O6-methylguanine-DNA methyltransferase (P140K) (MGMT P140K)

O6-methylguanine-DNA methyltransferase (P140K) is a mutant form of the human DNA repair enzyme MGMT, specifically engineered to contain a proline-to-lysine substitution at residue 140 (UniProt P09188). This modification is critical because it renders the enzyme nearly insensitive to O6-benzylguanine (O6-BG), a potent pseudo-substrate inhibitor that typically inactivates the wild-type protein (Reese et al., 2001, Blood). In therapeutic applications, MGMT P140K serves as a key component in chemoprotection strategies for patients undergoing intensive chemotherapy with alkylating agents like temozolomide or carmustine (Zielske et al., 2003, J. Clin. Invest.). By delivering the MGMT P140K gene into hematopoietic stem cells via viral vectors, the patient's bone marrow can be shielded from the myelosuppressive effects of these drugs (Adair et al., 2012, Science Translational Medicine). This allows for the simultaneous administration of O6-BG to deplete MGMT activity in tumor cells, thereby increasing their sensitivity to chemotherapy without causing lethal bone marrow failure. Consequently, MGMT P140K acts as both a protective transgene and a selectable marker for gene-modified cells in clinical oncology (NCT00674440). The enzyme functions by transferring the alkyl group from the O6 position of guanine to a cysteine residue within its own structure, a self-sacrificing mechanism that restores DNA integrity.

Other names

O6-alkylguanine-DNA alkyltransferase (P140K)AGT (P140K)P140K-MGMTMethylated-DNA--protein-cysteine methyltransferase (P140K)

The MGMT P140K mutant repairs O6-alkylguanine DNA lesions through a suicide mechanism while remaining resistant to the inhibitor O6-benzylguanine, thereby providing chemoprotection to engineered cells.