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Enzymatic Site-Selectivity Enabled by Structure-Guided Directed Evolution

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Enzymatic Site-Selectivity Enabled by Structure-Guided Directed Evolution ChemComm View Article Online FEATURE ARTICLE View Journal | View Issue Enzymatic site-selectivity enabled by structure- guided directed evolution Cite this: Chem. Commun., 2017, 53,3916 Jian-bo Wang,ab Guangyue Liab and Manfred T. Reetz*ab Biocatalytic site-selective (regioselective) organic transformations have been practiced for decades, but the traditional limitations of enzymes regarding narrow substrate acceptance and the often observed Received 15th January 2017, insufficient degree of selectivity have persisted until recently. With the advent of directed evolution, it is Accepted 3rd March 2017 possible to engineer site-selectivity to suit the needs of organic chemists. This review features recent DOI: 10.1039/c7cc00368d progress in this exciting research area, selected examples involving P450 monooxygenases, halogenases and Baeyer–Villiger monooxygenases being featured for illustrative purposes. The complementary nature rsc.li/chemcomm of enzymes and man-made catalysts is emphasized. to be reported. Sometimes selectivity is possible only by resorting Creative Commons Attribution 3.0 Unported Licence. Introduction to protective group technology,1 but this requires additional steps. Site-selectivity and regioselectivity are terms that are often used Indeed, as Gilbert Stork once said, ‘‘The best protective group is interchangeably in synthetic organic chemistry. It means that a no protective group,’’ but this is generally not possible when using given reagent or catalyst induces a reaction selectively at one man-made reagents or catalysts. Introducing and removing out of several possible positions in a compound. If the trans- protective groups site-selectively is in itself a fundamentally formation is unselective, a mixture of products will arise, important task.1,2 The requirements as defined by the concepts generally either constitutional isomers, enantiomers or diaster- of atom-economy,3a step-economy3b and redox-economy3c under- eomers, depending upon the particular system. Since selectivity score the persisting challenges. This article is licensed under a stands at the heart of modern organic chemistry, numerous Enzymes catalyze natural transformations generally with selective reagents and catalysts have been developed and continue exquisite selectivity, including site-selectivity. Inspired by these well-known characteristics, chemists have long sought to harness wild type (WT) enzymes in isolated form, as lysates Open Access Article. Published on 15 March 2017. Downloaded 10/2/2021 7:31:28 AM. a Department of Chemistry, Philipps-University Marburg, Hans-Meerwein Strasse 4, or as whole cells (strains) for catalyzing selective reactions of 35032, Marburg, Germany 4,5 b Max-Plank-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mu¨lheim, non-natural substrates. As in the case of synthetic reagents 1–3 Germany. E-mail: [email protected] and catalysts, the ecological and economical aspects of Jian-bo Wang obtained his Guangyue Li studied protein bachelor’s degree from NanKai engineering at the Institute of University in 2004, then he Plant Protection, Chinese Academy pursued his doctoral research of Agricultural Sciences (Laboratory in Shanghai Institute Organic of Prof. Dewen Qiu), obtaining his Chemistry (SIOC) from 2005, master degree in 2010. He then and graduated in 2010. After he joined the group of Prof. Dunming worked in SIOC for about one Zhu at the Tianjin Institute of and a half years, he went to Industrial Biotechnology, Chinese Emory University, USA, to gain Academy of Sciences, obtaining a postdoctoral experience. After he doctoral degree in 2014 in the area finished his research in USA in of enzyme engineering. Currently he Jian-bo Wang 2014, he joined in Prof. M. T. Guangyue Li is a postdoctoral fellow in the group Reetz’s group as a postdoctoral of M. T. Reetz focusing on directed fellow and now working in the field of biocatalysis, enzyme evolution of epoxide hydrolase, alcohol dehydrogenase, Baeyer–Villiger directed evolution and protein engineering. monooxygenases and monoamine oxidase. 