Carboxypeptidase G

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Introductions

Carboxypeptidase G2 is 42 kDa zinc-dependent metalloenzyme obtained from Pseudomonas aeruginosa using recombinant gene technology, which can catabolize folic acid and its analogues into glutamic acid and another compound. CPG2 has been widely used as an MTX detoxifying agent because of its high affinity for methotrexate (MTX) and its ability to rapidly alleviate MTX-induced nephrotoxicity. On the other hand, CPG2 can be combined with antibody-directed or gene-directed technologies to achieve targeted tumor therapy in combination with non-toxic prodrugs.

Source and distribution

According to the source classification, carboxypeptidases can be divided into animal carboxypeptidases, plant carboxypeptidases and microbial carboxypeptidases. A series of metallo-carboxypeptidases are contained in different blockages of mammals to perform the corresponding physiological functions. For example, pancreatic carboxypeptidases A and B mainly help to digest food, carboxypeptidase E selectively processes. Bioactive peptides, carboxypeptidase M is selectively involved in the processing of peptide hormones, and carboxypeptidase D (in Golgi) and carboxypeptidase N (in plasma) are involved in the processing of peptides and proteins. Studies on animal-derived carboxypeptidases. The main focus is on human, pig, bovine, and small house mouse.

Mechanism of Action of CPG2

Folic acid plays a key role in DNA synthesis and cell replication. MTX enters the cell with an affinity 1,000 times greater than that of folic acid and is the first to bind to DHFR, competitively inhibiting its conversion to THF and causing the cell to lose its ability to divide and produce protein. MTX has the greatest effect on rapidly dividing cells. It has been shown that the carboxypeptidase family, which catabolizes folic acid and its analogs, can be used to break down excess MTX in the body, and that CPG2 of this family has a specific affinity for MTX and rapidly metabolizes MTX in the circulatory system to glutamate and 2,4-diamino-N10-methylpteroic acid.

CPG2 in targeted pre-drug therapy

• Antibody-directed enzyme prodrug therapy

Antibody-directed enzyme prodrug therapy is a system that uses the principle of antigen-antibody recognition and binding to chemically couple tumor-specific antibodies to CPG2 and direct them to the tumor site to convert a non-toxic nitrogen mustard prodrug into a cytotoxic drug to specifically kill tumor cells). Currently, the system is in clinical trials.

• Gene-directed enzyme prodrug therapy

Gene-directed enzyme prodrug therapy (GDEPT) is the introduction of a gene encoding a "suicide enzyme" into tumor tissue to express the CPG2 enzyme, which selectively converts non-toxic prodrugs into cytotoxic drugs in tumor tissue, but not in normal tissue (Figure 2). This method converts the CPG2 gene into a cytotoxic drug in tumor tissue, but not in normal tissue. This method encodes the CPG2 gene into tumor tissues and converts the non-toxic nitrogen mustard prodrug into a potent DNA cross-linking agent for the purpose of killing tumor cells. This system is currently in the clinical phase.

• Ligand-directed enzyme prodrug therapy

In a ligand-directed enzyme prodrug therapy (LDEPT) strategy, CPG2 is directed to the tumor site via a protein or peptide ligand, converting a non-toxic nitrogen mustard prodrug into a cytotoxic drug that causes cancer cell death.