Folate metabolism in humans.

Abstract

AbstractSeveral lines of evidence have linked flate metabolism to the expression of the fragile site at Xq27. Sutherland (1979) observed that expression of this marker depends on the composition of the culture medium and that deficiency of folic acid and thymidine promotes expression of the fragile site in lumphocytes, as does the addition of methotrexate. Several investigators (Glover, 1981; Tommerup et al, 1981) independently showed that expression of the fragile site can be elicited by adding 5‐fluorodexyuridine, an inhibitor of thymidylate synthase to culture medium containing folic acid but not thymidine. Indeed, Lejeune (1981) has claimed sucessful treatment of males with fragile X syndrome, the administration of folic acid and folinic acid (5‐formyltetrahydrofolate) leading to decreased expression of the Xq27 fragile site and greatly reduced aggressiveness. These and other studies have stimulated persons of diverse backgrounds to ocnfront complicated aspects of folate metabolism. The information that follows is intended to facilitate discusion and investigation in the context of the fragile X syndrome.The history of folic acid can be said t date from the description by Channing in 1842 of severe, rapidly progressive and sometimes fatal anemia of pregnancy. In a series of studies begun in 1930, Lucy Wills observed that the diets of mothers of premature infants in India were usually markedly deficient in a vitamin that later proved ot be folic acid. Folic acid was first isolated and specifically maned in 1941 by investigators who prepared it from spinach leaves. It was first synthesized in 1946 and given the chemical designation pteroylglutamic acid. Syntheitic folic acid is now prepard in commercial quantities but is an unnatural substance. Biologically active folates are derivatives of tetrahydrofolate (THF) shown in Fig. 1. The has three major components, namely, the pteridine ring, the p‐aminobenzoate protion and an L‐glutamyl residue. The similarity of the sulfonamides ot the aminobenzoate protion of THF is the basis for the lethal effects sulfonamides have on microorganinsms, this treatment interfering with synthesis of folates. THF is the parent compound of all biologically active folates and is simply folic acid reduced on the pteridine ring at positons 5,6, 7 and 8 (Fig. 1). Two protions of the THF molecule are especially important to its functions. The nitrogen atoms at positions 5 or 10 or both carry the substituents that make up the one‐carbon pool. Of these compounds, 5‐methylTHF is the main serum and tissue form of folate, while, in most tissues, there are in addition lesser amounts of 10‐formylTHF and still smaller amounts of 5,10‐methyleneTHF, THF itself and other folate compounds. Very few of these folates are stable enough to be useful under clinical and cell folinic acid or leucovorin. This stable folate can be prepared in large quantities and can be given t patients orally or parenterally.