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Literature summary for 2.1.1.63 extracted from
- Exploiting the role of O6-methylguanine-DNA-methyltransferase (MGMT) in cancer therapy (2006), Curr. Opin. Pharmacol., 6, 355-363.
Activating Compound
| Activating Compound | Comment | Organism | Structure |
|---|---|---|---|
| activator of protein kinase C | increases the level of AGT mRNA and increases resistance to N,N'-bis(2-chloroethyl)-N-nitrosourea in HeLa cells | Homo sapiens | |
| glucocorticoid | regulates AGT expression | Homo sapiens | |
| inhibitor of protein phosphatase | increases the level of AGT mRNA and increases resistance to N,N'-bis(2-chloroethyl)-N-nitrosourea in HeLa cells | Homo sapiens | |
| ionizing radiation | induces AGT | Mus musculus | |
| P53 | regulates MGMT promoter | Homo sapiens |  |
Application
| Application | Comment | Organism |
|---|---|---|
| medicine | alkyltransferase activity in tumors protects them from therapeutic agents such as temozolomide and N,N'-bis(2-chloroethyl)-N-nitrosourea, polymorphisms in the AGT gene | Homo sapiens |
| medicine | expression of additional AGT in a variety of tissues in transgenic mice protects against carcinogenesis | Mus musculus |
| medicine | transgenic rats expressing Ada-C are resistant to mammary tumor induction by N-methyl-N-nitrosourea but not by N-ethyl-N-nitrosourea | Escherichia coli |
Cloned(Commentary)
| Cloned (Comment) | Organism |
|---|---|
| expression in Escherichia coli | Mus musculus |
| expression in Escherichia coli, transgenic overexpression in mouse skin, expression in CHO cells | Homo sapiens |
Crystallization (Commentary)
| Crystallization (Comment) | Organism |
|---|---|
| Cys acceptor site is buried in the protein and, in order for reaction with a DNA substrate to take place, a change in conformation of either the substrate or the protein must occur, Glu-172 and Asn-137 play a major structural role in the AGT protein | Escherichia coli |
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| C145A | binds to alkylated DNA in a similar manner to wild type AGT but is unable to carry out the repair transfer, expressed in Escherichia coli, this mutant increases killing and mutagenesis by N-methyl-N'-nitro-N-nitrosoguanidine | Homo sapiens |
| C145F | appears to cause a similar change in the AGT structure as alkylation of the active site and provides a model for detailed study of the mechanism of degradation | Homo sapiens |
| G160R | is as effective as wild-type in protecting cells from N-methyl-N'-nitro-N-nitrosoguanidine and N,N'-bis(2-chloroethyl)-N-nitrosourea, is strongly resistant to O6-benzylguanine | Homo sapiens |
| I143V/K178R | no significant effect on AGT activity, may be an increased risk for lung cancer in individuals with this change | Homo sapiens |
| K165R | does not abolish activity on 6-O-methylguanine but greatly reduces the ability to react with O6-benzylguanine | Homo sapiens |
| additional information | mutation of Arg-128 to Ala greatly reduces the ability of AGT to repair O6-methylguanine in DNA but has no effect on the alkyl transfer reaction when the free base substrate, O6-benzylguanine is used, stability of AGT is reduced by most mutations at Lys-165 | Homo sapiens |
| P140K | stable and extremely resistant to O6-benzylguanine | Homo sapiens |
| V139F | has an increased ability to protect against the cytotoxic and mutagenic effects of N-methyl-N'-nitro-N-nitrosoguanidine | Escherichia coli |
| Y158H | stable and extremely resistant to O6-benzylguanine | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| formaldehyde | decreases activity at levels up to 3fold higher than the maximally allowed workplace concentration, no decrease at the maximally allowed level | Homo sapiens | |
