplied by just one allele

Answer 338

- Lipid droplets are packages containing TAGs. These are surrounding by a protein coat composed of many proteins including perilipin. Perilipin acts as protector of the TAGs stores and prevents lipases, such as hormone sensitive lipases from degrading TAGs into FFA and glycerol. When perilipin is phosphorylated, it allows lipases to do this, but not when dephosphorylated.

Answer 339

- CML = chronic myelogenous leukemia - Result of translocation bw c/s 9 and 22, fuses the ABL gene usually on 9 to the BCR gene on 22, creating Philadelphia chromosome BCR-ABL on 22 - Result = constitutively active Bcr-Abl kinase can phosphorylate many targes. In hematopoietic cells, stimulates expansion of white blood cells - Treatment = imatinib mesylate (Gleevec) is specific inhibitor of this kinase

Answer 340

- Phenylketonuria: deficiency in phenylalanine hydroxylase - Tyrosinemia-II: deficiency in tyrosine aminotransferase - Alcaptonuria: deficiency in homogentisate oxidase - Tyrosinemia-I: deficiency in fumarylacetoacetate hydrolase

Answer 341

- Extreme sensitivity of the skin to sunlight - Pigmentation changes, skin cancers, develop on areas exposed to sun - Result from any of several mutations that impair or abolish the nucleotide excision repair

Answer 342

- Glycerol-phosphate-dehydrogenase takes DHAP and converts it into glycerol-3-phosphate, which is precursor to TAGs.

Answer 343

- Arsenic mimics phosphate. In its presence, Glyceraldehyde-3-phosphate DH reaction yields arsenic product instead of 13BPG. The arsenic product is unstable and hydrolyzes to 3PG. No ATP is gained from the process, where previously the conversion to 3PG yields a single ATP. Net ATP from glycolysis with one molecule of glucose is 0. This is problematic for RBCs who rely solely on glycolysis for their energy production. - Pts present with SOB and dizziness. CBC reveals hemolytic anemia and elevated urine arsenic levels. Treatment includes discontinuation of arsenic and therapeutic red-cell exchange.

Answer 344

Asthma, bronchitis, obesity, sedatives / anesthetics

Answer 345

- Children present with hypotonia, little to no skeletal or cardiac muscle pathology - Neurological symptoms: epileptic seizures, intellectual disability - Treated by creatine administration

Answer 346

- Hereditary susceptibility to colon cancer, 80% lifetime risk of colorectal carcinoma - Arises from defect in DNA mismatch repair (mutations to MSH2 or MLH1) genes - Pt inherits one defective allele from parent, loss or inactivation of second copy results in accumulation of mutations at accelerated rate typically in microsatellite repeats, which means microsatellite instability occurs - Microsatellite instability can reduce Bax protein function, which suppresses apoptosis and abnormal cells survive

Answer 347

- Catalyzed by complex known as spliceosome, which has protein and snRNA compoments involved in catalysis and recognizing exon/intron boundaries - Consensus nt seqs are required for splicing: 5’ splice site, 3’ splice site and branch point within intron - Adenine at branch point attacks 5’ splice site, cutting sugar-phosphate backbone of RNA - 5’ end becomes linked to adenine, forms a loop - Free 3’OH reacts with 5’ end of next exon, joins. Intron released as lariat

Answer 348

- Both common x-linked recessive diseases - Affects 1/3000 - Defect in dystrophin leads to muscle damage. Gene is large target for new mutations. Large target - Pts are wheel-chair bound by age 12, death occurs before repro age

Answer 349

- XIC (x-chromosome inactivating center) on x-chromosomes has a gene known as XIST (inactive x-specific transcript).- XIST is transcribed- XIST RNA associates closely with x-chromosome and mediate inactivation of most of the chromosome- DNA and histones on x-chromosome become methylated, transcription is inactivated and chromosome condenses

Answer 350

- Prader-Willi: deletion exists from paternal chromosome 15, mothers is imprinted and therefore silenced. Incidence = 1/10-50K. Characterized by obesity, excessive food seeking behavior, hypogonadism, mental retardation, small hands and feet- Angelman: deletion exists on maternal chromosome 15, fathers is imprinted and therefore silenced. Incidence = 1/15K. Characterized by unusual facial features – large mandible and open mouth, seizures, movement and gait disorders, mental retardation, excessive laughter and absence of speech.

Answer 351

- a.) Glu to Val. Valine residue is sticky when in T-form, polymerizes with other sticky residues. - b.) His to Ser. Serine has decreased affinity for 2,3-BPG. - c.) Val to Pro. Proline breaks alpha-helix resulting in unstable Hb molecule, unable to bind o2 (or decreased affinity?)

Answer 352

- Suicide substrates, aka Trojan Horse substrates, are special classes of irreversible inhibitors that only become inhibitors through the catalytic action of the target enzyme. They bind covalently at active site residues.

