Improving catalytic function by ProSAR-driven enzyme evolution

doi:10.1038/nbt1286

2007-02-18

491

PRE

DOI：10.1038/nbt1286

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摘要

En 中文

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.

Keyword:

DIRECTED EVOLUTION

HALOALCOHOL DEHALOGENASE

MOLECULAR EVOLUTION

SEARCH ALGORITHM

IN-VITRO

PROTEIN

BIOCATALYSIS

PROGRAM

DESIGN

FAMILY

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期刊

Nature Biotechnology

IF:

41.7

论文数:

1.2W

被引数:

10.1W

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暂无机构信息

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