Defective leukocyte metabolism in human cobalamin deficiency: impaired propionate oxidation and serine biosynthesis reversible by cyanocobalamin therapy.

Biochemical disturbances common to vitamin B12 and folate deficiency were investigated in leukocytes from patients with cobalamin deficiency. The investigations focused on the only two human metabolic pathways known to require vitamin B12. In the propionate pathway, deoxyadenosylcobalamin is required for isomerization of methylmalonyl-CoA to succinyl-CoA. Leukocyte oxidation of 14C-propionate to 14CO2 was markedly decreased in 9 patients with Addisonian cobalamin deficiency and 2 patients with low serum cobalamin associated with folate deficiency, whereas 14C-succinate oxidation was normal. Three of the Addisonian patients had only minimal anemia. Within 4 days after one injection of 1,000 mug of cyanocobalamin, in 7 out of 8 patients studied, leukocyte propionate oxidation increased to normal levels. In folate-mediated one-carbon metabolism, as measured by serine biosynthesis from formate, methylcobalamin is required for conversion of methyl-folate to tetrahydrofolate. Leukocyte formation of 14C-serine from 14C-formate was significantly depressed in 5 patients with low serum cobalamin, little or no anemia, and only marginally low total red cell folate, the low serum cobalamin in 2 of these patients was associated with folate deficiency. After 1,000 mug of cyanocobalamin, in 2 of 3 patients, leukocyte serine biosynthesis increased to the normal range. These observations demonstrated that these two metabolic pathways in leukocytes were sensitive to cobalamin deficiency, and responsive to cobalamin therapy. Although there was no correlation between either of these metabolic activities and the serum cobalamin, red cell folate, or hematocrit, there was a striking correlation between impairment of leukocyte propionate oxidation and of leukocyte serine biosynthesis in 5 patients who were minimally anemic. The remarkably close correspondence between effects of low cobalamin on these two metabolic pathways, in nonanemic patients, must be a direct consequence of their common requirements for a cobalamin co-enzyme. These findings emphasize the importance of cobalamin in folate metabolism, and are consistent with the hypothesis that folate is "trapped" as methyl-folate in cobalamin deficiency, but do not exclude the possibility that this "trapping" is caused by a third metabolic function of cobalamin which might mediate transport of folate into cells.