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Improving catalytic function by ProSAR-driven enzyme evolution
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DOI：10.1038/nbt1286.png)
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Abstract
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We describe a directed evolution approach that should find broad application in generating enzymes that meet predefined process-design criteria. It augments recombination-based directed evolution by incorporating a strategy for statistical analysis of protein sequence activity relationships (ProSAR). This combination facilitates mutation-oriented enzyme optimization by permitting the capture of additional information contained in the sequence-activity data. The method thus enables identification of beneficial mutations even in variants with reduced function. We use this hybrid approach to evolve a bacterial halohydrin dehalogenase that improves the volumetric productivity of a cyanation process B4,000-fold. This improvement was required to meet the practical design criteria for a commercially relevant biocatalytic process involved in the synthesis of a cholesterol-lowering drug, atorvastatin (Lipitor), and was obtained by variants that had at least 35 mutations.
Keywords:
DIRECTED EVOLUTION
HALOALCOHOL DEHALOGENASE
MOLECULAR EVOLUTION
SEARCH ALGORITHM
IN-VITRO
PROTEIN
BIOCATALYSIS
PROGRAM
DESIGN
FAMILY
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41.7
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