B12 and Folate Flashcards
General structure of cobalmin
vit B12, corrin ring system, has colbalt (CO)
Cofactor and use of Metionine synthase
- methyl cobalamin
- used to resynthesize met from homocysteine, form tetrahydrofolate forms from metal tetrahydrofolate
- homocysteeine N-methyltransferase
Methylmalonyl-CoA mutase (MCM)
- uses 5’-deoxyadenosylcobalmin
- methylmalonyl-CoA—>succinyl-CoA
- for odd-chain fatty acid oxidation and metabolism of ile, val, thre, met (get converted to propionyl-CoA)
- propionyl-CoA (3 carbon product of odd-chain fatty acid β-oxidation) carboxylated to d-methylmalonyl-CoA (propionyl-coa carboxylase, biotin, atp, hco3-), which is converted to the L form by a specific epimerase, then MCM will work
SAM
- S-adenosylmethionine
- S-Adenosyl-methionine syntetase: L-Met + ATP–>SAM + Pi + PPi (requires Mg2+)
- used as a methyl group donor by methyltransferases (ex: norepinepherine–>epinephrine; PE–>PC; mRNA methylation (5’ cap)
- S-adenosylhomocysteins (SAH) is product of methyltranferase rxn
- SAH is degraded to L-homocysteine
Methionine synthase
- L-homocysteine + N5-methyltetrahydrofolate—>L-methioinine + tetrahydrofoalte
- requires methylcobalamin (Methyl-B12)
Methionine to cysteine
- S-Adenosyl-methionine syntetase: L-Met + ATP–>SAM + Pi + PPi (requires Mg2+)
- methyltransferase: SAM–>S-adenosylhomocysteine
- SAH + H2O –> homocysteine + adenosine
- cystathione β-synthase (B6/PLP): homocysteine + serine–>cystathionine + H2O
- γ-cystathionase (B6/PLP): cystathione + H2O—>cysteine + α-ketobutyrate + NH4+
Effect of B12 deficiency
- homocysteine cannot be recycled by methionine synthase and accumulates (homocysteinemeia)
- THF trapped in methyl-THF form
- inhibits purine synthesis and synthesis of dTMP which require other forms of THF (and thus DNA replication and transcription)
- accumulation of abnormal fatty acids–>CNS effects (irreversable)
- pernicious anemia (treat with lifetime IM cyanocobalamin injections)
- megaloblastic anemia (DNA systhesis of RBC precursors inibited, cells just grow since they can’t make it through M phase) (treat with folate and B12)–>anemia is reversable
- progressive peripheral neuropathy
- methlmaonyl acidura
- takes years to develop
Homocysteinemia/uria
•associated with B12, folate (methioinine synthase), or B6 deficiencies (cystationine synthetase and lyase/gamma cystathioininase)
- damages blood vessels and poses risk for thrombosis
- lipid oxidation and increased platelet aggregation–>fibrosis adn cacification fo aterosclerotic plaques
-hyperhomocysteinemia: homocystinuria caused by deficiency of cystationine synthase; lens dislocation after age 3 and other ocular abnormalities, osteoporosis in childhood, mental retardation, atheromas
Causes of B12 deficiency
- pernicious anemia–>lack of intrinsic factor due to autoimmunie destruction of parietal cells
- pure vegan diet
- chronic pancreatitis (can’t clave of R factor)
- chron’s disease (terminal ileal disease)
Uses of cystein metabolites
- cysteine dioxygenase: cys–>taurine (for bile salt synthesis)
- sulfate from catabolism used as precursor fo 3’-phosphoadenosine-5’-phosphosulfate (PAPS)—>glycolipid and GAG synthesis
Dietary sources of B12
animal sources, not in plants
Dietary ofurce of B9
- aka folic acid
- green leafy vegetables, liver, lima beans, whole-grain cereals
Important uses of B9
- active as forms of tetraydrofolate (THF) derivatives
- does carbon unit transfers
- purine and thymidine synthesis
- glycineserine
- synthesis of methionine from homocysteine
- degradation of histidine
Synthesis of folic acid
- done in bacteria and plants
- enzyme: dihydropteroate synthetase is inhibited competetively by sulfonamides (most are antibiotics)
Synthesis of THF
-Dihyrofolate reductase
Folic acid + 2 NADPH ——>THF + 2 NADP+
- Inhibited by methotrexate, used to treat neoplastic disesase, psoriasis adn rheumatoid arthritis
- 2 step reaction
- carbon units are carried by THF bound to N5 and/or N10
