Folylpolyglutamate synthesis and role in the regulation of one-carbon metabolism.

The physiological importance of folylpolyglutamates is now well established. These derivatives are the intracellular substrates and regulators of one-carbon metabolism, and their synthesis is required for normal folate retention by tissues. Over the last few years, a considerable amount of information has been obtained on the mechanism by which these compounds are synthesized, on how this synthesis is regulated, and on the effects of the polyglutamate chain on the interaction of folate substrates and inhibitors with folate-dependent enzymes. Many regulatory implications have been suggested by these studies, but the physiological relevance of some of these observations remains to be explored. Folates in mammalian tissues are metabolized to polyglutamates of chain lengths considerably longer than that required for folate retention, but the metabolic advantages of this are not entirely clear. Several in vivo model systems have been developed to explore the functioning of specific folylpolyglutamate chain lengths in metabolic cycles of one-carbon metabolism, and these are likely to shed further light on this point. The role of folate-binding proteins in folate transport, the metabolic role of glutamylhydrolases, and the role of folylpolyglutamates in putative multifunctional protein complexes are also areas that are being actively pursued at present and are likely to produce new insights in the future. Recent studies on the retention of antifolates by cells and on their substrate efficacy for folylpolyglutamate synthetases have also suggested mechanisms for the differential cytotoxicity of these agents for different tissues.