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Enzyme Name | UniProtKB | KEGG |
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| P16455 |
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Protein name | Methylated-DNA--protein-cysteine methyltransferase | methylated-DNA---[protein]-cysteine S-methyltransferase |
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Synonyms | EC 2.1.1.636-O-methylguanine-DNA methyltransferaseMGMTO-6-methylguanine-DNA-alkyltransferase |
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Pfam | PF01035 (DNA_binding_1) PF02870 (Methyltransf_1N) [Graphical view]
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UniProtKB:Accession Number | P16455 |
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Entry name | MGMT_HUMAN |
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Activity | DNA (containing 6-O-methylguanine) + protein L-cysteine = DNA (without 6-O-methylguanine) + protein S-methyl-L- cysteine. |
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Subunit |
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Subcellular location | Nucleus. |
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Cofactor | Binds 1 zinc ion. |
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Compound table: links to PDB-related databases & PoSSuM |
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| Substrates | Products |
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KEGG-id | C04250 | C02743 | C00039 | C03800 |
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Compound | DNA containing 6-O-methylguanine | Protein cysteine | DNA | Protein S-methyl-L-cysteine |
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Type | amine group,carbohydrate,nucleic acids | peptide/protein,sulfhydryl group | nucleic acids | peptide/protein,sulfide group |
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ChEBI |
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PubChem |
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1eh6A01 |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound |
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1eh7A01 |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound |
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1eh8A01 |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound |
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1qntA01 |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound |
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1eh6A02 |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound |
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1eh7A02 |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Bound:SMC |
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1eh8A02 |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Analogue:BCS |
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1qntA02 |  |  |  |  |  |  |  | Unbound | Unbound | Unbound | Unbound |
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References for Catalytic Mechanism | References | Sections | No. of steps in catalysis |
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[1] | Figure 5, p.9319 | 1 | [3] | Fig.3, p.1498, p.1499 |
| [11] | Scheme 2, p.6805-6806 |
| [13] | Fig.5, p.1727 | 1 |
references | [1] |
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PubMed ID | 3174452 |
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Journal | Nucleic Acids Res |
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Year | 1988 |
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Volume | 16 |
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Pages | 9307-21 |
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Authors | Yamagata Y, Kohda K, Tomita K |
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Title | Structural studies of O6-methyldeoxyguanosine and related compounds: a promutagenic DNA lesion by methylating carcinogens. |
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[2] |
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PubMed ID | 2164681 |
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Journal | Proc Natl Acad Sci U S A |
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Year | 1990 |
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Volume | 87 |
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Pages | 5368-72 |
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Authors | Dolan ME, Moschel RC, Pegg AE |
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Title | Depletion of mammalian O6-alkylguanine-DNA alkyltransferase activity by O6-benzylguanine provides a means to evaluate the role of this protein in protection against carcinogenic and therapeutic alkylating agents |
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[3] |
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PubMed ID | 8156986 |
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Journal | EMBO J |
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Year | 1994 |
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Volume | 13 |
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Pages | 1495-501 |
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Authors | Moore MH, Gulbis JM, Dodson EJ, Demple B, Moody PC |
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Title | Crystal structure of a suicidal DNA repair protein: the Ada O6-methylguanine-DNA methyltransferase from E. coli. |
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[4] |
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Comments | CHARACTERIZATION |
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PubMed ID | 8202360 |
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Journal | Nucleic Acids Res |
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Year | 1994 |
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Volume | 22 |
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Pages | 1613-9 |
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Authors | Liem LK, Lim A, Li BF |
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Title | Specificities of human, rat and E. coli O6-methylguanine-DNA methyltransferases towards the repair of O6-methyl and O6-ethylguanine in DNA. |
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Related UniProtKB | P16455 |
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[5] |
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PubMed ID | 8632775 |
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Journal | Mutat Res |
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Year | 1996 |
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Volume | 363 |
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Pages | 15-25 |
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Authors | Crone TM, Goodtzova K, Pegg AE |
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Title | Amino acid residues affecting the activity and stability of human O6-alkylguanine-DNA alkyltransferase. |
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[6] |
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PubMed ID | 9403175 |
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Journal | Chem Res Toxicol |
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Year | 1997 |
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Volume | 10 |
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Pages | 1234-9 |
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Authors | Terashima I, Kawate H, Sakumi K, Sekiguchi M, Kohda K |
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Title | Substrate specificity of human O6-methylguanine-DNA methyltransferase for O6-benzylguanine derivatives in oligodeoxynucleotides |
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[7] |
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PubMed ID | 9757089 |
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Journal | Acta Crystallogr D Biol Crystallogr |
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Year | 1998 |
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Volume | 54 |
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Pages | 750-6 |
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Authors | Cowtan K |
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Title | Modified phased translation functions and their application to molecular-fragment location. |
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[8] |
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PubMed ID | 9445381 |
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Journal | Biochem J |
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Year | 1998 |
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Volume | 329 |
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Pages | 545-50 |
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Authors | Kanugula S, Goodtzova K, Pegg AE |
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Title | Probing of conformational changes in human O6-alkylguanine-DNA alkyl transferase protein in its alkylated and DNA-bound states by limited proteolysis. |
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[9] |
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PubMed ID | 9730821 |
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Journal | Biochemistry |
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Year | 1998 |
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Volume | 37 |
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Pages | 12489-95 |
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Authors | Goodtzova K, Kanugula S, Edara S, Pegg AE |
