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Molecular evolution...
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
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- Larsson, Anna-Karin (författare)
- Uppsala universitet,Institutionen för biokemi och organisk kemi
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- Shokeer, Abeer (författare)
- Uppsala universitet,Institutionen för biokemi och organisk kemi
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- Mannervik, Bengt (författare)
- Uppsala universitet,Institutionen för biokemi och organisk kemi
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(creator_code:org_t)
- Elsevier BV, 2010
- 2010
- Engelska.
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Ingår i: Archives of Biochemistry and Biophysics. - : Elsevier BV. - 0003-9861 .- 1096-0384. ; 497:1-2, s. 28-34
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences (hsv//eng)
Nyckelord
- Glutathione transferase (GST)
- 1
- 3-Bis-(2-chloroethyl)-1-nitrosourea (BCNU) Chloroethylnitrosoureas (CENUs)
- Directed evolution
- Alkyltransferase
- Alkylating agents
- Chemistry
- Kemi
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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