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Lack of dihydrofolate reductase activity in brain tissue of mammalian species: possible implications 1
Author(s) -
Makulu D. R.,
Smith E. F.,
Bertino J. R.
Publication year - 1973
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1973.tb04244.x
Subject(s) - dihydrofolate reductase , enzyme , transferase , methyltransferase , biochemistry , serine , metabolism , cofactor , thymidylate synthase , biology , methylation , chemistry , gene , genetics , cancer , fluorouracil
IT IS becoming increasingly clear that folates play a vital, yet until recently an unrecognized, role in the development and function of the brain. Thus several groups of patients have been found with severe maldevelopment of the brain and mental retardation associated with inborn errors of folate metabolism resulting from congenital deficiency in one or more enzymes involved in folate metabolism (ARAKAWA et al ., 1965; 1966; 1967; MUDD, LEVY and ABELES, 1969; ARAKAWA, 1970). The presence of folate coenzymes in brain tissue has been reported by several investigators (ALLEN and KLIPSTEIN, 1970; MCCLAIN and BRIDGERS, 1969). MCCLAIN and BRIDGERS (1969) showed that much less of the folates in brain are in the form of the N5‐methyl derivatives than is the case for folates in plasma, red blood cells and liver. Appreciable activity of several folate interconverting enzymes have been demonstrated in brain tissue; for example, N5‐methyl tetrahydrofolate homocysteine methyl transferase has been found to exist in higher levels in brain than in liver or kidney (MANGUM, 1972); N5‐methyl FH,N‐dimethyl‐dopamine methyl transferase (LADURON, 1972) and serine transhydroxymethylase (EC 2.1.1; L‐Serine: tetrahydrofolate 5, 10‐hydroxymethyl transferase) (BRIDGERS, 1968) have recently been detected in brain. The last enzyme is known to catalyse a reaction responsible for the generation of a major portion of one‐carbon units. In mouse brain, the activity of this enzyme declines during the first 2 weeks of extra‐uterine life (BRIDGERS, 1968). The aim of the present study was to determine the levels of dihydrofolate reductase(5,6,7,8‐tetrahydrofolate:NADP+ oxidoreductase; EC 1.5.1.3) in mammalian brain tissues in comparison to the levels in other tissues. This enzyme occupies the first and key position in folate metabolism, reducing the metabolically inert vitamin, folic acid, to tetrahydrofolate. This enzyme also functions in thymidylate synthesis to regenerate tetrahydrofolate from dihydrofolate, a product of the reaction (HWHREYS and GREENBERG, 1958). In this reduced state the molecule can accept one‐carbon units from various sources to give rise to metabolically active coenzyme forms of folate. This communication reports the complete absence of dihydrofolate reductase in brain tissue of several mammalian species.