Folate & B12 metabolism

Question 1

3 major carrier molecules for 1-carbon metabolism

Answer 1

• THF
• methycobalamin
• SAM: methylation rxn

Question 2

B12 essential for 2 rxn

Answer 2

• Homocysteine methyltransferase aka methionine synthase: converts Homocysteine -> Methionine
• Methylmalonyl CoA mutase: converts Methylmalonyl CoA -> Succinyl CoA

Question 3

Methyl trap

Answer 3

• Homocysteine methyltransferase aka methionine synthase: converts Homocysteine -> Methionine
• requires both B12 & folate
• a defect in enzyme or B12 def. will lock the relatively small amount of intracell THF in stable methylTHF state and cause a deficiency of other THF intermediates

Question 4

B12 deficiency

Answer 4

• pernicious anemia & megaloblastic anemia
• methyl & folate trap
• could result from dietary deficiency (vegetarians) or diseases of the ileum
• Dx:
  
  • Hyperhomocysteinemia: increased risk of cardiovascular disease
  • methylmalonate in urine
• Neuropsych sx
  
  • myelin degeneration in both motor & sensory pathways due to methylmalonyl CoA accumulation
  • irreversible
  • megaloblastic anemia should never be treated with folic acid alone. Ideal rx is a combo of folate & B12 till definite cause of anemia is established

Question 5

Formation of THF

Answer 5

• folate cannot be synthesised by humans as we do not have Dihydropteroate Synthase, which is present in bacteria
• Sulphonamides block Dihydropteroate Synthase
• active form of folic acid: THF
• THF serves as a reversible carrier of methyl, formyl, methylene & methenyl groups (1-C)
• imp for pyrimidine synthesis synthesis
• Dihydropteroate Reductase: converts folate -> dihydrofoalte
• Dihydrofolate Reductase: converts dihydrofolate -> tetrahydrofolate
• methotrexate & trimethoprim inhibits Dihydrofolate Reductase

Question 6

3 different forms of THF

Answer 6

• Formyl THF & Methylene THF used for synthesis of purines & thymidine
• Methyl THF: cannot be converted to other forms, i.e. storage forms

Question 7

Folate trap

Answer 7

• methyl THF can be converted to THF only in presence of B12
• B12 deficiency, all cell folate is trapped as methyl THF
• Methyl THF cannot be converted to other forms of THF (irreversible rxn)

Question 8

Folate deficiency

Answer 8

• megaloblastic anemia
• macrocytes in peripheral blood smears & megaloblasts in bone marrow
• FiGLU excreted

Question 9

2 fates of Homocysteine

Answer 9

• conversion to Cystathione: requires Cystathione synthase & PLP
• conversion to Methionine: requires methyB12 & methyTHF

Question 10

Significance of homocysteine

Answer 10

• elevated plasma homecysteine
  
  • oxidative damage
  • inflammation
  • endothelial dysfunction
  • neurological manifestations: seizures
• Homocystinuria
  
  • inherited disorder: AR
  • defect in Cystathione Synthase
  • Sx: premature vascular disease, neuro sx, MSK sx, Marfan-like habitus