Folylpolyglutamate synthase (FPGS)

Folylpolyglutamate synthase is an ATP-dependent enzyme responsible for the addition of multiple glutamate residues to the gamma-carboxy group of folate and its derivatives, a process known as polyglutamylation. This modification is essential for retaining active forms of folates within cellular compartments—particularly in proliferating cells—and supports critical metabolic processes like one-carbon transfer reactions required for nucleotide biosynthesis. The enzyme plays a central role in both cytosolic and mitochondrial pools of polyglutamated folates, impacting cell survival and growth. In cancer therapy, the activity level of FPGS influences the effectiveness of antifolate drugs because these agents must be polyglutamated to remain active inside target cells. Defects or altered expression in this enzyme can disrupt normal cell function or reduce drug efficacy.

Other names

Folylpolyglutamyl synthetaseFolylpoly-gamma-glutamate synthetaseTetrahydrofolate synthaseTetrahydrofolylpolyglutamate synthase

Drugs such as antifolates act as competitive inhibitors by mimicking tetrahydrofolate structure; their effectiveness depends on polyglutamylation by FPGS to increase retention and potency inside cells