Pteroylpolyglutamates

Abstract

Reduced derivatives of the vitamin pteroylglutamic acid (folic acid) are essential coenzymes for the biosynthesis of purine nucleotides, methionine, thymidylate and for many other enzyme catalyzed reactions involving the transfer, oxidation and reduction of single carbon units. Pteroylglutamic acid is found in tissues in the form of poly-gamma-glutamyl derivatives of varying chain length. The present review covers the detection, distribution, synthesis, degradation, coenzyme function and inhibitory activities of pteroyl-gamma-glutamates. The biosynthesis and inhibitory activities of poly-gamma-glutamyl derivatives of methotrexate, an analog of pteroylglutamic acid having antitumor activity, are also considered. An hypothesis on the coenzymatic role of pteroylpoly-gamma-glutamates in the coordination of sequential enzymatic steps in the metabolism of single carbon units is presented.

Chronic cobalamin inactivation impairs folate polyglutamate synthesis in the rat.

“…Pteroylpolyglutamates have been the subject of two recent reviews (27,28) but neither discuss the relation to cobalamin. In untreated pernicious anemia the fall in erythrocyte folate is due almost entirely to a fall in the predominant folate polyglutamate component (18,19).…”

Impaired Folic Acid Metabolism Leading to Increased Urinary Folate Loss in Streptozotocin-induced Diabetic Rats

“…These polyglutamyl forms of folate serve as more active cofactors, than their corresponding monoglutarnyl forms, in various one-carbon transfer reactions such as in the synthesis of nucleic acid precursors, for initiation of protein synthesis and in the metabolism of certain amino acids (2). The role of polyglutamyl folates in the one-carbon metabolism has recently been reviewed (3).…”

Different Antifolate-resistant L1210 Cell Variants with either Increased or Decreased Folylpolyglutamate Synthetase Gene Expression at the Level of mRNA Transcription

“…Their metabolism to polyglutamates and that of folate analogues are mediated (1)(2)(3)(4)(5) by the enzyme, folylpolyglutamate synthetase (FPGS), 1 and metabolic turnover of these anabolites appears to be modulated by folylpolyglutamate hydrolase after their mediated entry into lysosomes (for review, see Ref. 6).…”

“…The process of folylpolyglutamylation in normal proliferative and neoplastic mammalian tissues is important (1)(2)(3)(4)(5) to the conservation and efficient utility of folate coenzymes that are required for one-carbon transfer reactions during macromolecular biosynthesis. Consequently, levels of FPGS activity appear to be highest in the proliferative fraction of normal differentiating tissues (7,(17)(18)(19).…”

“…20 -23) that normal proliferative and tumor cells might control their macromolecular synthesis through regulation of intracellular folate homeostasis. In addition to the biosynthesis and metabolic interconversion of these compounds (20,21), folate homeostasis could also be regulated at the level of mediated entry of exogenous folate (23) and/or through biosynthesis of folylpolyglutamates (1)(2)(3)(4)(5). With the recent derivation (24) of the cDNA for human FPGS, studies addressing this issue at the level of FPGS gene expression and its regulation are now possible.…”