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    Lecture: Recent Methodology Developments in Directed Evolution of Enzymes
    Update time: 2018-05-04
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    Recent Methodology Developments in Directed Evolution of Enzymes


    Prof. Manfred T. Reetz, Department of Chemistry, Philipps-University


    9:00-11:00am, May 8, 2018, Tuesday


    214 Lecture Hall, Administration Building


    Since its conception two decades ago (M. T. Reetz, A. Zonta, K. Schimossek, K. Liebeton, K.-E. Jaeger, Angew. Chem. Int. Ed. Engl. 1997, 36, 2830-2832), directed evolution of stereoselective enzymes as a fundamentally novel approach to asymmetric catalysis has been generalized by us and others to include hydrolases, ligases, reductases, oxygenases, transferases, and C-C bond forming enzymes such as aldolases, oxynitrilases and pyruvate decarboxylases. In addition to asymmetric catalysis using chiral transition metal complexes or organocatalysts, directed evolution is the third major way to catalytically access enantiomerically enriched or pure compounds in a reliable manner. Recently, a comprehensive monograph has appeared (Reetz, M. T. Directed Evolution of Selective Enzymes: Catalysts for Synthetic Organic Chemistry and Biotechnology, Wiley-VCH, Weinheim, 2016). This protein engineering approach involves repeating cycles of gene mutagenesis and screening, which builds up “evolutionary pressure” in each round. Since the screening step is the bottleneck of this Darwinian laboratory evolution, the real challenge is to obtain mutant libraries of highest quality requiring a minimum of screening effort. Keeping this in mind, we introduced some time ago systematic saturation mutagenesis at sites lining the binding pocket (CASTing) as well as the use of highly reduced amino acid alphabets in addition to iterative saturation mutagenesis (ISM), which have proven to be exceptionally valuable tools (see for example: Z. Sun, R. Lonsdale, X.-D. Kong, J.-H. Xu, J. Zhou, M. T. Reetz, Angew. Chem. Int. Ed. 2015, 54, 12410-12415). Since methodology development constitutes the heart of directed evolution, we have recently increased our efforts for obtaining even more efficient methods and concepts, which is the subject of this lecture. Applications of these refined techniques concern the control of regio- and stereoselectivity of P450-catalyzed late-stage oxidative hydroxylation of steroids and of non-natural compounds, ADH-catalyzed asymmetric reduction of “difficult-to-reduce” ketones, regioselective Baeyer-Villiger reactions with formation of “abnormal” products catalyzed by BVMOs, and designer cells for cascade processes. Many of these transformations can be considered to be “dream reactions”. Yet another new development concerns the generation of focused mutant libraries generated not by the traditional molecular biological technique of saturation mutagenesis, but by combinatorial chemical solid-phase gene synthesis, especially synthetic systems functioning on micro-chips.

    Biography of Lecturer: 

    Manfred T. Reetz is an emeritus of the Max-Planck-Institut für Kohlenforschung (MPI) in Mülheim/Germany and the University of Marburg/Germany, and most recently Adjunct Professor at the Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences. Over the years Manfred T. Reetz has held many different offices and administrative positions, such as Chairman of the Chemistry Department at Marburg University, Director of the Max-Planck-Institut für Kohlenforschung, and Senator of the German National Academy of Sciences Leopoldina. He has also been a member of numerous boards, including Editorial Board of Angewandte Chemie and other journals such as Chemistry and Biology, Committee of the Fonds of the German Industrial Organization (FCI), and Committee of the prestigious Krupp-Foundation.

    As a chemist he developed numerous novel synthetic methods, reagents and catalysts for application in synthetic organic chemistry. The preparation of organotitanium reagents for chemo- and stereoselective C-C bond forming reactions is an early example, which at the time opened a whole new field, including Lewis acid mediated chelation controlled processes. In 1986 Reetz wrote a book on organotitanium reagents and Ti-catalysts. Many other synthetic developments followed, including methods for the size-selective synthesis of nanostructured transition metal colloids, new applications of amino acids as chiral building blocks, and the use of economically viable chiral BINOL-derived monodentate phosphites as ligands in asymmetric transition metal catalyzed reactions. These and other highlights have enriched academic and industrial organic chemistry worldwise.  

    In the 1990s the Reetz-group pioneered the concept of directed evolution of stereo- and regioselective enzymes as efficient catalysts in organic chemistry and biotechnology, a unique achievement. As a result, a new research field unfolded with the participation of many groups around the world, which led to the elimination of the long-standing limitations of enzymes. Today it constitutes a prolific source of catalysts for a wide variety of different asymmetric transformations, including enantioselective hydrolysis, oxidation, reduction, and C-C bond forming reactions. Ongoing methodology development in the Reetz group continues to enhance the efficacy of this protein engineering method.

    M. T. Reetz has published more than 600 peer-reviewed papers, a dozen book chapters and a book on organotitanium reagents. Another monograph on “Directed Evolution of Selective Enzymes” appeared in late 2016 (Wiley-VCH). He has authored 27 patents/applications. Reetz has been cited more than 45,000 times and has an h-index of 109 (Google). Manfred T. Reetz has won many prizes and awards, the latest being the Distinguished Scientist Award 2018 (Chinese Academy of Sciences).


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