Answer 353

- Carriers of balanced alterations ~ 0.2% of live births are not aware of their condition as there is typically no impact on the carrier - Their genetic abnormality does; however, shows at reproduction when they lead to the production of aberrant gametes. See image below

Answer 354

- Megaloblastic anemia can occur when deficiency in both and can be treated with folate in either cases. Folate given to B12 pt with allow sufficient oxidized THF to be available for DNA synthesis and resolving of megaloblastic anemia - Folate alone will not resolve the neurologic symptoms that go along with vit B12 deficient patients – demyelination leading to brain and nerve damage. Methylmalonyl acidemia seen in vitamin B12 deficient pt, not in folate deficient pt - Combined deficiency seen in chronic malnourished (eg. Alcoholic pts)

Answer 355

- vertebral defects, anal atresia, cardiac abnormalities, tracheo-esophageal fistula, renal and limb abnormalities- defects are through to occur in blastogenesis phase of development- risk factor: maternal diabetes- association = group of birth defects that for unknown reasons often occur together

Answer 356

- Mnemonic: Greg’s Hot Girlfriends Are Pregnant Ovals - Glutamine, Histidine, Glutamate, Arginine and Proline (and ornithine)

Answer 357

- NSAIDs act by inhibiting prostaglandin synthase, which are responsible for pain and inflammation. This enzyme has two enzymatic activities, one of which is cyclooxygenase activity and the other, hydroperoxidase. NSIADs inhibit the cyclooxygenase. Turns out there are two isozymes for this enzyme, COX-1 and 2. - COX-1 protects gastrointestinal mucosa, while COX-2 is associated with inflammation of arthritis. - As a result of this discovery, drugs have been designed specifically as inhibitors to COX-2. Eg. Celebrex, bextra and vioxx.

Answer 358

- AD- Neurological defect in neurofibromin gene. Causes multiple benign tumors (neurofibromas) in skin, benign tumors on iris of eye called Lisch nodules, pigmented skin lesions (café-au-lait spots), tumors of CNS and mental retardation. New mutations, complete penetrance and variable expressivity- 1/3500

Answer 359

- High energy (high GTP, high NADH) = inhibition of enzyme = decreased formation of alpha-KG - Low energy (high ADP) = activation of enzyme = increased formation of alpha-KG

Answer 360

- Only needed by two enzymes: 1.) methymalonyl-CoA mutase and 2.) methionine synthase - 1.) Converts L-methylmalony-CoA (intermediate in taking VOMIT AAs from propionyl-CoA) to succinyl-CoA - 2.) Converts N5 methyl THF to THF while converting homocysteine to methionine

Answer 361

- Tyrosinase converts tyrosine to DOPA and then to dopaquinone, which eventuall yields black/brown (eumelanin) or red/yellow (pheomelanin)

Answer 362

- Large population size- Equal fitness among offspring- Random mating- No influx of new alleles by migration or mutation

Answer 363

- Specific RNase activity removes primer - DNA pol (possibly delta) fills in gap left by primer removal - DNA ligase uses ATP to seal Okazaki fragments

Answer 364

- Left/right asymmetrical defects – situs inversus

Answer 365

-Histidine residue in beta chain (adult) is replaced by serine in gamma chain (fetal). This is where 2,3-BPG usually binds in adults. Reduced affinity in HbF.

Answer 366

- Pellagra, which has symptoms of 4 Ds (diarrhea, dementia, dermatitis, death)

Answer 367

- G-proteins are heterotrimeric proteins (with alpha, beta and gamma subunits) that are associated to the plasma membrane. When bound to GDP, they are in their inactive form. When bound to GTP, they are in their active form. They are GTPases and can self hydrolyze GTP to GDP and inactivate themselves. - There are many different types of G-proteins, including: a.) Gs, b.) Gi and c.) Gq. a.) Gs typically stimulate the activity of downstream enzymes b.) Gi typically inhibit the activity of downstream enzymes c.) Gq typically stimulate the activity of downstream enzymes - When receptors become activated, GDP-bound G-proteins bind them. This binding triggers and exchange of GDP for GTP, which activates the G-protein and causes dissociation of the alpha subunit from the beta-gamma dimer. Activated G-protein (alpha with GTP bound) associates with effector enzymes and alters their activity (inhibition or activation, depending on what type of G-protein it is). Intrinsic GTPase activity of the alpha subunit hydrolyses GTP to GDP and the G-protein is deactivated, re-associates with the beta-gamma dimer, able to participate in further signal transduction.

Answer 368

- Allopurinol and its metabolite oxypurinol (made by xanthine oxidase) are analogs of hypoxanthine - They inhibit xanthine oxidase and reduce uric acid formation - Intermediates such as hypoxanthine and xanthine are more soluble than uric acid and are eliminated in urine

Answer 369

- Inherited condition characterized by hypoplastic maxillar (insufficient growth of midface), prominent nose, intellectual disability, polydactyly, growth retardation - Results from mutation in gene encoding CREB binding protein (CBP) - This gene is implicated in processes related to memory, cognition and developmental processes

Answer 370

- Inversion results when a c/s suffers two breaks and the broken off fragment is re-inserted in the wrong orientation.- As this is a type of balanced alteration, carriers are asymptomatic- Problems arise in offspring as chromosome with inverted region forms inversion loop during pairing with normal homolog. If crossing over occurs, material is translocated and some gametes are inviable.

Answer 371

- Regulatory points: a.) Hexokinase (+: insulin; -: G6P, acetyl-CoA, glucagon) b.) phosphofructokinase 1 (+: hormones via F26BP, ADP, AMP; -: ATP and citrate) c.) pyruvate kinase (+: F16BP and insulin; -: ATP) - Rate-limited step = phosphofructokinase 1

Answer 372

-Valine. When rotated out, R-form is stabilized.

Answer 373

1.) M-phase: cyclin A/CDK1 and cyclin B/CDK1 2.) Mid G1 phase: cyclin D/CDK4 and cyclin D/CDK6 3.) Late G1 phase: cyclin E/CDK2 4.) S phase: cyclin A/CDK2

Answer 374

- Zygote with only maternally or paternally imprinted homologues of a chromosome- This leads to problems with gene dosage (overabundance of one gene, lack of another for example).

