|
UniProtKB:Accession Number | P29372 |
---|
Entry name | 3MG_HUMAN |
---|
Activity | Hydrolysis of alkylated DNA, releasing 3- methyladenine, 3-methylguanine, 7-methylguanine and 7- methyladenine. |
---|
Subunit | Binds MBD1. |
---|
Subcellular location | Nucleus (Potential). |
---|
Cofactor |
|
---|
Compound table: links to PDB-related databases & PoSSuM |
---|
| Substrates | Products |
---|
KEGG-id | C00871 | C00001 | C00913 | C02230 | C02242 | C02241 | C02270 |
---|
Compound | Alkylated DNA | H2O | 3-Methyladenine | 3-Methylguanine | 7-Methylguanine | 7-Methyladenine | Base-removed DNA |
---|
Type | nucleic acids | H2O | amine group,aromatic ring (with nitrogen atoms) | amine group,aromatic ring (with nitrogen atoms) | amide group,amine group,aromatic ring (with nitrogen atoms) | amine group,aromatic ring (with nitrogen atoms) | carbohydrate,nucleic acids,phosphate group/phosphate ion |
---|
ChEBI |
| 15377
| 38635
| 46893 46892 27564
| 46897 46894 28664
| 28921
|
|
---|
PubChem |
| 962 22247451
| 1673
| 76292
| 11361
| 71593
|
|
---|
| | | | | | | | | | | | | | |
---|
1bnkA |  |  |  |  |  |  |  | Unbound | | Unbound | Unbound | Unbound | Unbound | Analogue:G-A-C-A-T-G-YRR-T-T-G-C-C-T(chain D) |
---|
1ewnA |  |  |  |  |  |  |  | Analogue:G-A-C-A-T-G-EDA-T-T-G-C-C(chain D) | | Unbound | Unbound | Unbound | Unbound | Unbound |
---|
1f4rA |  |  |  |  |  |  |  | Analogue:G-A-C-A-T-G-EDA-T-T-G-C-C(chain D) | | Unbound | Unbound | Unbound | Unbound | Unbound |
---|
1f6oA |  |  |  |  |  |  |  | Unbound | | Unbound | Unbound | Unbound | Unbound | Analogue:G-A-C-A-T-G-YRR-T-T-G-C-C-T(chain D) |
---|
References for Catalytic Mechanism | References | Sections | No. of steps in catalysis |
---|
[1] | Fig.1B | 1 | [2] | Fig.1B | 1 | [3] | p.251-252, Fig.4B | 1 | [4] | p.670-671 |
| [5] | p.4281-4282 |
| [6] | p.208 |
| [7] | p.13577-13578 |
| [9] | p.312 |
|
references | [1] |
---|
PubMed ID | 7806489 |
---|
Journal | J Biol Chem |
---|
Year | 1994 |
---|
Volume | 269 |
---|
Pages | 32709-12 |
---|
Authors | Dodson ML, Michaels ML, Lloyd RS |
---|
Title | Unified catalytic mechanism for DNA glycosylases. |
---|
[2] |
---|
PubMed ID | 7642635 |
---|
Journal | J Biol Chem |
---|
Year | 1995 |
---|
Volume | 270 |
---|
Pages | 19501-8 |
---|
Authors | Sun B, Latham KA, Dodson ML, Lloyd RS |
---|
Title | Studies on the catalytic mechanism of five DNA glycosylases. Probing for enzyme-DNA imino intermediates. |
---|
[3] |
---|
Comments | X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 80-199. |
---|
PubMed ID | 9790531 |
---|
Journal | Cell |
---|
Year | 1998 |
---|
Volume | 95 |
---|
Pages | 249-58 |
---|
Authors | Lau AY, Scharer OD, Samson L, Verdine GL, Ellenberger T |
---|
Title | Crystal structure of a human alkylbase-DNA repair enzyme complexed to DNA: mechanisms for nucleotide flipping and base excision. |
---|
Related PDB | 1bnk |
---|
Related UniProtKB | P29372 |
---|
[4] |
---|
PubMed ID | 10440863 |
---|
Journal | Bioessays |
---|
Year | 1999 |
---|
Volume | 21 |
---|
Pages | 668-76 |
---|
Authors | Wyatt MD, Allan JM, Lau AY, Ellenberger TE, Samson LD |
---|
Title | 3-methyladenine DNA glycosylases: structure, function, and biological importance. |
---|
[5] |
---|
PubMed ID | 10660595 |
---|
Journal | J Biol Chem |
---|
Year | 2000 |
---|
Volume | 275 |
---|
Pages | 4278-82 |
---|
Authors | Roy R, Biswas T, Lee JC, Mitra S |
---|
Title | Mutation of a unique aspartate residue abolishes the catalytic activity but not substrate binding of the mouse N-methylpurine-DNA glycosylase (MPG). |
---|
[6] |
---|
PubMed ID | 10946229 |
---|
Journal | Mutat Res |
---|
Year | 2000 |
---|
Volume | 460 |
---|
Pages | 201-10 |
---|
Authors | Hollis T, Lau A, Ellenberger T |
---|
Title | Structural studies of human alkyladenine glycosylase and E. coli 3-methyladenine glycosylase. |
---|
[7] |
---|
