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      Novel carbon–carbon bond formations for biocatalysis

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          Research highlights

          ► Novel C–C bond formations from lyases, oxidoreductases and transferases reviewed. ► Highlights from lyases are the Stetter reaction, and the synthesis of N-heterocyclases and the first intermolecular Diels-Alderase. ► The highlight from oxidoreductases is the aerobic oxidative C–C coupling.

          Abstract

          Carbon–carbon bond formation is the key transformation in organic synthesis to set up the carbon backbone of organic molecules. However, only a limited number of enzymatic C–C bond forming reactions have been applied in biocatalytic organic synthesis. Recently, further name reactions have been accomplished for the first time employing enzymes on a preparative scale, for instance the Stetter and Pictet–Spengler reaction or oxidative C–C bond formation. Furthermore, novel enzymatic C–C bond forming reactions have been identified like benzylation of aromatics, intermolecular Diels-Alder or reductive coupling of carbon monoxide.

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          Most cited references45

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          Computational design of an enzyme catalyst for a stereoselective bimolecular Diels-Alder reaction.

          The Diels-Alder reaction is a cornerstone in organic synthesis, forming two carbon-carbon bonds and up to four new stereogenic centers in one step. No naturally occurring enzymes have been shown to catalyze bimolecular Diels-Alder reactions. We describe the de novo computational design and experimental characterization of enzymes catalyzing a bimolecular Diels-Alder reaction with high stereoselectivity and substrate specificity. X-ray crystallography confirms that the structure matches the design for the most active of the enzymes, and binding site substitutions reprogram the substrate specificity. Designed stereoselective catalysts for carbon-carbon bond-forming reactions should be broadly useful in synthetic chemistry.
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            Improving catalytic function by ProSAR-driven enzyme evolution.

            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 approximately 4,000-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.
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              Vanadium nitrogenase reduces CO.

              Vanadium nitrogenase not only reduces dinitrogen to ammonia but also reduces carbon monoxide to ethylene, ethane, and propane. The parallelism between the two reactions suggests a potential link in mechanism and evolution between the carbon and nitrogen cycles on Earth.
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                Author and article information

                Journal
                Curr Opin Biotechnol
                Curr. Opin. Biotechnol
                Current Opinion in Biotechnology
                Current Biology
                0958-1669
                1879-0429
                December 2011
                December 2011
                : 22
                : 6
                : 793-799
                Affiliations
                Department of Chemistry, Organic and Bioorganic Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria
                Article
                COBIOT859
                10.1016/j.copbio.2011.02.002
                3271363
                21354781
                48d603d8-3b3d-4a47-8a74-043770624c1b
                © 2011 Elsevier Ltd.

                This document may be redistributed and reused, subject to certain conditions.

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                Biotechnology
                Biotechnology

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