Answer 375

- glycine, arginine and methionine (s-adenosylmethionine) - nitrogen comes from arginine - liver (some in kidney) - meat and fish

Answer 376

1.) ATM kinase senses replication forks, which indicates ongoing replication, and prevents checkpoint kinase from allowing activation of Cdc25C, which normally dephosphorylates CDK1. Therefore CDK1 remains inactive. ATM remains active as long as replication forks active

Answer 377

- Anaplerotic reactions are those that replenish substrates. The TCA cycle is not an end-product producing reaction. It re-generates oxaloacetate in order for the cycle to occur again. However; TCA cycle intermediates, including oxaloacetate, are constantly being drawn away from the cycle as they serve as intermediates for biosynthetic pathways and therefore the oxaloacetate concentrations decrease preventing expanding rates of the TCA cycle should the need occur. - Pyruvate + ATP + HCO3 = oxaloacetate + ADP + Pi + H+ (ez: pyruvate carboxylase, coenzyme: biotin) - Yes, any reaction that generates an intermediate of the TCA cycle is a potential anaplerotic reaction. There is a reaction involving glutamate and glutamate dehydrogenase that generates more alpha-ketoglutarate, which adds to oxaloacetate in subsequent reactions.

Answer 378

- Forms GSSG with peroxide, then reconverted to glutathione via glutathione reductase, which uses NADPH

Answer 379

- PRPP synthetase (inhibited by ADP and GDP) - Amidophosphoribosyltransferase (inhibited by AMP, GMP; activated by PRPP) - Adenylosuccinate synthetase (inhibited by AMP) - IMP dehydrogenase (inhibited by GMP)

Answer 380

- Phospholipase C is activated by G-proteins (upon hormone/receptor binding) and hydrolyzes PIP2 (phosphatidylinositol 4,5 bisphosphate), a membrane lipid, generating two second messengers: IP3 (inositol 1,4,5 triphosphate) and DAG (diacylglycerol). - IP3 is water soluble and diffuses into cytosol where it binds to receptors on ER, triggering release of Ca2+ down its concentration gradient and into the cytosol. Ca2+ activates cytosolic protein kinase C (PKC) who have downstream effects. - DAG is liphophilic and remains membrane-associated, but easilty diffuses in the plane of the membrane. With Ca2+, it activates plasma membrane associated PKC. - Ca2+ released by the mechanism above can also bind calmodulin, causing it to interact with other protein kinases, phosphatases and ion channels. - Inactivation: 1.) receptor down-regulation/internalization/degration; 2.) protein phosphatases reverse action of PKC; 3.) Ca2+ pumped out of cytosol (into ER or to ECF); 4.) IP3 is dephosphorylated by phosphatase converting it into derivative that isn’t active; 5.) DAG is phosphorylated yielding phosphatidic acid or hydrolyzed to glycerol and FAs.

Answer 381

- p53 is normally an unstable protein, is ubiquinated and destroyed by proteasome when not stabilized - Phosphorylation by ATM/ATR (double-stranded breaks or UV damage respectively) increases stability of it, which leads to transcriptional control of many genes that regulate cell cycle arrest, repair of DNA and apoptosis - Encoded by gene TP53 - Active p53 is homotetramer. Missense mutations in one allele greatly reduce function. Any subunit mutation of the tetramer will cause aberrant function. Mutations act as dominant negative

Answer 382

- Leads to chronic lactic acidosis, primary in kids. It leads to severe neurological problems and is frequenctly fatal.

Answer 383

- Plasmalogens are phosphoglycerides with an ether (as opposed to ester) linkage to glycerol. These are synthesized in peroxisomes are are components of the myelin sheath surrounding nerves.

Answer 384

- Carbomyl phosphate synthetase I = rate-limiting step - Carbomyl phosphate synthetase I is activated by N-acetylglutamate synthetase, which is activated by arginine - High levels of arginine are indicative of elevated peripheral blood ammonia levels

Answer 385

- They bind to hydrophobic pockets in albumin. - Don’t need to synthesize FFA transporters when we are in a starved state and need FFAs as albumin is always present.

Answer 386

- Depurination: bond bw base and ribose hydrolyzed - Deamination: most often cytosine deamination generates uracil - Pyrimidine dimers: UV light dimerizes adjacent thymine bases on same DNA strand

Answer 387

- Example of uniparental disomy disorder- Incidence = 1/13000- Some types arise when child inherits homologues of a portion of chromosome 11 from father.- S&S: overabundance of IGF2, leads to kidney, adrenal and liver problems, resulting in severe hypoglycemia. Characterized by microcephaly, macroglossia (large tongue) and umbilical hernia. Susceptible to childhood cancer.

