UW FMR Biochem Week 5

intrinsic factor (IF)

gastric parietal cells; allows absorption of B12

cyanide poisoning

forms cyanocobalamin (in addition to CytC disruption)

dihydrofolate reductase (DHFR)

folate → DHF → THF

methionine synthase

N5-Methyl-THF + Homocysteine + B12 → THF + Methionine

sequelae of B12 deficiency

methylmalonic acid in urine; homocystinuria

methylmalonyl CoA mutase

methylmalonyl CoA → succinyl CoA (needs B12)

geriatric decrease in intrinsic factor

elderly people may not absorb B12

long term reduced gastric acidity

proton-pump inhibitors prevent pepsin from releasing B12 from food

long term reduced gastric acidity

autoimmune attack on gastricl parietal cell H+/K+ ATPase or IF

atrophy of gastric mucosa

results in parietal cell deficiency; GI less acidic and less IF made

celiac disease

damage to intestinal lining can result in B12 deficiency

intestinal resection

lower ileum removal results in poor B12 absorption

thymidylate synthase

dUMP → dTMP (needs N5,N10-methylene-THF)

megaloblasts

lack of THF results in continued cell growth with inability to divide (DNA not replicated)

nitrous oxide toxicity (N₂O)

oxidizes cobalt in corrin ring of B12; inactivates B12 but does not lower its levels

methotrexate

inhibits DHFR

N10-formyl-THF

used in building purine ring on ribose

N5,N10-methylene THF

thymidine and serine synthesis

N5-methyl-THF

methionine synthesis from homocysteine

5-fluorouracil (5-FU)

inhibits thymidylate synthase

phosphoribosyl pyrophosphate synthase

converts ribulose-5-phosphate to phosphoribosylpyrophosphate (PRPP)

synthesis of purines

ring built on PRPP

synthesis of pyrimidines

ring built first, then attached to PRPP

inosine monophosphate (IMP)

purine precursor

adenylosuccinate synthase

inhibited by AMP; forms AMP from IMP

IMP dehydrogenase

inhibited by GMP; forms GMP from IMP

Gln-PRPP amidotransferase

forms phosphoribosylamine from PRPP and Gln

carbamoyl phosphate synthetase II (CPSII)

cytosolic enzyme; CO2 + NH3 + 2 ATP → urea

steps of UMP synthesis

carbamoyl phosphate → carbamoyl aspartate → dihydroorotate → orotate → OMP → UMP

viral thymidine kinase

not as specific as mammalian kinase; toxic nucleotide analogs preferentially incorporated into viral genomes

purine salvage pathways

readds purine rings to PRPP (HGPRT, adenine phosphoribosyltransferase)

consequences of purine salvage enzyme deficiency

overproduction of purines (increased PRPP stimualtes purine synthesis) → gout

adenosine deaminase deficiency

excess dATP levels disable RNR; results in severe combined immunodeficiency (SCID) because immune cells are rapidly dividing