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Engineering of an Efficient and Enantioselective Biocatalyst for the Preparation of Chiral Pharmaceutical Intermediates

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Engineering of an Efficient and Enantioselective Biocatalyst for the Preparation of Chiral Pharmaceutical Intermediates ENGINEERING OF AN EFFICIENT AND ENANTIOSELECTIVE BIOCATALYST FOR THE PREPARATION OF CHIRAL PHARMACEUTICAL INTERMEDIATES BY WENG LIN TANG DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemical Engineering in the Graduate College of the University of Illinois at Urbana-Champaign, in the program jointly administered with the National University of Singapore, 2011 Doctoral Committee: Professor Huimin Zhao, Chair Associate Professor Zhi Li, NUS, Co-Director of Research Associate Professor Shing Bor Chen, NUS Associate Professor Christopher V. Rao Assistant Professor Rudiyanto Gunawan, ETH Z¨urich Professor Daniel W. Pack Abstract This Ph.D. thesis focuses on the engineering of an efficient and enantioselective biocatalyst via direct evolution and genetic engineering for the enantioselective hydroxylation of non-activated carbon atom, a useful but challenging reaction for the synthesis of chiral pharmaceutical intermediates. Our target enzyme is the novel P450pyr enzyme from Sphingomonas sp. HXN-200 that was found to catalyze the regio- and stereoselective hydroxylation of non-activated carbon atom with broad substrate range, high activity, excellent regioselectivity, and good to excellent enantioselectivity. Our target reaction is the enzymatic hydroxylation of N- benzyl pyrrolidine to its corresponding (R)- and (S)-N-benzyl-3-hydroxypyrrolidines which are important pharmaceutical intermediates. In this thesis, a two-enzyme-based colorimetric high-throughput ee screening assay and a mass spectrometry-based high-throughput ee screening assay were developed. The P450pyr monooxygenase was engineered by directed evolution for the enantioselective hydroxylation of N-benzyl pyrrolidine. Several mutants exhibiting increased and/or inverted enantioselectivity were identified, with product ee of 83% (R) and 65% (S) for mutants 1AF4A and 11BB12, respectively. The wild type P450pyr and its mutants were also purified and reconstituted with their auxiliary electron transport proteins, ferredoxin and ferredoxin reductase in vitro. The mutants were then used to catalyze the hydroxylations of a range of different substrates using whole-cell assays to investigate the changes in product ee. In addition, an efficient biocatalytic system with cofactor recycling was developed by co- expressing a glucose dehydrogenase from Bacillus substilis or a phosphite ii dehydrogenase from Pseudomonas stutzeri together with the P450pyr system in a recombinant Escherichia coli. iii To Papa, Mama, Jun Jun and Pippo iv Acknowledgements This Ph.D. thesis would not have been possible without my advisors, Professor Huimin Zhao and Associate Professor Zhi Li, whose constant guidance, great patience and understanding have led me through to the completion of my graduate career. Many thanks to my thesis examiners, Associate Professor Shing Bor Chen (Chair), Professor Wilfred Chen, Associate Professor Christopher V. Rao and Assistant Professor Rudiyanto Gunawan, for their valued support and suggestions. In particular, I am indebted to Dr. Sheryl Rubin Pitel, my mentor, who taught me the basics of molecular biology and how to conduct high quality research. I would also like to thank Dr. Ryan Sullivan, Dr. Nikhil Nair, Dr. Yoo-Seong Choi, Dr. Zengyi Shao, Dr. Michael McLachlan and Dr. Zunsheng Wang for their helpful discussions and extremely useful suggestions. A big thank you to Carl Denard, Luigi Chanco, Ryan Cobb, Ning Sun, Dr. Byoungjin Kim, Liang Xue, Wei Zhang, Wen Wang, Quang Son Pham and all the current and former members of Prof. Huimin Zhao’s and Prof. Zhi Li’s laboratory for their wonderful friendship and for making my Ph.D. life interesting and wonderful. Special thanks to Dr. Yongzheng Chen who worked with me on the high-throughput mass spectrometry-based assay and for helping me to synthesize various chemical compounds for my biocatalysis work. Lastly but most importantly, I would like to thank my family for their love, support and encouragement. Everything that I have achieved today would not have been possible without them. v Table of Contents List of Tables ................................................................................................................ ix List of Figures ................................................................................................................ x List of Schemes ............................................................................................................ xii List of Abbreviations ................................................................................................. xiii Chapter 1 : Introduction ............................................................................................ 1 1.1 Industrial Biotechnology ................................................................................. 1 1.2 Chemo-, Regio- and Enantioselective Biocatalysis ........................................ 2 1.3 Enzymatic Hydroxylation of Non-Activated Hydrocarbons ........................... 5 1.3.1 Cytochrome P450 Monooxygenase ......................................................... 5 1.3.2 Methane Monooxygenases....................................................................... 8 1.3.3 Membrane-bound Alkane Hydroxylase (AlkB) ....................................... 9 1.4 Protein Engineering ......................................................................................... 9 1.4.1 Rational Design ...................................................................................... 10 1.4.2 Directed Evolution ................................................................................. 11 1.4.3 Screening and Selection ......................................................................... 14 1.5 Cofactor Regeneration ................................................................................... 24 1.5.1 NAD(P)H Regeneration ......................................................................... 25 1.6 Project Overview ........................................................................................... 27 Chapter 2 : Development of a High-throughput Enantiomeric Excess (ee) Screening Assay ........................................................................................................... 31 2.1 Introduction ................................................................................................... 31 2.2 Two-Enzyme-Based Colorimetric ee Screening Assay ................................ 33 vi 2.2.1 Results and Discussion .......................................................................... 33 2.2.2 Conclusion and Outlook ........................................................................ 38 2.3 Mass Spectrometry-Based High-Throughput ee Screening Assay ............... 39 2.3.1 Results and Discussion .......................................................................... 39 2.3.2 Conclusion ............................................................................................. 44 2.4 Materials and Methods .................................................................................. 45 2.4.1 Two-Enzyme-Based Colorimetric ee Screening Assay ......................... 45 2.4.2 Mass Spectrometry-Based High-Throughput ee Screening Assay ........ 49 Chapter 3 : Inverting the Enantioselectivity of P450pyr Monooxygenase by Directed Evolution ....................................................................................................... 63 3.1 Introduction ................................................................................................... 63 3.2 Results ........................................................................................................... 65 3.2.1 Homology Modeling .............................................................................. 65 3.2.2 Cloning and Expression of Cytochrome P450pyr Electron Transport System ................................................................................................................ 70 3.2.3 Iterative Targeted Site Saturation Mutagenesis ..................................... 72 3.2.4 Screening Strategy ................................................................................. 74 3.2.5 Combination of Beneficial Mutations by Site Directed Mutagenesis ... 78 3.3 Discussion ..................................................................................................... 78 3.3.1 Evolutionary Strategy ............................................................................ 78 3.3.2 Structural Analysis of Mutations ........................................................... 80 3.4 Conclusions and Outlook .............................................................................. 81 3.5 Materials and Methods .................................................................................. 82 Chapter 4 : Development of a Simple, Efficient and General Method for Cofactor Recycling in a Bio-Oxidation ...................................................................................... 90 4.1 Introduction ................................................................................................... 90 vii 4.2 Results and Discussion .................................................................................. 92 4.2.1 Construction of Recombinant E. coli Strains ......................................... 92 4.2.2 Cell Culture and Protein Expression ...................................................... 95 4.2.3 Biohydroxylation of N-Benzyl-pyrrolidine 1 with Recombinant
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