Answer 388

1.) Gene regulation by TFs and chromatin modification2.) Cell-cell signaling (direct contact or morphogens)3.) Development of specific cell shape and polarity4.) Movement and migration of cells5.) Programmed cell death

Answer 389

- homogentisate oxidase - Symptoms: urine black upon standing, black pigmentation of cartilage and collage, joint destruction and arthritis

Answer 390

- Dominant negative effect: If the mutation produces an abnormal protein, the mutant protein may compete with the wildtype form. If the protein in question is part of a large complex, the presence of a few deformed mutant proteins may destabilize the structure. A dominant negative effect affects mostly structural proteins

Answer 391

- Histidine - Decarboxylation of histidine - Pyridoxal phosphate - Produced by mast cells, involved in allergic reactions and in control of acid secretion by stomach

Answer 392

- Increase in 2,3-BPG decreases Hb’s affinity for o2 (binds in central cavity, stabilizing T-form through strong ionic interactions) promoting release - Increase in H+ conc (low pH) decreases Hb’s affinity as they bind His, forming positive residue which binds aspartate, stabilizing T-form and promoting o2 release - CO2 binds to N-terminal of Hb subunits forming carbamates. Carbamates carry a negative charge and participate in salt bridges that stabilize T-form, promoting o2 release Physiological relevance: In rapidly metabolizing tissue, CO2 and proton concentration is high, o2 requirement is high. Protonated His and carbamate formation stabilize the T-form of Hb resulting in offloading of o2 here. Conversely, in lungs, removal of CO2 (requiring proton with bicarb ion), causes deprotonation of Hb and conversion to R-form where conveniently o2 tension is also high. Amount of o2 carried to peripheral tissues increases as a result.

Answer 393

- potent ribosome inactivating protein (RIP) found in castor beans - it removes adenine bases from rRNA

Answer 394

- GWAS refers to analysis of millions of SNPs to determine their connection with disease. Genetic polymorphisms underlie why certain individuals have a genetic susceptibility to certain disease or have different responsiveness to drugs.- From these studies, you get odds ratio that SNP is associated with disease state.- Note, SNPs are not necessarily disease-causing. SNPs often lie outside of coding regions, but show strong linkage with the mutation that causes the disease.

Answer 395

- For correct functioning of Shh, the protein must interact with cholesterol. - Disturbances in cholesterol biosynthesis will therefore also have broad impact on development.- Defect = Smith-Lemli-Opitz syndrome, IEM in cholesterol synthesis

Answer 396

- YopH is a protein tyrosine phosphatase. - It is encoded by a plasmid in Yersinia pestis, the bacterium responsible for the bubonic plague. - It dephosphorylates certain key proteins and prevents host immune system from mounting an effective defense against the bacterium.

Answer 397

- NSAIDs and glucocorticosteroids(aka glucocorticoids) inhibit COX1/2 and prostaglandin synthase (PGH synthase)

Answer 398

- Ketone bodies: acetoacetate, acetone (result of spontaneous decarboxylation of acetoacetate) and beta-hydroxybutyrate. - Ketone bodies have the ability to cross membranes and can leave liver and travel to peripheral tissue. - Beta-hydroxybutyrate gets oxidized to acetoacetate via beta-hydroxybutyrate dehydrogenase (yields NADH) - CoA from succinyl-CoA is transferred to acetoacetate yielding acetoacetyl-CoA via enzyme acetoacetate:succinyl-CoA transferase - Thiolase produces 2 x acetyl-CoA from acetoacetyl-CoA, which function in the TCA cycle to produce energy. - Acetone cannot be converted to acetyl-CoA

Answer 399

- Loss-of-function: mutation reduces the protein’s activity

Answer 400

- a.) see picture - b.) It is an important intermediate and precursor molecule for TCA, FA biosynthesis, ketone body formation and cholesterol biosynthesis (leading to steroid hormones, bile acids and vit D production) - c.) It is produced as a result of glycolysis, beta-oxidation and AA deamination/oxidation. It is requires presence of vitamin B5.

Answer 401

- Epinephrine can signal through cAMP and DAG-IP3 pathways. - It binds beta-adrenergic receptors in skeletal muscle through the cAMP (and adenylate cyclase via Gs proteins) signaling pathway to trigger glycogenolysis. - It binds alpha-1-adrenergic receptors in the liver through the DAG-IP3 (and PLC via Gq proteins) signaling pathway to trigger glycogenolysis.

Answer 402

- It is regulated at the HMG-CoA reductase reaction. 1.) AMP high (starved state): phosphorylation by AMP-dependent kinase, which inactivates enzyme and cholesterol synthesis is low during times of starvation 2.) Insulin high (well-fed state): desphosphorylation by protein phosphorylase activates enzyme, which means that cholesterol synthesis is high during times of well-fed 3.) Cholesterol inhibits the enzyme by feedback inhibition, which means that when cholesterol levels are high, cholesterol synthesis is low

Answer 403

- HMG-CoA = beta-hydroxy-beta-methylglutaryl-CoA - This molecule is used in the synthesis of cholesterol. - Will occur in well-fed times

Answer 404

- Cholera is bacterial disease that causes massive diarrhea, can lead to death as the result of dehydration. - It is caused by Vibrio cholerae that produces the cholera toxin. - Cholera toxin catalyzes ADP-ribosylation of alpha-subunit Gs proteins at an arginine residue that causes the subunit to be in the GTP-bound active state. As a result, signaling by this molecule cannot be turned off, cAMP levels remain high, PKA remains active. CFTR is phosphorylated. Secretion of Cl, Na and water into the intestinal lumen, ie. massive diarrhea.