Comments | X-ray crystallography |
---|
PubMed ID | 11106395 |
---|
Journal | Proc Natl Acad Sci U S A |
---|
Year | 2000 |
---|
Volume | 97 |
---|
Pages | 13573-8 |
---|
Authors | Lau AY, Wyatt MD, Glassner BJ, Samson LD, Ellenberger T |
---|
Title | Molecular basis for discriminating between normal and damaged bases by the human alkyladenine glycosylase, AAG. |
---|
Related PDB | 1f4r,1f6o,1ewn |
---|
[8] |
---|
PubMed ID | 11554308 |
---|
Journal | Prog Nucleic Acid Res Mol Biol |
---|
Year | 2001 |
---|
Volume | 68 |
---|
Pages | 305-14 |
---|
Authors | Hollis T, Lau A, Ellenberger T |
---|
Title | Crystallizing thoughts about DNA base excision repair. |
---|
[9] |
---|
PubMed ID | 11554309 |
---|
Journal | Prog Nucleic Acid Res Mol Biol |
---|
Year | 2001 |
---|
Volume | 68 |
---|
Pages | 315-47 |
---|
Authors | Hosfield DJ, Daniels DS, Mol CD, Putnam CD, Parikh SS, Tainer JA |
---|
Title | DNA damage recognition and repair pathway coordination revealed by the structural biochemistry of DNA repair enzymes. |
---|
[10] |
---|
PubMed ID | 12323378 |
---|
Journal | Chem Biol |
---|
Year | 2002 |
---|
Volume | 9 |
---|
Pages | 1033-41 |
---|
Authors | Connor EE, Wyatt MD |
---|
Title | Active-site clashes prevent the human 3-methyladenine DNA glycosylase from improperly removing bases. |
---|
[11] |
---|
PubMed ID | 12202763 |
---|
Journal | Nucleic Acids Res |
---|
Year | 2002 |
---|
Volume | 30 |
---|
Pages | 3778-87 |
---|
Authors | Guliaev AB, Hang B, Singer B |
---|
Title | Structural insights by molecular dynamics simulations into differential repair efficiency for ethano-A versus etheno-A adducts by the human alkylpurine-DNA N-glycosylase. |
---|
comments | By analogy to the cleavage of polysaccharides by glycosidases and N-glycosidic bonds in nucleosides by nucleoside hydrolase, the hydrolysis of N-glycosylic bonds by DNA glycosylases is likely to involve a transition state with considerable oxocarbenium ion character [3]. According to the paper [3], the bound water molecule is the nucleophile that is activated by nearby amino acids. The bound water is nearly aligned for attack of the N-glycosylic bond with subsequent release of the N-alkylated base via a backside displacement mechanism. O4' of a 2'-deoxyribonucleoside substrate would not attract the water, enabling its alignment for attack of the anomeric carbon. Glu125 could act as a general base, deprotonating the water for nucleophilic attack of the sugar [3]. According to the paper [5], Asp132 plays an essential role either by donating a proton to the substrate base and, thus, facilitating its release, or by stabilizing the steric configuration of the active site pocket. However, this aspartate residue, Asp132, is too distant from the substrate for the proton donation [5]. The papers, [6] & [9], reported that Glu125 might deprotonate the water, which is ideally positioned for an in-line displacement of the glycosidic bond via a backside attack of the ribose, to form a strong nucleophile that could then attack the C1' of the substrate ribose and subsequently release the base. The literature [7] suggested that some alkylation-damaged bases are electron deficient and have a delocalized positive charge, enabling the alkylated bases to be recognized by tight-binding ineractions with ana aromatic side chains of the glycosylase active site, which would constitute a pi-electron donor-acceptor pair with considerably more potential binding energy than a neutral pi-electron stacking interaction. Another feature is that a positively charged alkylated base is a good leaving group with a weakened glycosidic bond. With minimal catalytic assistance, these destabilized bases could be readily excised by a glycosylase lacking the catalytic strength to efficiently excise normal bases [7].
|
created | updated |
---|
2002-09-06 | 2009-03-24 |
|
|