γ-Glutamyl hydrolase

Glucarpidase is a recombinant carboxypeptidase G2 produced by genetically modified Escherichia coli bacteria. It is a 390-amino acid homodimer protein. High-dose [methotrexate], an antifolate agent, has been widely and safely used for many decades in treating various cancers; however, even with aggressive hydration, urine alkalinization, and leucovorin rescue, some patients still develop high-dose methotrexate-induced nephrotoxicity. This can lead to delayed renal clearance of methotrexate and elevated drug plasma levels, increasing the risk of methotrexate toxicity. After the discovery of certain bacteria with the capacity to inactivate folate analogs such as methotrexate, carboxypeptidase G was identified and Carboxypeptidase G1 was first isolated from Pseudomonas stutzeri in 1967. In 1983, the gene for carboxypeptidase G2, or glucarpidase, was derived from Pseudomonas sp. strain RS-16 to be cloned into Escherichia coli, allowing the enzyme to be produced in sufficient quantities for therapeutic purposes. Glucarpidase is an enzyme that can rapidly hydrolyze methotrexate into its nontoxic metabolites. It prevents methotrexate toxicity in patients with renal dysfunction who are undergoing high-dose methotrexate treatment, as it provides an alternative non-renal pathway for methotrexate elimination. Glucarpidase was first approved by the FDA in January 2012, followed by the European Commission's approval in January 2022. It is marketed as VORAXAZE.