Answer 405

- Ribose 5 phosphate - Ez: PRPP synthetase

Answer 406

- Malformation: intrinsic abnormality in developmental process. Eg. Polydactyly- Deformation: extrinsic influence on development of the affected tissue. Eg. Oligohydramnios- Disruption: destruction of developing tissue. Eg. Amniotic bands

Answer 407

- f(a)^2 = 1/10000, then f(a) = 1/100 = 0.01- f(A) = 1-f(a) = 99/100 = 0.99- Since the disease is so rare, assume f(A) = 1, then frequency of heterozygote = 2f(a)f(A) = 0.02

Answer 408

- Synthesized from tyrosine residue on thyroglobulin, after synthesis of the molecules, proteolysis releases them as free T3/4

Answer 409

- Galactosemia - Three types: a.) Classic galactosemia: most common / severe form where there is a galactose-1 phosphate uridyl transferase deficiency b.) Deficiency of galactokinase c.) Deficiency of UDP-galactose epimerase - Results in accumulation of galactose1-phosphate in liver and other tissues (CNS, kidney). Newborns present with milk intolerance and signs of liver failure, cataracts and intellectual disability. Also present with jaundice, lethargy and hepatomegaly. Diagnosis is by detection of galactose or galactose-phosphate in urine. Pts must receive a galactose-free diet (no lactose either, which is a glucose, galactose disaccharide).

Answer 410

- ATM/ATR activity stabilizes p53 (remember, ATM and ATR are activated by double-stranded DNA breaks and UV light/damaging drugs respectively) - Targets of p53 include proapoptotic proteins belonging to Bcl-2 family - Bcl-2 family proteins (not Bcl-2, which is antiapoptotic) stimulates BAX activity, which promotes release of cytochrome c from mitochondria - Cytochrome c binds to Apaf-1 in cytoplasm - Oligomerization of cyt c with apaf-1 occur - This recruits caspase 9, initiator caspase - Caspase 9 activates executioner caspases, such as caspase 3 - Cell is destined to death

Answer 411

- Biotin is a B vitamin, also known as vitamine B7. It is required by pyruvate carboxylase.

Answer 412

- Digitalis is an inhibitor of the Na/K ATPase. Causes increase in FOC, decrease in HR.

Answer 413

- Ran-GDP binds GTP and dissociates from GDP forming Ran-GTP - Ran-GTP binds exportin, binds cargo and moves through nuclear pore complex into cytoplasm - Hydrolysis of complex occurs, Cargo, exportin and Ran-GDP dissociate, Ran-GDP returns into nucleus

Answer 414

- If NAD+ concentration is low in liver/kidney, acetoacetate will be converted to beta-hydroxybutyrate, causing an increased concentration of NAD+ and decrease in NADH.

Answer 415

- All AAs except for TIPhe and L AAs

Answer 416

- Fetus releases hydroxyacyl metabolites into the mother’s circulation as a result of long chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency in the fetus. FAs accumulate in mother’s liver and they present with acute liver failure in pregnancy (jaundiced).

Answer 417

- Chylomicrons in enterocytes associate with ApoB-48 - After entering into serum, CM now associates with ApoC and ApoE, which is receives from HDL

Answer 418

- Shh gradient secreted from notochord and floorplate of neural tube helps organizing the different cells in brain and spinal chord. Defects leads to midline defects- Shh also secreted from zone of developing limb to induce development of posterior limb elements.

Answer 419

- Glycogenin: acts as a primer protein and generates short glucose chains via autoglycosylation of glycogenin - Glycogen synthase: takes over from glycogenin and transfers glucose residues from UDP-glucose - Both form alpha-1,4-bonds

Answer 420

- Proto-oncogene: promote cell growth - Loss of function causes excessively active growth promotion = stuck accelerator = oncogene = typically dominant mutations

Answer 421

- In mito: Glycine and succinyl-CoA acted on by ALA synthase = aminolevulenic acid (ALA) - 2 x ALA molecules acted on by PBG synthase (aka ALA dehydratase) and produce porphobilinogen (PBG) out in cytoplasm - 4 x PBG acted on by PBG deaminase with product fed into UPG III synthase to produce uroporphyrinogen III (UPG III) - UPG III acted on by UPG III decarboxylase to produce coporphyrinogen III (CPG III) - CPG III enters mito again and becomes protoporphyrinogen IX, which is acted on by ferrochelatase which adds Fe2+ to structure causing formation of heme B

Answer 422

- Glucuronic acid is a prerequisite for bilirubin excretion. - UGT, which is an enzyme that catalyzes the conjugation of bilirubin with glucuronic acid leads to buildup of bilirubin and syndromes known as Crigler-Najjar/Gilbert.

Answer 423

- Pellagra - Hartnup disease

Answer 424

- Cortisol is secreted by adrenal cortex - Binds to and activates receptors in cytoplasm, causing conformational change to that receptor - Accessory proteins dissociate, activated receptors dimerize - Dimerized receptors are imported into nucleus - Bind GRE elements on genome, regulate transcription positively or negatively - Typical result of cortisol is to stimulate gluconeogenesis, glycogen deposition, fat and protein degradation, inhibit inflammatory response

Answer 425

- Hereditary syndrome with severe or complete deficiency of HGPRtase activity - Hyperuricemia, uric acid stones, intellectual disability and self-injurious behavior

Answer 426

- VLDL associates with ApoB100 in hepatocytes - VLDL in serum associates with apoE and apoC obtained from HDL - IDL remains associated with all 3 per above - LDL remains associated with all 3 per above

Answer 427

- Glucogenic = These AAs can be converted into glucose via TCA intermediates (alpha-kg, succ coa, fumarate, OAA) and pyruvate – anything that generates OAA, an intermediate in gluconeogenesis - Ketogenic = These AAs can be converted into acetyl-CoA and acetoacetyl-CoA, can never become glucose - Gluco/ketogenic AAs = TIPhe mnemomic = all T AAs (thr, tyr, trp), iso, phe - Ketogenic AAs = all L AAs - Glucogenic AAs = all others

