Glucarpidase is an enzyme that has garnered significant interest in the scientific and medical communities due to its potential applications for disease treatment. This article covers the discovery, gene locus, protein structure, function, disease-related signaling pathways, associated pathology, and drug candidates related to Glucarpidase.
Background Information on Glucarpidase
Glucarpidase, also known as carboxypeptidase G2 (CPDG2), was originally identified from the bacteria Pseudomonas sp. strain Rs-16. Its characteristic ability is to catalyze the hydrolysis of glutamate residues from the carboxy-terminal ends of proteins and peptides.
The "CPDG2" gene, responsible for the coding of Glucarpidase, generally can be found located on the 9q34.13 locus in humans. Protein-wise, Glucarpidase encompasses 390 amino acids that form a structure comprising an alpha/beta hydrolase fold and a lid domain. The key features of this protein include two Zn2+ ions within its active site, which are essential for its function.
Glucarpidase Function
The primary function of glucarpidase is to break down folates, a type of vitamin B that is not naturally produced by the human body. These vitamins are essential for DNA synthesis and cell division. The unique function of glucarpidase is to metabolize the chemotherapeutic agent methotrexate (MTX) to its inactive metabolites, which are then more readily eliminated from the body. This mechanism is incredibly useful in the case of high-dose MTX therapy, where glucarpidase can be employed to rapidly reduce toxic MTX levels, thereby averting potential adverse effects.
Glucarpidase-Related Signaling Pathways
In terms of signaling pathways, glucarpidase isn't directly involved in cell signaling but is pertinent due to its interaction with MTX. MTX inhibits dihydrofolate reductase (DHFR), an enzyme involved in the synthesis of tetrahydrofolate, a co-factor in thymidylate and purine synthesis. This inhibitory action indirectly affects downstream signaling pathways crucial for DNA synthesis and cell division, thus having far-reaching implications in cellular growth and proliferation.
Glucarpidase-Related Diseases and its Role in Diseases
Glucarpidase has been predominantly linked with diseases related to MTX toxicity, typically associated with high-dose chemotherapy treatment. Conditions such as acute kidney injury and myelosuppression are commonly triggered by MTX toxicity. In these scenarios, glucarpidase can play a significant therapeutic role by quickly reducing MTX levels and alleviating the harmful implications.
Glucarpidase has also been studied in conjunction with tumor-targeting therapy where it has been found to possess the capability to convert a non-toxic prodrug into a toxic drug selectively at the tumor site.
The Application of Glucarpidase in Medicine
In the medical world, glucarpidase has been successfully used to manage MTX toxicity in patients undergoing chemotherapy. It has been successful in quickly reducing plasma MTX concentration, especially in patients with renal impairment. Its unique ability to convert a prodrug into a cytotoxic agent has also made it a promising tool in targeted anti-cancer therapy.
List of Drug Candidates Related to Glucarpidase
Voraxaze (generic name glucarpidase) is the most notable drug candidate linked to glucarpidase. Launched by BTG International Inc., this biologic response modifier has been approved by the U.S. Food and Drug Administration (FDA) for reducing toxic plasma methotrexate concentrations in patients with delayed methotrexate clearance.
Another drug candidate that has shown promise is CP-610, a CPDG2-antibody fusion protein. It is investigated as a prodrug-activating system for the treatment of malignancies that overexpress certain antigens.
In drug-to-antibody conjugates, glucarpidase has been used to convert the antibody-bound prodrug to an active cytotoxic agent selectively at the tumor site. This technique has shown potential in some pre-clinical cancer models.
