Carboxypeptidase G2 (CPG2)

Carboxypeptidase G2 (CPG2) is a **bacterial zinc-dependent exopeptidase** originally derived from *Pseudomonas sp.* strain RS-16, and has no human homolog[1][2][5]. It catalyzes the hydrolysis of the C-terminal glutamic acid from folic acid and its analogues, such as methotrexate, yielding inactivated or less toxic products[1][5][6]. Clinically, CPG2 has two primary uses: as the drug **glucarpidase** (Voraxaze), it is administered to rapidly lower toxic methotrexate plasma levels in patients with impaired renal function[2][7]; as an enzyme/prodrug component in **antibody-directed enzyme prodrug therapy (ADEPT)**, it is conjugated to tumor-targeting antibodies to localize activation of cytotoxic drugs to cancerous tissues, thus increasing specificity and reducing systemic toxicity[3][4]. The enzyme is a dimeric protein with a catalytic domain containing two zinc ions at the active site[1]. Notable challenges include potential immunogenicity, limited window for safe prodrug administration, and risk of off-target toxicity due to enzyme leakage or systemic drug activation[3][4][7].

Other names

GlucarpidaseFolate hydrolase G2Glutamate carboxypeptidasePteroylmonoglutamic acid hydrolase G2CPDG2

Hydrolysis of peptide bond in folates/antifolates to inactivate methotrexate or activate chemotherapeutic prodrugs[2][7]