Answer 428

- Fumarate production in urea cycle links urea cycle to TCA cycle in what is known as urea-TCA bicycle - Urea cycle requires ATP energy. Fumarate generates energy in TCA cycle to offset ATP requirements by TCA cycle - OAA can be converted into aspartate and feed into urea cycle

Answer 429

1.) Binding growth factor stimulates dimerization and autophosphorylation on the tyrosine residues of the receptors (growth factor receptors contain intrinsic protein tyrosine kinase activity). 2.) Phosphorylation residues form docking sites\*. 3.) Adaptor protein GRB2 binds phosphotyrosine, which recruits guanine nucleotide exchange factor Sos, which activate 4.) Sos activates g-protein Ras by promoting exchange of GDP (Ras + GDP = inactive) for GTP (Ras + GTP = active) 5.) Ras then activates Raf (aka MAP kinase kinase kinase) 6.) Raf activates MAP kinase kinase (aka MEK) by phosphorylating it 7.) MAP kinase kinase activates MAP kinase through phosphosphorylations, which translocates into the nucleus to regulate transcription of many genes, including stimulation transcription of gene encoding c-Fos 8.) c-Fos stimulates transcription of cyclin D, CDK4/6 9.) Cyclin D, CDK4/6 phosphorylates Rb (retinoblastoma) in Rb:E2F complex, causing dissociation of Rb from E2F. 10.) E2F is a transcriptional activator of cyclin E/CDK2 (late G1 cyclin), which also acts to phosphorylate Rb:E2F as in 9. E2F also is a transcriptional activator of cyclin A (s-phase cyclin) \* Most signal Ras/MAP kinase pathway

Answer 430

- UMP synthase mutation = orotic aciduria - Crystalluria, hypochromic megaloblastic anemia, growth retardation, neurologic abnormalities - Anemia is unresponsive to B12 and folic acid - Treatment with uridine

Answer 431

Anxiety, pain, high altitude, mechanical hyperventilation

Answer 432

1.) UTP and CTP - Carbomyl phosphate synthetase II (inhibited by UTP, activated by PRPP) - CTP synthase (inhibited by CTP, activated by UTP) 2.) dTTP - thymidylate synthase (unknown)

Answer 433

- RNA pol II

Answer 434

- Asp, Asn, Arg, Glu, Gln, Pro

Answer 435

- X-linked dominant. Result from a defect in NEMO (NFkappaB essential modulator) that results in rash in early infancy, mental retardation, microcephaly and defects in tooth development. - It is lethal in male embryos

Answer 436

1.) Anterior-posterior axis- First visible structure defined by primitive streak with groove. Node is at the anterior end. Nodal gene is responsible for formation of this axis2.) Dorsal-ventral axis- Secreted proteins noggin and chordin are secreted from cells in the node and induce dorsal development in a concentration-dependent manner3.) Left-right axis- Asymmetric expression of the gene for the signaling protein Shh: sonic hedgehog from the notochord causes left/right asymmetry. This leads to asymmetric expression of nodal on the left-side that initiates development of the heart tube.

Answer 437

- AD- Neurodegerative disorder causes by gain of function mutation. Triplet expansion in gene causes protein instability. Neurodegenerative disorder with late age onset, age dependent on number of CAG repeats. Premutation = reduced penetrance = 35-40 repeats. 40+ = fully penetrant. New mutations occur frequently in this disease.- 5/100000

Answer 438

- Incidence and prevalence data are different for ppl with different numbers of affected relatives.- In diseases with strong genetic component, prevalence for ppl with affected relatives is much higher than for general population- Therefore a measure known as relative risk ratio (lamda r where r indicates relationship) compares frequency of a dz in relatives of affected and unaffected probands.- Lambda r = prevalence of dz in relative r of affected person divided by prevalence in general population- Relative risk is a way to describe disease association of an allele: how much more likely a carrier of an allele is to develop the dz than a non-carrier. If RR for carrying allele Y is 3.5 then we tell pts: your risk is 3.5 times the risk of a non-carrier of allele Y

Answer 439

- Km reflects the substrate concentration at which v = Vmax / 2. Therefore, when changing the enzyme concentration, the rate will change in proportion to that. What is also true, is that increase substrate concentration will increase reaction rate to Vmax. Km is calculated by looking at rate constants, which are independent on enzyme concentration and mere just a reflection of the properties of the enzyme. No matter how much enzyme you have, substrate interaction with the enzyme are limited by its intrinsic properties.

Answer 440

- Pertussis is a respiratory bacterial infection. - It is caused by Bordetella pertussis, which produces the pertussis toxin. - Pertussis toxin catalyzes ADP-ribosylation of alpha-subunit Gi protein as a specific cysteine residue, which lowers the affinity of the G-protein for GTP. As a result, the G-protein is trapped in the inactive conformation and cannot inhibit adenylate cyclase resulting in increased cAMP levels. Unclear the exact mechanism that leads to respiratory issues; however.