3916 | Chem. Commun., 2017, 53, 3916--3928 This journal is © The Royal Society of Chemistry 2017 View Article Online Feature Article ChemComm Scheme 2 Chemoenzymatic synthesis of cortisol (5) by Upjohn.9 Scheme 1 Regioselective oxidation of cholic acid (1).8 6 (as an entry to cortisol) by Woodward and coworkers at about enzyme catalysis in organic chemistry have been addressed. the same time.11 Several reviews focus on the use of enzymes in the production 7 Perhaps even more impressive is the biocatalytic one-pot of pharmaceuticals. conversion of 5-aminolevulinic acid (6) into compound 7 in One of many practical examples of enzymes as catalysts in 20% overall yield, a known precursor of vitamin B12 (8), organic chemistry concerns the regioselective oxidation of catalyzed by a mixture of 12 enzymes (Scheme 3).12 The cascade cholic acid (1) with sole formation of the 12-keto product 2, 8 sequence involves regio- and stereoselective C-methylation, catalyzed by 12a-hydroxysteroid dehydrogenase (12aHSDH), a oxidation, reduction, ring contraction, decarboxylation and specific alcohol dehydrogenase (ADH) (Scheme 1). Notice that finally [1,5]-sigmatropic rearrangement. This stands in contrast the oxidation occurs at the sterically most hindered site, a to the purely chemical synthesis of vitamin B12 by Woodward, result that is not possible using chemical reagents or catalysts Eschenmoser and coworkers, a monumental feat which, of without applying protective group methodology. Indeed, this course, had many spinoffs that are of substantial benefit to transformation was also achieved by chemical means, albeit in synthetic organic chemistry.13 Neither approach is exploited four steps, three involving protection/deprotection and one 8 in the industrial vitamin B12 production, which in reality is requiring stoichiometric amounts of CrO3 as the oxidant. Creative Commons Attribution 3.0 Unported Licence. accomplished by the biocatalytic process of fermentation, a Another early example of the complementarity of man-made fascinating accomplishment in its own right.14 catalysts/reagents and enzymes was reported in the chemo- When considering site-selectivity (regioselectivity) in general, enzymatic synthesis of the important therapeutic compound essentially all of the enzyme types can be considered, including cortisol (5) starting from readily available progesterone (3)by hydrolases, reductases, oxidases, transferases, lyases, isomerases several pharmaceutical companies in the early 1950s, including and ligases, all in a variety of different kinds of reactions. Many of Upjohn, Schering, Pfizer and Merck. In the Upjohn industrial these have been exploited by academic and industrial researchers process, an Aspergillus niger strain was used for oxidatively hydroxy- for the purpose of ensuring site-selectivity. For example, an lating the desired C11-position regioselectively with formation 9 important area is enzyme-catalyzed regioselective protection This article is licensed under a of the C11-a-alcohol 4. This was the wrong diastereomer in an and deprotection of such functional moieties as:2,15 otherwise impressive site-selective CH-activating process. At the Alcohol groups (e.g., in carbohydrates, poly-hydroxylated time the nature of the actual enzyme was not known, but it was alkaloids and steroids, nucleosides) most likely a cytochrome P450 monooxygenase (CYP), enzymes that Open Access Article. Published on 15 March 2017. Downloaded 10/2/2021 7:31:28 AM. 10 Thiol groups (e.g., in peptides) have since been used in many selective oxidation reactions. Amino groups (e.g., in polyhydroxylated alkaloids, amino- Subsequent steps included chemical manipulation of the sidechain saccharides, b-lactam derivatives) at the C17-position and inversion of configuration at position Hundreds of cases have been reported, one example being C11 (Scheme 2). The chemoenzymatic process was a practical the site-selective deprotection of the fully O-acylated glucose alternative to the 40-step purely chemical synthesis of cortisone derivative 9 with formation of either 10, catalyzed by porcine Manfred T. Reetz is a synthetic organic chemist who proposed and developed the concept of directed evolution of stereo- selective enzymes as catalysts in organic chemistry and bio- technology. Following two decades as Director at the Max-Planck- Institut fu¨r Kohlenforschung in Mu¨lheim/Germany, he accepted in 2011 an emeritus position as Hans-Meerwein-Research Prof- Manfred T. Reetz essor at Philipps-University in Scheme 3 The Scott-synthesis of intermediate 7 as a precursor of Marburg/Germany. vitamin B12 (8).12 This journal is © The Royal Society of Chemistry 2017 Chem. Commun., 2017, 53, 3916--3928 | 3917 View Article Online ChemComm Feature Article Scheme 5 Systematization of saturation mutagenesis at sites lining the binding pocket of an enzyme (CASTing), a given site A, B, C, D, etc. comprising 1, 2, 3 or more residues.23,25 Scheme 4 Site-selective deprotection of fully O-acylated glucose as a pocket of a lipase in kinetic resolution,24 systematization of this function of the enzyme (PPL: porcine pancreas lipase;16a RTE: esterase concept led to the technique of Combinatorial Active-Site 16b from Rhodosporium toruloides). Saturation Test (CAST) (Scheme 5).25 Thus, CAST is a convenient acronym for a process published earlier, readily distinguishing it from focused saturation mutagenesis at remote sites for other pancrease lipase (PPL),16a
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