Methionine gamma-lyase (MGL) (MGL)

Methionine gamma-lyase (MGL) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that plays a crucial role in the catabolism of sulfur-containing amino acids by catalyzing the alpha,gamma-elimination of L-methionine and its analogs (UniProt: P13254). This enzyme is notably absent in humans but present in various bacteria, fungi, and protozoa, which makes it an attractive target for both antimicrobial and anticancer drug development (PubMed: 28651551). In the context of oncology, MGL is utilized to exploit the methionine dependence of many tumor cells, a phenomenon known as the Hoffman effect, where cancer cells fail to proliferate under methionine-restricted conditions (PubMed: 15595151). Therapeutic approaches include the administration of recombinant MGL (often called methioninase) to deplete systemic methionine levels or the use of MGL to convert non-toxic prodrugs into lethal metabolites within the target cells (PubMed: 30153431). Research continues to focus on improving the enzyme's stability and reducing its immunogenicity through PEGylation to enhance its clinical utility. The enzyme's active site utilizes the PLP cofactor to facilitate the cleavage of carbon-sulfur bonds in substrates like methionine and homocysteine. By targeting this specific metabolic vulnerability, MGL-based therapies aim to selectively starve cancer cells while minimizing impact on normal physiology.

Other names

MethioninaseMETaseL-methionine gamma-lyaseL-methionine methanethiol-lyase (deaminating)

Depletion of systemic L-methionine to induce methionine starvation in methionine-dependent cancer cells; enzymatic conversion of prodrugs into cytotoxic metabolites.