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Title | Investigation of the role of tyrosine-114 in the activity of human O6-alkylguanine-DNA alkyltranferase. |
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[10] |
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PubMed ID | 9556560 |
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Journal | J Biol Chem |
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Year | 1998 |
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Volume | 273 |
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Pages | 10863-7 |
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Authors | Pegg AE, Kanugula S, Edara S, Pauly GT, Moschel RC, Goodtzova K |
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Title | Reaction of O6-benzylguanine-resistant mutants of human O6-alkylguanine-DNA alkyltransferase with O6-benzylguanine in oligodeoxyribonucleotides. |
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[11] |
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PubMed ID | 10346901 |
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Journal | Biochemistry |
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Year | 1999 |
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Volume | 38 |
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Pages | 6801-6 |
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Authors | Spratt TE, Wu JD, Levy DE, Kanugula S, Pegg AE |
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Title | Reaction and binding of oligodeoxynucleotides containing analogues of O6-methylguanine with wild-type and mutant human O6-alkylguanine-DNA alkyltransferase. |
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[12] |
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PubMed ID | 10508414 |
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Journal | Biochemistry |
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Year | 1999 |
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Volume | 38 |
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Pages | 12097-103 |
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Authors | Encell LP, Loeb LA |
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Title | Redesigning the substrate specificity of human O(6)-alkylguanine-DNA alkyltransferase. Mutants with enhanced repair of O(4)-methylthymine. |
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[13] |
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Comments | X-ray crystallography |
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PubMed ID | 10747039 |
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Journal | EMBO J |
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Year | 2000 |
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Volume | 19 |
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Pages | 1719-30 |
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Authors | Daniels DS, Mol CD, Arvai AS, Kanugula S, Pegg AE, Tainer JA |
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Title | Active and alkylated human AGT structures: a novel zinc site, inhibitor and extrahelical base binding. |
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Related PDB | 1eh6,1eh7,1eh8 |
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[14] |
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PubMed ID | 10677686 |
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Journal | Mutat Res |
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Year | 2000 |
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Volume | 459 |
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Pages | 81-7 |
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Authors | Brown LR, Deng J, Clarke ND |
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Title | Dominant sensitization variants of human O(6)-methylguanine-DNA-methyltransferase obtained by a mutational screen of surface residues. |
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[15] |
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Comments | X-ray crystallography |
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PubMed ID | 10606635 |
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Journal | Nucleic Acids Res |
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Year | 2000 |
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Volume | 28 |
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Pages | 393-401 |
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Authors | Wibley JE, Pegg AE, Moody PC |
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Title | Crystal structure of the human O(6)-alkylguanine-DNA alkyltransferase. |
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Related PDB | 1qnt |
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[16] |
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PubMed ID | 11708909 |
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Journal | J Med Chem |
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Year | 2001 |
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Volume | 44 |
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Pages | 4050-61 |
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Authors | Reinhard J, Hull WE, von der Lieth CW, Eichhorn U, Kliem HC, Kaina B, Wiessler M |
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Title | Monosaccharide-linked inhibitors of O(6)-methylguanine-DNA methyltransferase (MGMT): synthesis, molecular modeling, and structure-activity relationships. |
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[17] |
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PubMed ID | 11983993 |
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Journal | Acta Crystallogr C |
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Year | 2002 |
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Volume | 58 |
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Pages | o284-6 |
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Authors | Low JN, Quesada A, Marchal A, Nogueras M, Sanchez A, Glidewell C |
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Title | 4-Amino-6-benzyloxy-2-(methylsulfanyl)-5-nitrosopyrimidine: hydrogen-bonded dimers linked into pi-stacked chains. |
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[18] |
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PubMed ID | 11983995 |
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Journal | Acta Crystallogr C |
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Year | 2002 |
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Volume | 58 |
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Pages | o289-94 |
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Authors | Low JN, Quesada A, Marchal A, Melguizo M, Nogueras M, Glidewell C |
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Title | Hydrogen bonding in 2-amino-4,6-dimethoxypyrimidine, 2-benzylamino-4,6-bis(benzyloxy)pyrimidine and 2-amino-4,6-bis(N-pyrrolidino)pyrimidine: chains of fused rings and a centrosymmetric dimer. |
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[19] |
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PubMed ID | 12549918 |
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Journal | Biochemistry |
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Year | 2003 |
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Volume | 42 |
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Pages | 980-90 |
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Authors | Rasimas JJ, Kanugula S, Dalessio PM, Ropson IJ, Fried MG, Pegg AE |
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Title | Effects of zinc occupancy on human O6-alkylguanine-DNA alkyltransferase. |
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[20] |
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PubMed ID | 12974631 |
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Journal | Biochemistry |
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Year | 2003 |
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Volume | 42 |
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Pages | 10965-70 |
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Authors | Guengerich FP, Fang Q, Liu L, Hachey DL, Pegg AE |
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Title | O6-alkylguanine-DNA alkyltransferase: low pKa and high reactivity of cysteine 145. |
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comments | According to the literature [3] & [13], the transfer of methyl group proceeds via SN2 mechanism as follows: (1) A general base, His146, which is likely to be neutral, donating a hydrogen bond to carboxylate sidechain of Glu172, can abstract a proton from the thiolate group of Cys145, through a water molecule. (2) Cys145 acts as a nucleophile, which attacks the methyl-group of O6-methylguanine. (3) In addition, Tyr114 may protonate N3 atom of the guanine substrate as a general acid. According to another paper [11], Asn137 might stabilize the N1- and N2- positions of guanine. Unique feature of this enzyme is that there is no acceptor substrate for the methyl group transferred to Cys145, which will not be removed. Therefore, the transfer reaction inactivates the enzyme, which will be rapidly degraded by proteases (see [13]).
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created | updated |
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2004-03-17 | 2009-02-26 |
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