B12 and Folate Flashcards Preview

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Flashcards in B12 and Folate Deck (20):
1

General structure of cobalmin

vit B12, corrin ring system, has colbalt (CO)

2

Cofactor and use of Metionine synthase

•methyl cobalamin
•used to resynthesize met from homocysteine, form tetrahydrofolate forms from metal tetrahydrofolate
•homocysteeine N-methyltransferase

3

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

4

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

5

Methionine synthase

•L-homocysteine + N5-methyltetrahydrofolate--->L-methioinine + tetrahydrofoalte
•requires methylcobalamin (Methyl-B12)

6

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+

7

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

8

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

9

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)

10

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

11

Dietary sources of B12

animal sources, not in plants

12

Dietary ofurce of B9

-aka folic acid
-green leafy vegetables, liver, lima beans, whole-grain cereals

13

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

14

Synthesis of folic acid

-done in bacteria and plants
-enzyme: dihydropteroate synthetase is inhibited competetively by sulfonamides (most are antibiotics)

15

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

16

SerineGlycine

Serine hydroxymethyltransferase catalyzes:
Ser + THF Gly + N5, N5-methyleneTHF

17

Histidine degradation

1. Histidase: his--->urocanic acid + NH3
2. some more steps
3. Formiminotransferase cyclodeaminase: N-Formimoglutamate (FLGlu) + THF ----> 5-Formimino-THF + glutamate

18

N-Formimoglutamate

-intermediate in histidine degragation
-gives formimino group to THF forming glutamate
-elevated following ingestion of large dose of histidine in Folic acid deficiency
-FLGlu excretion test used to diagnose deficiency of folic acid

19

Histidinemia

-caused by deficiency of histidinase
-his--->urocanic acid + NH3

20

Causes and effects of Folate deficiency

-diet lacking in fruits and vegetables
-chemotheraputics like methotrexate or trimethoprim which are dihydrofolate reductase inhibitors-->prevent purine and thymidine synthesis-->kill blast cells and acuse macrocytic anemia
-phenytoin (inhibits intestinal conjugase)
-oral contraceptives (inhibits absorption of monoglutamate in jejunum)
-alcohol (block absorption)
-rapidly growing cancers (use more folic acid than normal cells)
-small bowel malabsorption (i.e: celiac)
-sulfa drugs (sulfanilamide) inhibit folic acid synthesis by intestinal flora

-most common in pregnant women (linked with neural tube defects) and alcoholics (important too in malnourished individuals)

-deficiency causes homocystinuria/emia and megaloblastic anemia
-develops in 3-4 months
-increased cardiovascular disease risk