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Literature summary for 2.1.1.63 extracted from

  • Liu, L.; Watanabe, K.; Fang, Q.; Williams, K.M.; Guengerich, F.P.; Pegg, A.E.
    Effect of alterations of key active site residues in O6-alkylguanine-DNA Alkyltransferase on its ability to modulate the genotoxicity of 1,2-dibromoethane (2007), Chem. Res. Toxicol., 20, 155-163.
    View publication on PubMed

Application

Application Comment Organism
medicine even slight alterations in the active site pocket of AGT do not prevent its ability to protect cells from alkylating agents, can block the paradoxical enhancement of the genotoxicity of the larger alpha,omega-dihaloalkanes by reducing the reaction with Cys145 Homo sapiens

Cloned(Commentary)

Cloned (Comment) Organism
recombinant AGT and mutants expressed in Escherichia coli, pQE expression vectors for wild-type and mutant AGT production and plasmid pREP4 cotransformed into TRG8 cells to suppress basal AGT protein expression Homo sapiens

Protein Variants

Protein Variants Comment Organism
G156A 40% reduced ability of the protein to react with Br(CH2)2Br Homo sapiens
G160R 28% reduced ability of the protein to react with Br(CH2)2Br Homo sapiens
P140A 70% reduced ability of the protein to react with Br(CH2)2Br Homo sapiens
P140K 95% reduced ability of the protein to react with Br(CH2)2Br as measured by loss of activity, no change in the stability of the AGT-Cys145S-(CH2)2Br intermediate Homo sapiens
R128A substantially reduced AGT-mediated increase in toxicity and the induction of mutations in Escherichia coli cells treated with Br(CH2)2Br, is able to react with Br(CH2)2Br at the Cys145 acceptor site, but the resulting AGT-Cys145S-(CH2)2Br is much less able to produce a covalent adduct with DNA Homo sapiens
Y114A reduced ability of the protein to react with Br(CH2)2Br as measured by loss of activity Homo sapiens
Y114E substantially reduced AGT-mediated increase in toxicity and the induction of mutations in Escherichia coli cells treated with Br(CH2)2Br Homo sapiens
Y158H 78% reduced ability of the protein to react with Br(CH2)2Br as measured by loss of activity, no change in the stability of the AGT-Cys145S-(CH2)2Br intermediate Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
Br(CH2)2Br inactivates purified AGT and mutant R128A to approximately the same extent; inactivates purified AGT and mutant R128A to approximately the same extent, small reduction in the loss of activity in the absence of DNA, but no effect at all in the presence of DNA, inactivates mutant Y114A much less than wild-type, and DNA completely prevents this inactivation, mutants P140K and Y158H are less inactivated than wild-type AGT, specifically in the presence of DNA Homo sapiens
Br(CH2)3Br mutant P140K requires higher concentrations than wild-type AGT for inactivation Homo sapiens
Br(CH2)5Br mutant P140K requires higher concentrations than wild-type AGT for inactivation Homo sapiens
BrCH2Br wild-type AGT and mutant P140K show no difference in sensitivity to BrCH2Br Homo sapiens
O6-benzylguanine mutants P140K and Y158H are the most resistant Homo sapiens

Organism

Organism UniProt Comment Textmining
Homo sapiens
-
-
-

Purification (Commentary)

Purification (Comment) Organism
-
Homo sapiens

Synonyms

Synonyms Comment Organism
AGT
-
Homo sapiens
O6-alkylguanine-DNA alkyltransferase
-
Homo sapiens

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.0001
-
wild-type Homo sapiens O6-benzylguanine
0.004
-
mutant P140A Homo sapiens O6-benzylguanine
0.005
-
mutant G160R Homo sapiens O6-benzylguanine
0.015
-
mutant G156A Homo sapiens O6-benzylguanine
0.62
-
mutant Y158H Homo sapiens O6-benzylguanine
1.2
-
mutant P140K Homo sapiens O6-benzylguanine