Review Question - QID 100077

Vitamin B12 (cobalamin) is a necessary cofactor for the enzyme methylmalonyl CoA mutase, which isomerizes methylmalonyl CoA into succinyl CoA, an intermediate of the TCA cycle. Therefore, Vitamin B12 deficiencies lead to a build up of methylmalonic acid, a downstream product of methylmalonyl CoA.

Valine, isoleucine, methionine, and threonine are amino acids that can be converted into intermediates of the TCA cycle through the production of propionyl CoA. Using biotin as a cofactor, propionyl CoA is then converted into methylmalonyl CoA. If the downstream enzyme methylmalonyl CoA mutase is lacking B12 cofactor, serum and urine methylmalonic acid levels will increase. Clinically, B12 deficiency presents as a macrocytic, megaloblastic anemia in a patient with complaints of paresthesias and gait abnormalities. Even with B12 supplementation, neurologic sequelae may be irreversible.

Langan and Zawistoski indicate that B12 is needed for 2 reactions. The first is conversion of methylmalonyl CoA to succinyl CoA, in which a deficiency leads to a build up of methylmalonic acid in plasma and urine. In the second reaction, homocysteine is converted to methionine with both B12 and folate serving as cofactors. Therefore, B12 deficiency is associated with elevated serum levels of both methylmalonic acid and homocysteine.

Stabler discusses strategies for diagnosis and evaluation of vitamin B12 deficiency. Measurement of serum B12 level is typically the first line approach despite the fact that false negative and positive tests can occur up to 50% of the time. Serum levels of methylmalonic acid and homocysteine will be elevated in the majority of patients with B12 deficiency, even if they do not have anemia. These levels decrease after B12 supplementation.

Illustration A depicts the synthesis of succinyl-CoA from methylmalonyl-CoA. Without the necessary B12 cofactor, methylmalonyl-CoA is not converted to succinyl-CoA and is instead diverted to methylmalonic acid.

Incorrect Answers:
Answer 1: Vitamin C is needed for the hydroxylation of proline and lysine in collagen synthesis. Deficiency leads to scurvy.
Answer 2: Vitamin B1 (AKA thiamine) is a cofactor for decarboxylation enzymes including pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. Deficiencies can lead to Beriberi or Wernicke-Korsakoff syndrome.
Answer 4: Biotin is a cofactor for carboxylation enzymes. While rare, deficiency is associated with excessive ingestion of raw eggs and presents with dermatitis and alopecia.
Answer 5: Folic acid is needed for the synthesis of DNA and RNA nitrogenous bases. Deficiency presents as a macrocytic, megaloblastic anemia.