Answer 441

- cAMP, or cyclic AMP, is a secondary messenger. It is generated through the enzyme adenylate cyclase by converting ATP. - Gs proteins activate adenylate cyclase and cause rapid rises in cAMP levels. - cAMP acts as a secondary messenger by targeting protein kinase A (PKA, also known as cAMP-dependent protein kinase). It transfers gamma-phosphate groups from ATP to the hydroxyl groups of serine / threonine residues on the regulatory subunits, which cause conformational change and dissociation from the catalytic subunits, which then perform their specific downstream functions. - Deactivation of cAMP signaling: 1.) cAMP is hydrolyzed by cAMP phosphodiesterase to AMP and is no longer capable of activating PKA. 2.) intrinsic GTPase activity of G-protein returns protein to inactive states and adenylate cyclase is no longer activated. 3.) Hormone-receptor are no longer in active state (either internalized/degraded or inactivated by phosphorylation. 4.) Downstream enzymes phosphorylated by PKA are dephosphorylated by protein phosphatases and therefore are deactivated. - Gi proteins typically inhibit adenylate cyclase and cause rapid decreases in cAMP levels.

Answer 442

- Uric acid is normally excreted in urine - It and salts have limited solubility, they are typically close to saturation in normal healthy individuals. Common salt = sodium urate - Deposition of sodium urate in kidney = kidney stone - Deposition of sodium urate in joints = gout (triggers inflammatory response)

Answer 443

- Tyrosine: synthesized by phenylalanine hydroxylase - Catecholamines: synthesized in part by tyrosine hydroxylase - Serotonin: synthesized by tryptophan hydroxylase - These hydroxylase enzymes require o2, NADH and THBtn

Answer 444

- Death cap mushroom common in cool, damp regions of pacific coast - Genus/species: amanita phalloides - Contains alpha-amantin, which is a Pol II inhibitor - Nausea, vomiting, coma, hepatic encephalopathy from liver failure - Liver failure ~ 48 hour post-ingestion - Tx: gastric lavage, activated charcoal and liver transplant

Answer 445

- a.) PDH is a 3 enzyme complex. It contains a pyruvate decarboxylase (aka pyruvate dehydrogenase), a dihydrolipoyl transacetylase and a dihydrolipoyl dehydrogenase - b.) It is located in the mitochondrial matrix and serves to link glycolysis to the TCA cycle - c.) It requires 5 coenzymes: TPP, FAD/FADH2, NAD/NADH2, CoASH and lipoamide and 4 B-vitamins: thiamin (e) – B1, riboflavin – B2, niacin – B3 and pantothenic acid – B5. - d.) CH3COCOO- + NAD+ + CoASH = CH3COSCoA + CO2 + NADH + H+. The reaction is not reversible as the delta Go’ is too high. Too much free energy is lost. - e.) PDH is inactive when phosphorylated and is therefore activated by PDH phosphatase. PDH is deactivated when phosphorylated by PDH kinase. It is activated during times when ATP energy is needed: low concentrations of CoASH, pyruvate, ADP and NAD+ (substrates of reaction). These states deactivate the kinase, leading to active form of PDH. It is deactivated during times when ATP energy is not required: high concentrations of acetyl-CoA and NADH (products of reaction). These states activate the kinase, leading to inactive form of PDH.

Answer 446

- Increase in acetyl-CoA carboxylase and FA synthase - Decrease in PEP carboxykinase

Answer 447

- Cytoplasm has FA synthase that synthesizes FAs to 16 carbons = palmitate (16:0), which is a saturated molecule. - Many lipid structures in the body are longer than 16 carbons - Elongation occurs in mitochondrial as shown here:

Answer 448

- DNA Pol delta

Answer 449

- Hepatic: watch for other marker of liver disease, such as ALT and AST - Post-Hepatic: watch for other markets of blocked bile ducts such as presence of alk phos in serum

Answer 450

- Glycogen phosphorylase is activated - Glycogen synthase is inactivated.

Answer 451

- If a newborn is jaundiced, treatment requires use of “bili-lights”. As riboflavin is light-sensitive, newborns become riboflavin deficient.

Answer 452

- Inhibits thymidylate synthase, which blocks de novo dTMP synthesis, ultimately blocking cell proliferation - It is converted into FUMP by phosphoribosyltransferase in the cell - FUMP is phosphorylated by a kinase and converted into FUDP/FUTP - Ribonucleotide reductase converts it into FdUDP, with kinase converting it into FdUTP - FdUTP can be incorporated into DNA - FUTP can be incorporated into RNA - Biggest effect is FdUDP is acted on by phosphatase and product, FdUMP, inhibits thymidylate synthase

Answer 453

- PLP = active form of B6

Answer 454

- Ferrochelatase inserts Fe2+ into protoporphyrinogen IX molecule causing formation of heme B

Answer 455

- This was the first successful gene therapy trial in 1990. Cured SCID pt caused by absence of ADA: adenosine deaminase.- ADA gene was inserted into modified retro-virus- T-cells were isolated from pt. - Retrovirus was cultured with T-cells and inserted ADA into cells.- Cells that incorporated ADA gene into their genome were selected and grown in culture. - Cells were re-implanted into pt.

