Gamma-glutamyl hydrolase (GGH) (GGH)

Gamma-glutamyl hydrolase (GGH) is a lysosomal enzyme that plays a critical role in folate homeostasis by catalyzing the removal of gamma-linked polyglutamate tails from both natural folates and antifolate drugs like methotrexate (Source: UniProt Q92820). By converting long-chain polyglutamates into shorter forms or monoglutamates, GGH facilitates their efflux from the cell, thereby regulating the intracellular concentration of these essential cofactors (Source: NCBI Gene 8836). In the context of oncology, GGH is a significant determinant of drug resistance; high levels of GGH mRNA and protein expression are associated with reduced accumulation of active methotrexate polyglutamates, leading to decreased efficacy in treating conditions such as acute lymphoblastic leukemia and various solid tumors (Source: PMID: 11502515). Consequently, GGH mRNA has emerged as a therapeutic target for RNA interference (RNAi) or antisense strategies aimed at silencing the gene to restore sensitivity to antifolate chemotherapies (Source: PMID: 15150115). Beyond cancer, GGH activity is also relevant in inflammatory diseases like rheumatoid arthritis, where it influences the therapeutic response to low-dose methotrexate (Source: PMID: 21642383). The enzyme's ability to modulate the polyglutamylation state of antifolates makes it a key focus for improving the precision and efficacy of folate-based treatments.

Other names

Folylpolyglutamate hydrolaseConjugaseGHGamma-Glu-X carboxypeptidaseGamma-glutamyl hydrolase mRNA

GGH catalyzes the hydrolysis of the gamma-glutamyl bond in folylpolyglutamates and antifolylpolyglutamates, converting them into monoglutamates or shorter-chain polyglutamates to facilitate cellular efflux and regulate the activity of folate-dependent enzymes.