O-6-methylguanine-DNA methyltransferase (MGMT) (MGMT)

O-6-methylguanine-DNA methyltransferase (MGMT) is a specialized DNA repair enzyme that provides the primary defense against O6-alkylguanine adducts, which are highly mutagenic and cytotoxic [UniProt P16455]. It operates via a direct reversal mechanism where it transfers the alkyl group from the DNA to a cysteine residue (Cys145) in its own active site [PubMed: 25103512]. This process is stoichiometric and leads to the irreversible inactivation of the enzyme, often referred to as suicide inhibition [StatPearls: NBK559134]. In clinical oncology, MGMT expression is a major determinant of resistance to alkylating agents like temozolomide, especially in glioblastoma multiforme [NCBI: PMC3078540]. Epigenetic silencing of the MGMT gene through promoter methylation is a well-established biomarker that predicts a favorable response to chemotherapy and improved overall survival [PubMed: 15758003]. Therapeutic strategies have focused on using MGMT inhibitors to deplete the enzyme in resistant tumors, although this approach is limited by increased systemic toxicity [PubMed: 17008439].

Other names

O6-alkylguanine-DNA alkyltransferaseMethylguanine-DNA methyltransferaseAGTAGAT6-methylguanine-DNA methyltransferase

MGMT inhibitors act as pseudo-substrates that covalently bind to the active site cysteine residue, leading to irreversible inactivation and degradation of the MGMT protein (suicide inhibition), which prevents the repair of chemotherapy-induced DNA damage [PubMed: 11560118].