Folate, Vitamin B₁₂, and Vitamin B₆

Abstract

Editorial Changes in erythropoiesis associated with aging have been described in both humans and animals, yet in transplantation models marrow cells from old donors function as well as cells from young donors (1). This suggests that factors extrinsic to the hematopoietic stem cell may affect erythropoiesis in the elderly. Many nutritional factors are required to support erythropoie-sis, but three essential vitamins stand out: vitamin B12 (cyanoco-balamin), folic acid, and vitamin B6 (pyridoxine) (2). Vitamin B12 and folic acid are required to maintain the high rate of DNA synthesis in the erythron. Vitamin B6 functions as a coenzyme in a wide variety of reactions, most of which involve amino acid metabolism. The primary role of vitamin B6 in erythropoiesis is as a cofactor (pyridoxal phosphate) in the formation of amino-levulinic acid, the first and rate-limiting step in the heme biosyn-thetic pathway. Several inherited disorders respond to pharma-cologic doses of pyridoxine, even though pyridoxine deficiency is not present. These disorders include cystathioninuria, homo-cystinuria, xanthurenic aciduria, and pyridoxine-responsive sid-eroblastic anemia. In this issue of The Journal, Cotter and colleagues describe two elderly patients who were initially thought to have acquired sideroblastic anemia, a relatively common myelodysplastic disorder (3). These patients differed from the usual in that the anemia was microcytic rather than macrocytic. Both patients demonstrated striking responses to the administration of pyri-doxine. In both cases, point mutations in the erythroid-specific form of 6-aminolevulinate synthase were identified. The mutations rendered recombinant mutant proteins markedly unstable. Stability was made normal by the addition of pyridoxal phosphate in an in vitro system. A microcytic sideroblastic anemia was not apparent until the eight and ninth decade in these two cases, strongly suggesting that an age-related alteration in vitamin B6 metabolism was responsible for full expression of the phenotype. Several recent studies have indicated that deficiencies of vitamin B6, as well as vitamin B12 and folate, occur commonly in elderly people (4, 5). These studies used measurements of methylmalonic acid, homocysteine, 2-methylcitric acid, and cystathionine to demonstrate vitamin-limited enzymatic reactions even when serum vitamin concentrations were normal. Abnormal concentrations of these metabolites were corrected by the administration of vitamin supplements (5). Subtle alterations in vitamin B6 availability or metabolism related to age might not be associated with a clinical phenotype unless a mutation is present in a gene that encodes a protein highly dependent upon the normal availability of pyridoxal phosphate. The role of coenzyme in determining the intracellu-lar content of pyridoxal-dependent aminotransferases has been studied (6). The tertiary structure of the protein appears to be the major determinant of intracellular degradation. Presumably, the structure of the mutant 8-arninolevulinate sy...