Document Detail


Molecular evolution of Theta-class glutathione transferase for enhanced activity with the anticancer drug 1,3-bis-(2-chloroethyl)-1-nitrosourea and other alkylating agents.
MedLine Citation:
PMID:  20211594     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Glutathione transferase (GST) displaying enhanced activity with the cytostatic drug 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) and structurally related alkylating agents was obtained by molecular evolution. Mutant libraries created by recursive recombination of cDNA coding for human and rodent Theta-class GSTs were heterologously expressed in Escherichia coli and screened with the surrogate substrate 4-nitrophenethyl bromide (NPB) for enhanced alkyltransferase activity. A mutant with a 70-fold increased catalytic efficiency with NPB, compared to human GST T1-1, was isolated. The efficiency in degrading BCNU had improved 170-fold, significantly more than with the model substrate NPB. The enhanced catalytic activity of the mutant GST was also 2-fold higher with BCNU than wild-type mouse GST T1-1, which is 80-fold more efficient than wild-type human GST T1-1. We propose that GSTs catalyzing inactivation of anticancer drugs may find clinical use in protecting sensitive normal tissues to toxic side-effects in treated patients, and as selectable markers in gene therapy.
Authors:
Anna-Karin Larsson; Abeer Shokeer; Bengt Mannervik
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-04
Journal Detail:
Title:  Archives of biochemistry and biophysics     Volume:  497     ISSN:  1096-0384     ISO Abbreviation:  Arch. Biochem. Biophys.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-03     Completed Date:  2010-05-20     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0372430     Medline TA:  Arch Biochem Biophys     Country:  United States    
Other Details:
Languages:  eng     Pagination:  28-34     Citation Subset:  IM    
Copyright Information:
Copyright 2010 Elsevier Inc. All rights reserved.
Affiliation:
Department of Biochemistry and Organic Chemistry, Uppsala University, Biomedical Center, SE-751 23 Uppsala, Sweden.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents, Alkylating / pharmacology*
Carmustine / pharmacology*
Catalysis
Escherichia coli / genetics
Evolution, Molecular*
Glutathione Transferase / chemistry*,  genetics,  metabolism*
Humans
Mice
Models, Molecular
Mutation
Nitrobenzenes
Structure-Activity Relationship
Substrate Specificity / genetics
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Alkylating; 0/Nitrobenzenes; 154-93-8/Carmustine; 5339-26-4/4-nitrophenethyl bromide; EC 2.5.1.18/Glutathione Transferase

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