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Literature summary extracted from

  • Sabharwal, A.; Middleton, M.R.
    Exploiting the role of O6-methylguanine-DNA-methyltransferase (MGMT) in cancer therapy (2006), Curr. Opin. Pharmacol., 6, 355-363.
    View publication on PubMed

Activating Compound

EC Number Activating Compound Comment Organism Structure
2.1.1.63 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
2.1.1.63 glucocorticoid regulates AGT expression Homo sapiens
2.1.1.63 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
2.1.1.63 ionizing radiation induces AGT Mus musculus
2.1.1.63 P53 regulates MGMT promoter Homo sapiens

Application

EC Number Application Comment Organism
2.1.1.63 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
2.1.1.63 medicine expression of additional AGT in a variety of tissues in transgenic mice protects against carcinogenesis Mus musculus
2.1.1.63 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)

EC Number Cloned (Comment) Organism
2.1.1.63 expression in Escherichia coli Mus musculus
2.1.1.63 expression in Escherichia coli, transgenic overexpression in mouse skin, expression in CHO cells Homo sapiens

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
2.1.1.63 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

EC Number Protein Variants Comment Organism
2.1.1.63 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
2.1.1.63 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
2.1.1.63 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
2.1.1.63 I143V/K178R no significant effect on AGT activity, may be an increased risk for lung cancer in individuals with this change Homo sapiens
2.1.1.63 K165R does not abolish activity on 6-O-methylguanine but greatly reduces the ability to react with O6-benzylguanine Homo sapiens
2.1.1.63 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
2.1.1.63 P140K stable and extremely resistant to O6-benzylguanine Homo sapiens
2.1.1.63 V139F has an increased ability to protect against the cytotoxic and mutagenic effects of N-methyl-N'-nitro-N-nitrosoguanidine Escherichia coli
2.1.1.63 Y158H stable and extremely resistant to O6-benzylguanine Homo sapiens

Inhibitors

EC Number Inhibitors Comment Organism Structure
2.1.1.63 formaldehyde decreases activity at levels up to 3fold higher than the maximally allowed workplace concentration, no decrease at the maximally allowed level Homo sapiens
2.1.1.63 methyl bromide
-
 Mus musculus
2.1.1.63 methyl bromide
-
 Rattus norvegicus
2.1.1.63 additional information substances present in the saliva of tobacco and betel nut chewers Homo sapiens
2.1.1.63 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
2.1.1.63 O6-benzyl-2'-deoxyguanosine
-
 Homo sapiens
2.1.1.63 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

EC Number Localization Comment Organism GeneOntology No. Textmining
2.1.1.63 nucleus
-
 Homo sapiens 5634
-

Molecular Weight [Da]

EC Number Molecular Weight [Da] Molecular Weight Maximum [Da] Comment Organism
2.1.1.63 23000
-
-
 Homo sapiens

Organism

EC Number Organism UniProt Comment Textmining
2.1.1.63 Escherichia coli
-
-
-
2.1.1.63 Homo sapiens
-
-
-
2.1.1.63 Mus musculus
-
-
-
2.1.1.63 Rattus norvegicus
-
-
-

Purification (Commentary)

EC Number Purification (Comment) Organism
2.1.1.63 mutant V139F Escherichia coli

Source Tissue

EC Number Source Tissue Comment Organism Textmining
2.1.1.63 astrocyte level of AGT is much reduced in mice lacking p53 Mus musculus
-
2.1.1.63 bone marrow low level Homo sapiens
-
2.1.1.63 breast AGT expression is increased in breast cancer compared to normal breast Homo sapiens
-
2.1.1.63 colon
-
 Mus musculus
-
2.1.1.63 fibroblast
-
 Homo sapiens
-
2.1.1.63 glioma cell
-
 Homo sapiens
-
2.1.1.63 HeLa cell
-
 Homo sapiens
-
2.1.1.63 HeLa-S3 cell
-
 Homo sapiens
-
2.1.1.63 liver
-
 Mus musculus
-
2.1.1.63 liver lowered in cirrhotic liver Homo sapiens
-
2.1.1.63 lung
-
 Mus musculus
-
2.1.1.63 lung increased in lung cancers from smokers rather than non-smokers Homo sapiens
-
2.1.1.63 additional information 3T3 cell line has an amplification of the MGMT gene Mus musculus
-
2.1.1.63 additional information absent from brain Homo sapiens
-
2.1.1.63 skin
-
 Mus musculus
-
2.1.1.63 thymus lymphoma cell line
-
 Mus musculus
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.1.1.63 DNA containing 4-O-methylthymine + [protein-L-cysteine
-
 Escherichia coli DNA lacking 4-O-methylthymine + [protein]-S-methyl-L-cysteine
-
 ?
2.1.1.63 DNA containing 4-O-methylthymine + [protein-L-cysteine very poor substrate Homo sapiens DNA lacking 4-O-methylthymine + [protein]-S-methyl-L-cysteine
-
 ?
2.1.1.63 DNA containing 6-O-methylguanine + [protein]-L-cysteine
-
 Escherichia coli DNA lacking 6-O-methylguanine + [protein]-S-methyl-L-cysteine
-
 ?
2.1.1.63 DNA containing 6-O-methylguanine + [protein]-L-cysteine prefered substrate Homo sapiens DNA lacking 6-O-methylguanine + [protein]-S-methyl-L-cysteine
-
 ?
2.1.1.63 DNA containing O6-(4-oxo-4-(3-pyridyl)butyl)guanine
-
 Homo sapiens ?
-
 ?
2.1.1.63 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

EC Number Synonyms Comment Organism
2.1.1.63 Ada-C
-
 Escherichia coli
2.1.1.63 AGT
-
 Mus musculus
2.1.1.63 AGT
-
 Escherichia coli
2.1.1.63 AGT
-
 Homo sapiens
2.1.1.63 AGT
-
 Rattus norvegicus
2.1.1.63 carboxyl terminal domain of the inducible Escherichia coli ada alkyltransferase
-
 Escherichia coli
2.1.1.63 MGMT
-
 Mus musculus
2.1.1.63 MGMT
-
 Homo sapiens
2.1.1.63 O6-alkylguanine-DNA alkyl-transferase
-
 Mus musculus
2.1.1.63 O6-alkylguanine-DNA alkyl-transferase
-
 Escherichia coli
2.1.1.63 O6-alkylguanine-DNA alkyl-transferase
-
 Homo sapiens
2.1.1.63 O6-alkylguanine-DNA alkyl-transferase
-
 Rattus norvegicus