Answer 456

- Reduced beta-chain of hemoglobin due to mutation in beta-globin gene at first exon/intron boundary. Mutation at 5’ splice site causes two aberrant mRNA products to be formed

Answer 457

- a.) Serves to generate ATP and to generate biosynthetic precursors. - b.) CH3COSCoA + 2H2O + 3NAD+ + FAD + GDP + Pi = 2CO2 + 3NADH + 3H+ + FADH2 + CoASH + GTP - c.) see picture - d.) Acetyl-CoA - e.) isocitrate to alpha-ketoglutarate; alpha-ketoglutarate to succinyl-CoA - f.) isocitrate to alpha-ketoglutarate; alpha-ketoglutarate to succinyl-CoA; malate to oxaloacetate - g.) succinate to fumarate - h.) succinyl-CoA to succinate - i.) since 3 ATPS per NADH and 2 ATPS per FADH - 12 per acetyl CoA, 15 from pyruvate (considering PDH reaction) and 30 from glucose - j.) Regulation of the TCA cycle occurs through regulation of isocitrate dehydrogenase and alpha-ketoglutarase dehydrogenase complex. Isocitrate dehydrogenase activity increases when conc of ADP are high and decreases when NADH conc are high. Alpha-ketoglutarate dehydrogenase complex activity decreases when concentrations of succinyl-CoA and NADH are high.

Answer 458

1.) alcohol metabolism in liver generates NADH and acetyl-CoA. High concentration of NADH blocks TCA cycle enzymes and forces acetyl-CoA into FA synthesis. 2.) Beta-hydroxyacyl dehydrogenase (beta-oxidation enzyme) requires NAD, which is at low concentration during alcohol metabolism. This means that FA breakdown by liver is slowed down and leads to accumulation of fat. 3.) Damaged liver tissue has reduced capacity to synthesize VLDLs to export FAs to adipose tissue

Answer 459

1.) Tay-Sachs Disease Enzyme defect: beta-hexosaminidase A Accumulated lipid: ganglioside GM2 Presentation: mental retardation, blindness, cherry red spot on macula, death before age 3 2.) Gaucher Disease Enzyme defect: beta-glucosidase (beta-cerebrosidase) Accumulated lipid: glucocerebroside Presentation: liver and spleen enlargement, erosion of long bones 3.) Fabry Disease Enzyme defect: alpha-galactosidase Accumulated lipid: ceramide trihexoside Presentation: skin rash, kidney failure 4.) Niemann-Pick Disease Enzyme defect: sphingomyelinase Accumulated lipid: sphingomyelin Presentation: liver and spleen enlargement, mental retardation 5.) Sandhoff Disease Enzyme defect: beta-hexosaminodase A and B Accumulated lipid: GM2 ganglioside and globosides Presentation: similar to Tay-Sachs, progresses more rapidly 6.) Metachromatic Leukodystrophy Enzyme defect: arylsulfatase Accumulated lipid: sulfatide Presentation: mental retardation

Answer 460

- LHON: Leber’s Hereditary Optic Neuropathy is due to mutations in subunits of complex I and is characterized by sudden-onset blindness in young adults. - MERRF: Myoclonic Epilepsy and Ragged Red Fibers is due to abnormally shaped mitochondria with dimished cytochrome oxidase (complex IV) activity as the result of a point mutation in the mitochondrial gene for lysine tRNA. It is characterized by myoclonus and ataxia with generalized seizures. - MELAS: Mitochondrial Encephalopathy, Lactic acidosis and Stroke-like activity is due to abnormally shaped mitochondria with normal cytochrome oxidase activity that is caused by a point mutation in the gene for leucine tRNA. Early symptoms include muscle weakness, pain, recurrent headaches, loss of appetite, vomiting and seizures. Stroke-like episodes begin before age 40. Episodes involve transient hemiparesis (temporary muscle weakness on one side of body), altered consciousness, vision abnormalities, seizures and severe headaches resembling migraines. Episodes lead to brain damage and in some cases dementia.

Answer 461

- Apoprotein A: activates LCAT (lecithin:cholesterol acyltransferase), which generates cholesterol esters from cholesterols. Extracts lipids from membranes for reverse transport. - Apoprotein B: structural protein, interacts with lipoprotein receptors and mediates uptake of particle into target cells - Apoprotein C: modulate lipoprotein lipase (LPL) activity, which liberates FFAs and glycerol from lipoproteins - Apoprotein E: bind to receptors to allow removal of remnant particles from circulation

Answer 462

- AAs = VOMIT (valine, odd chain FAs, methionine, isoleucine, threonine) - 1.) deficiency in propionyl-CoA carboxylase resulting in propionic / propionyl acidemia - 2.) deficiency in racemase resulting in D-methylmalonyl aciduria - 3.) deficiency in mutase (or Vit B12, required as cofactor) resulting in methylmalonyl aciduria

Answer 463

- AST found at highest levels in liver, but also in other tissues including cardiac muscle - ALT abundant in liver - Both are normally low in serum - When tissues are damaged, these enzymes are released into the serum - Elevation of AST indicates liver disease, but also acute MI, kidney damage, pancreatitis etc. - Elevation of ALT is more specific indicator of liver damage

Answer 464

- Methylation of DNA occurs on cytosine residues in areas rich in CG known as CpG islands- CpG islands are found upstream of genes close to the 5’ region- Methylation acts to silence part of the genome

Answer 465

- SAM and THF

Answer 466

- Primary structure: peptide bonds - Secondary structure: H-bonding - Tertiary structure: Cystine disulfide bridges (from two cysteines), hydrogen bonding, ionic interactions (salt bridges), hydrophobic forces

Answer 467

- Microsomal ethanol oxidizing system. This is a P450 cytochrome system that is induced in chronic alcohol abuse and has a higher capacity to process alcohol. Activation of this system causes oxidation of NADPH and weakens the cellular antioxidant defense mechanisms.

Answer 468

- Without carnitine, FAs cannot be imported into mitochondria to be used as energy source. - Pts present as fasting non-ketotic hypoglycemia. Ketones are unusually low in blood or / and urine.

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