Methylated-DNA–protein-cysteine methyltransferase

Methylated-DNA–protein-cysteine methyltransferase (MGMT), also known as O6-alkylguanine DNA alkyltransferase AGT, is a protein that in humans is encoded by the MGMT gene.

MGMT is crucial for genome stability. It repairs the naturally occurring mutagenic DNA lesion O6-methylguanine back to guanine and prevents mismatch and errors during DNA replication and transcription. Accordingly, loss of MGMT increases the carcinogenic risk in mice after exposure to alkylating agents.

Bacteria also use enzymes of this kind to protect their DNA. In E. coli, there are two versions (isozymes): Ada and Ogt.

Function and mechanism

Although alkylating mutagens preferentially modify the guanine base at the N7 position, O6-alkyl-guanine is a major carcinogenic lesion in DNA. This DNA adduct is removed by the repair protein O6-alkylguanine DNA alkyltransferase through an SN2 mechanism. This protein is not a true enzyme since it removes the alkyl group from the lesion in a stoichiometric reaction and the active enzyme is not regenerated after it is alkylated (referred to as a suicide enzyme). The methyl-acceptor residue in the protein is a cysteine.

→

M

G

M

T

{\displaystyle \mathrm {\ {\xrightarrow {MGMT}}} }

Demethylation of 6-O-methylguanosine to Guanosine

Clinical significance

In patients with glioblastoma, a severe type of brain tumor, the cancer medicine temozolomide is more effective in those with a methylation of the gene's promoter. Overall, MGMT methylation is associated with prolonged patient survival in clinical prediction models.