B₁₂/Folate Problem set

Question 4: A second reaction requiring B₁₂

Buildup of which metabolite in serum is a specific indicator of a vitamin B₁₂ deficiency?

A.	methylmalonic acid Methylmalonic acid is the form that shows up in the serum. Methylmalonyl CoA is the reactant of methylmalonyl CoA mutase, a B12-requiring enzyme, but its CoA is probably removed because it is used for other metabolic reactions and, anyway, CoA derivatives probably cannot even get out of the mitochondria, let alone the cell. Methylmalonic aciduria therefore is the result. The reason this is a good specific indicator of a B12 problem is that B12 is the only cofactor of this enzyme, while methionine synthase requires both folate and B12, confusing the issue. Turning to another matter, methylmalonic aciduria, whether due to B12 deficiency or even a specific defect of this enzyme, creates a secondary backup of propionyl CoA inside the cell (the immediate precursor to methylmalonate). Propionyl CoA, when at high concentration, may substitute for acetyl CoA in the citrate synthase reaction to form methyl citrate, a TCA cycle poison. Presumably, the severe consquences of this for neural tissue are due to its high oxidative demands. Now on to folate metabolism...
B.	methylmalonyl CoA
C.	N5-methyl THF
D.	methionine
E.	succinyl CoA