PROSITE documentation PDOC00320

Methylated-DNA--protein-cysteine methyltransferase active site

The major mutagenic and carcinogenic effect of methylating agents in DNA is the formation of O6-alkylguanine. The repair of DNA containing O6-alkylated guanine is carried out by the enzyme 6-O-methylguanine-DNA methyltransferase (EC 2.1.1.63) (methylated-DNA--protein-cysteine methyltransferase) (MGMT). The alkyl group at the O-6 position is transferred to a cysteine residue in the enzyme [1]. This is a suicide reaction: the enzyme is irreversibly inactivated and the methylated protein accumulates as a dead-end product. Most, but not all MGMT are also able to repair O-4-methylthymine. MGMT sequences have been obtained from various prokaryotic [2] and eukaryotic sources:

• Escherichia coli and Salmonella typhimurium inducible bifunctional protein ada. The N-terminal part of the ada protein functions as a transcriptional activator of its own gene and of other alkylation repair genes, while the C-terminal part functions as a MGMT.
• Bacillus subtilis adaB. In this bacteria the function of the ada complex is carried out by two proteins: adaA, a transcriptional activator, and adaB, a MGMT.
• Escherichia coli constitutive (non-inducible) Ogt enzyme.
• Bacillus subtilis constitutive (non-inducible) Dat1 enzyme.
• Yeast DNA repair enzyme MGT1.
• Mammalian MGMT protein [3].

In all these enzymes the region around the active site cysteine residue is conserved and can be used as a signature pattern.