| methyl bromide | - |
Mus musculus | |
| methyl bromide | - |
Rattus norvegicus | |
| additional information | substances present in the saliva of tobacco and betel nut chewers | Homo sapiens | |
| Ni2+ | purified protein is not very sensitive to this metal but the loss of AGT could contribute to the well-known carcinogenicity of nickel | Homo sapiens | |
| O6-benzyl-2'-deoxyguanosine | - |
Homo sapiens | |
| O6-benzylguanine | binds in the active site pocket, abolishes resistance against therapeutic agents temozolomide and N,N'-bis(2-chloroethyl)-N-nitrosourea | Homo sapiens | |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| nucleus | - |
Homo sapiens | 5634 | - |
Molecular Weight [Da]
| Molecular Weight [Da] | Molecular Weight Maximum [Da] | Comment | Organism |
|---|---|---|---|
| 23000 | - |
- |
Homo sapiens |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Escherichia coli | - |
- |
- |
| Homo sapiens | - |
- |
- |
| Mus musculus | - |
- |
- |
| Rattus norvegicus | - |
- |
- |
Purification (Commentary)
| Purification (Comment) | Organism |
|---|---|
| mutant V139F | Escherichia coli |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| astrocyte | level of AGT is much reduced in mice lacking p53 | Mus musculus | - |
| bone marrow | low level | Homo sapiens | - |
| breast | AGT expression is increased in breast cancer compared to normal breast | Homo sapiens | - |
| colon | - |
Mus musculus | - |
| fibroblast | - |
Homo sapiens | - |
| glioma cell | - |
Homo sapiens | - |
| HeLa cell | - |
Homo sapiens | - |
| HeLa-S3 cell | - |
Homo sapiens | - |
| liver | - |
Mus musculus | - |
| liver | lowered in cirrhotic liver | Homo sapiens | - |
| lung | - |
Mus musculus | - |
| lung | increased in lung cancers from smokers rather than non-smokers | Homo sapiens | - |
| additional information | 3T3 cell line has an amplification of the MGMT gene | Mus musculus | - |
| additional information | absent from brain | Homo sapiens | - |
| skin | - |
Mus musculus | - |
| thymus lymphoma cell line | - |
Mus musculus | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| DNA containing 4-O-methylthymine + [protein-L-cysteine | - |
Escherichia coli | DNA lacking 4-O-methylthymine + [protein]-S-methyl-L-cysteine | - |
? | |
| DNA containing 4-O-methylthymine + [protein-L-cysteine | very poor substrate | Homo sapiens | DNA lacking 4-O-methylthymine + [protein]-S-methyl-L-cysteine | - |
? | |
| DNA containing 6-O-methylguanine + [protein]-L-cysteine | - |
Escherichia coli | DNA lacking 6-O-methylguanine + [protein]-S-methyl-L-cysteine | - |
? | |
| DNA containing 6-O-methylguanine + [protein]-L-cysteine | prefered substrate | Homo sapiens | DNA lacking 6-O-methylguanine + [protein]-S-methyl-L-cysteine | - |
? | |
| DNA containing O6-(4-oxo-4-(3-pyridyl)butyl)guanine | - |
Homo sapiens | ? | - |
? | |
| additional information | in addition to repairing methyl groups, longer alkyl groups including ethyl-, n-propyl-, n-butyl-, 2-chloroethyl-, 2-hydroxyethyl-, iso-propyl and iso-butyl can be repaired | Homo sapiens | ? | - |
? | |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| Ada-C | - |
Escherichia coli |
| AGT | - |
Mus musculus |
| AGT | - |
Escherichia coli |
| AGT | - |
Homo sapiens |
| AGT | - |
Rattus norvegicus |
| carboxyl terminal domain of the inducible Escherichia coli ada alkyltransferase | - |
Escherichia coli |
| MGMT | - |
Mus musculus |
| MGMT | - |
Homo sapiens |
| O6-alkylguanine-DNA alkyl-transferase | - |
Mus musculus |
| O6-alkylguanine-DNA alkyl-transferase | - |
Escherichia coli |
| O6-alkylguanine-DNA alkyl-transferase | - |
Homo sapiens |
| O6-alkylguanine-DNA alkyl-transferase | - |
Rattus norvegicus |
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