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For the Love of SAM: Engineering Methyltransferase Catalysis Via S-Adenosylmethionine Analogues

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For the Love of SAM: Engineering Methyltransferase Catalysis Via S-Adenosylmethionine Analogues For the Love of SAM: Engineering Methyltransferase Catalysis via S-Adenosylmethionine Analogues by Kalli Corinne Catcott B.S. in Chemistry/Biochemistry, University of California, San Diego A dissertation submitted to The Faculty of the College of Science of Northeastern University in partial fulfillment of the requirements for the degree of Doctor of Philosophy 9 December 2016 Dissertation directed by Zhaohui Sunny Zhou Professor of Chemistry and Chemical Biology Faculty Fellow of the Barnett Institute of Chemical and Biological Analysis © 2016 by Kalli C. Catcott All rights reserved. i Dedication To my wonderful wife: the only Sam I want to spend the rest of my life with ii Acknowledgements Science is a field which grows continuously with ever expanding frontiers. […] Any particular advance has been preceded by the contributions of those from many lands who have set firm foundations for further developments. […] Further, science is a collaborative effort. The combined results of several people working together is often much more effective than could be that of an individual scientist working alone. —Prof. John Bardeen, Nobel Laureate1 I certainly have many people to thank for both laying the foundations for my work and for helping me along the way. First, I am grateful to Professor Zhaohui Sunny Zhou for taking me into his lab and giving me incredible freedom to operate. Sunny puts the philosophy in Doctor of Philosophy; and, our conversations always leave me thinking about more than just methyltransferases. Drs. Richard Duclos, Jason Guo, and Jared Auclair have been key experts in guiding my research and helping me acquire important data along the way. Additionally, Dr. Wanlu Qu’s work on AdoVin was fundamental in propelling forward my own. My labmates, Shanshan Liu and Kevin Moulton, have been key advisors and uncomplaining sounding boards throughout my graduate studies. I look forward to working for one of you someday. I also must thank the ambitious undergraduate researchers I’ve worked with: Michael Pablo, Dillon Cleary, Paige Dickson, Lenny Negrón, and Diego Arévalo. Our collaboration with Professor Vicki Wysocki and Jing Yan analyzing AdoVin by native mass spectrometry has been both fruitful and fulfilling. I feel lucky for having the chance to work with them. iii The gracious members of my committee—Professors Jeffrey Agar, George O’Doherty, Penny Beuning, and Dr. Nicholas Yoder—have markedly improved the work I have done. I have such respect for your experience and views. This dissertation is much better for your insights. Thank you to ImmunoGen, especially Nick, who allowed me to start at Northeastern while still working and were supportive when I transitioned to Northeastern full time. Many thanks to the Northeastern University chemistry community, who have often loaned/given me supplies/equipment/expertise. My best efforts would have been stymied if not for your generosity. My excellent parents gave me an outstanding foundation from which to build and have continued their support my whole life. I am privileged to be your daughter. My son, Gram, has only witnessed that last year and a half of my efforts, but has contributed immeasurably to my joy. Thank you for brightening every day. Finally, I must dedicate this work to my incredible wife, whose support—emotional, financial, and moral—has been paramount in my achievements. I would be lost without you. iv Abstract of Dissertation Enzymes are exquisite catalysts—selective and specialized. Yet, enzymes are frequently engineered to alter the substrates used or reaction catalyzed. Naturally-occurring catalytic promiscuity in enzymes was first described almost a hundred years ago. More recently, these properties have been exploited to expand the biocatalytic space available for synthetic chemistry and biological probes. Methyltransferases represent a large and diverse class of enzymes whose catalytic promiscuity has only been marginally explored. A vast majority of methyltransferases utilize S-adenosylmethionine (AdoMet, SAM) as a source of methyl for the transfer reaction. Detailed here are two AdoMet analogues, Se-adenosylselenohomocysteine selenoxide (SeAHO) and S-adenosylvinthionine (AdoVin), which can be used to induce catalytic promiscuity in their respective enzyme systems. SeAHO is an AdoMet analogue, wherein the methylsulfonium is replaced with a selenoxide. Here, SeAHO is shown to alter the activity of catechol-O-methyltransferase (COMT), converting it to a putative oxidoreductase. The synthesis and characterization of SeAHO is also described. Unlike the sulfur counterpart, S-adenosylhomocysteine sulfoxide (SAHO), SeAHO is readily reduced by thiols, cysteine and glutathione; and, no reduction is observed in the presence of thioethers. In AdoVin, the methylsulfonium is replaced with vinyl sulfonium. AdoVin is utilized as a thiopurine-S-methyltransferase (TPMT) substrate to form bisubstrate adducts, conferring putative ligase activity. Detailed here are routes of purification and characterization of AdoVin and its adducts. AdoVin has also been used as a probe in a newly described framework, IsoLAIT, which utilizes native mass spectrometry to identify enzyme-substrate pairs in cellular contexts. v Table of Contents Dedication ....................................................................................................................................... ii Acknowledgements ........................................................................................................................ iii Abstract of Dissertation .................................................................................................................. v Table of Contents ........................................................................................................................... vi List of Figures ................................................................................................................................ xi List of Tables ................................................................................................................................ xv List of Equations .......................................................................................................................... xvi List of Symbols and Abbreviations............................................................................................. xvii Introduction ..................................................................................................................................... 1 Catalytic Promiscuity .......................................................................................................... 2 Methyltransferases .............................................................................................................. 4 AdoMet Analogues ............................................................................................................. 5 1 Se-Adenosylselenohomocysteine Selenoxide ........................................................................... 8 1.1 Introduction ........................................................................................................... 10 1.2 Preparation ............................................................................................................ 11 1.3 Characterization .................................................................................................... 14 1.3.a NMR ......................................................................................................... 14 vi 1.3.b IR Spectroscopy ........................................................................................ 17 1.3.c Mass Spectrometry .................................................................................... 19 1.4 Stability ................................................................................................................. 26 1.4.a NMR Time Course .................................................................................... 26 1.4.b Aqueous Buffers at Various pH ................................................................ 28 1.5 Reactivity .............................................................................................................. 32 1.5.a Reactivity with Biological Thiols and Thioethers .................................... 33 1.5.b Reactivity with Whole Proteins ................................................................ 35 1.6 Conclusions ........................................................................................................... 41 1.7 Experimental Procedures ...................................................................................... 42 1.7.a NMR ......................................................................................................... 42 1.7.b IR Spectroscopy ........................................................................................ 42 1.7.c Mass Spectrometry .................................................................................... 42 1.7.d Reverse Phase HPLC ................................................................................ 42 1.7.e Methyltransferase-Catalyzed Reduction and Bottom-Up MS .................. 43 2 Engineering Methyltransferase Activity: Conversion to an Oxidoreductase ......................... 45 2.1 Introduction ........................................................................................................... 46 2.2 Catechol-O-Methyltransferase .............................................................................
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