Biochemistry: One-Carbon Transfer, B12, and SAM in DNA Synthesis

What are the three one-carbon carrier compounds?

Tetrahydrofolate (FH4), Vitamin B12, S-adenosylmethionine (SAM)

What is the primary one-carbon carrier?

Tetrahydrofolate (FH4)

What is the specialized cofactor in two major human reactions?

Vitamin B12 (cobalamin)

What is the major methyl donor?

S-adenosylmethionine (SAM)

How is FH4 different from B12 and SAM?

FH4 is the primary one-carbon carrier that can carry carbon groups at different oxidation states.

What is the most reduced form of FH4-bound carbon?

N5-methyl-FH4 (-CH3)

What is the most oxidized form of FH4-bound carbon?

N10-formyl-FH4 (-CHO)

What is the pathway that supplies dTMP for DNA synthesis?

dUMP + N5,N10-methylene-FH4 → dTMP + FH2

What enzyme catalyzes the conversion of dUMP to dTMP?

Thymidylate synthase

What is dihydrofolate and why is it produced?

Dihydrofolate (FH2) is produced when FH4 participates in the transfer/reduction of the one-carbon group.

What enzyme converts FH2 back to FH4?

Dihydrofolate reductase (DHFR)

What two inhibitors interrupt the dUMP to dTMP pathway?

5-Fluorouracil (5-FU) and Methotrexate

Why do sulfa drugs hurt bacteria but spare humans?

Bacteria must synthesize folate, whereas humans obtain folate from the diet.

What is the first B12-dependent reaction?

Transfer of methyl group from N5-methyl-FH4 to homocysteine to form methionine.

What is the second B12-dependent reaction?

L-methylmalonyl-CoA rearrangement by methylmalonyl-CoA mutase to form succinyl-CoA.

What is the consequence of B12 deficiency?

N5-methyl-FH4 becomes trapped, leading to functional folate deficiency and megaloblastic anemia.

What does SAM transfer?

A methyl (-CH3) group.

How is SAM synthesized?

From methionine and ATP.

What is the product of methylmalonyl-CoA mutase?

Succinyl-CoA

What happens to nucleotide synthesis in B12 deficiency?

It decreases due to the trapping of N5-methyl-FH4.

What is the memory rule for oxidation states of FH4?

Methyl = most reduced; Formyl = most oxidized.

What does 5-FU inhibit?

Thymidylate synthase

What does Methotrexate inhibit?

Dihydrofolate reductase (DHFR)

What is the classic trap regarding inhibitors?

5-FU inhibits thymidylate synthase; Methotrexate inhibits DHFR.

What is the methyl trap phenomenon?

B12 deficiency can produce a functional folate deficiency even when folate is present.

What are common SAM-dependent products?

Epinephrine, Creatine, Methylated nucleotides, Phosphatidylcholine, Melatonin.