The conventional analysis of enzyme evolution is to regard one single salient feature as a measure of fitness, expressed in a milieu exposing the possible selective advantage at a given time and location. Given that a single protein may serve more than one function, fitness should be assessed in several dimensions. In the present study we have explored individual mutational steps leading to a triple-point-mutated human GST (glutathione transferase) A2-2 displaying enhanced activity with azathioprine. A total of eight alternative substrates were used to monitor the diverse evolutionary trajectories. The epistatic effects of the mutations on catalytic activity were variable in sign and magnitude and depended on the substrate used, showing that epistasis is a multidimensional quality. Evidently, the multidimensional fitness landscape can lead to alternative trajectories resulting in enzymes optimized for features other than the selectable markers relevant at the origin of the evolutionary process. In this manner the evolutionary response is robust and can adapt to changing environmental conditions.
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Research Article|
June 15 2012
Multidimensional epistasis and fitness landscapes in enzyme evolution
Wei Zhang;
Wei Zhang
*Department of Biochemistry and Organic Chemistry, Uppsala University, SE-75123 Uppsala, Sweden
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Daniel F. A. R. Dourado;
Daniel F. A. R. Dourado
*Department of Biochemistry and Organic Chemistry, Uppsala University, SE-75123 Uppsala, Sweden
†Requimte/Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal
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Pedro Alexandrino Fernandes;
Pedro Alexandrino Fernandes
†Requimte/Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal
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Maria João Ramos;
Maria João Ramos
†Requimte/Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal
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Bengt Mannervik
Bengt Mannervik
1
*Department of Biochemistry and Organic Chemistry, Uppsala University, SE-75123 Uppsala, Sweden
‡Department of Neurochemistry, Stockholm University, SE-10691 Stockholm, Sweden
1To whom correspondence should be addressed (email Bengt.Mannervik@kemi.uu.se).
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Publisher: Portland Press Ltd
Received:
January 20 2012
Revision Received:
April 23 2012
Accepted:
April 26 2012
Accepted Manuscript online:
April 26 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 445 (1): 39–46.
Article history
Received:
January 20 2012
Revision Received:
April 23 2012
Accepted:
April 26 2012
Accepted Manuscript online:
April 26 2012
Citation
Wei Zhang, Daniel F. A. R. Dourado, Pedro Alexandrino Fernandes, Maria João Ramos, Bengt Mannervik; Multidimensional epistasis and fitness landscapes in enzyme evolution. Biochem J 1 July 2012; 445 (1): 39–46. doi: https://doi.org/10.1042/BJ20120136
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