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Selenium Vs. Sulfur: Investigating the Substrate Specificity of a Selenocysteine Lyase

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Selenium Vs. Sulfur: Investigating the Substrate Specificity of a Selenocysteine Lyase University of Central Florida STARS Electronic Theses and Dissertations, 2004-2019 2019 Selenium vs. Sulfur: Investigating the Substrate Specificity of a Selenocysteine Lyase Michael Johnstone University of Central Florida Part of the Biotechnology Commons Find similar works at: https://stars.library.ucf.edu/etd University of Central Florida Libraries http://library.ucf.edu This Masters Thesis (Open Access) is brought to you for free and open access by STARS. It has been accepted for inclusion in Electronic Theses and Dissertations, 2004-2019 by an authorized administrator of STARS. For more information, please contact [email protected]. STARS Citation Johnstone, Michael, "Selenium vs. Sulfur: Investigating the Substrate Specificity of a Selenocysteine Lyase" (2019). Electronic Theses and Dissertations, 2004-2019. 6511. https://stars.library.ucf.edu/etd/6511 SELENIUM VS. SULFUR: INVESTIGATING THE SUBSTRATE SPECIFICITY OF A SELENOCYSTEINE LYASE by MICHAEL ALAN JOHNSTONE B.S. University of Central Florida, 2017 A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science in the Burnett School of Biomedical Sciences in the College of Medicine at the University of Central Florida Orlando, Florida Summer Term 2019 Major Professor: William T. Self © 2019 Michael Alan Johnstone ii ABSTRACT Selenium is a vital micronutrient in many organisms. While traces are required for survival, excess amounts are toxic; thus, selenium can be regarded as a biological “double-edged sword”. Selenium is chemically similar to the essential element sulfur, but curiously, evolution has selected the former over the latter for a subset of oxidoreductases. Enzymes involved in sulfur metabolism are less discriminate in terms of preventing selenium incorporation; however, its specific incorporation into selenoproteins reveals a highly discriminate process that is not completely understood. In this work, we add knowledge to the mechanism for selenium-over-sulfur specificity in hopes of further understanding the controlled regulation of selenium trafficking and the prevention of its toxicity. We have identified SclA, a selenocysteine lyase in the nosocomial pathogen, Enterococcus faecalis, and characterized its enzymatic activity and specificity for L- selenocysteine over L-cysteine. Human selenocysteine lyase contains a residue, D146, which plays a significant role in determining its specificity. A D146K mutation eliminated this trait, allowing non-specific L-cysteine degradation. Using computational biology, we identified an orthologous residue in SclA, H100, and generated mutant enzymes with site-directed mutagenesis. The proteins were overexpressed, purified, and characterized for their biochemical properties. All mutants exhibited varying levels of activity towards L-selenocysteine, hinting at a catalytic role for H100. Additionally, L-cysteine acted as a competitive inhibitor towards all enzymes with higher affinity than L-selenocysteine. Finally, our experiments revealed that SclA possessed extremely poor cysteine desulfurase activity with each mutation exhibiting subtle changes in turnover. Our findings offer key insight into the molecular mechanisms behind selenium-over-sulfur specificity and may further elucidate the role of selenocysteine lyases in vivo. iii Dedicated to my parents, Steve and Sheri Johnstone. I hope I’ve made you proud. iv ACKNOWLEDGMENTS First and foremost, I would like to thank my formal mentor and thesis chair, Dr. William Self, for accepting me as his student and allowing me to work on this project. You always kept me on the right path whenever I would doubt myself and pushed me to strive for the best. Your curiosity, intuition, and professionalism have greatly contributed to my growth as a researcher. Thanks again, Doc. Second, I would like to thank the remaining members of my thesis committee, Dr. Hervé Roy and Dr. Sean Moore, for their contributions to my project. Your questions and critiques have vastly improved my ability to think as a scientist. My decisions as a researcher are majorly governed by a spirit of inquiry thanks to your assistance. Additionally, this entire project would not have been possible without Dr. Moore’s ‘Round-the-horn site-directed mutagenesis technique. Special thanks to Robert Wingo for taking the time to teach me ‘Round-the-horns, protein purification, and many other tricks of the trade in molecular biology. The outcome here would have certainly been different without your help, my friend. To Mrs. Jessica Wilson, lab coordinator for the UCF microbiology labs: I am sincerely grateful for your patience, sincerity, and overall guidance. My time as a microbiology teaching assistant mainly influenced my decision to study bacteriology in the first place. With your support, I came to dearly love a subject that I initially hated with every fiber of my being. To Kelly Rosch: thank you for the good times. Our late-night discussions about science whether it be about bacteriology or physics have kept me avidly curious about the universe. You have taught me that science truly is fun, and that the pursuit of knowledge is best enjoyed with a friend. v And to the past and present members of the Self lab: thank you. I have had the utmost pleasure working alongside all of you, and I would not be here without your advice and company. Finally, I present a quote from a famous scientist; his modesty set the foundation for microbial analysis and inspired me to press on with my studies: "I have therefore published the method, although I am aware that as yet it is very defective and imperfect; but it is hoped that also in the hands of other investigators it will turn out to be useful." – Hans Christian Gram, describing the Gram stain—an experiment which he deemed a “failure” and the first major microbiological technique I ever learned. vi TABLE OF CONTENTS LIST OF FIGURES ....................................................................................................................... ix LIST OF TABLES .......................................................................................................................... x LIST OF ACRONYMS / ABBREVIATIONS .............................................................................. xi CHAPTER 1: INTRODUCTION ................................................................................................... 1 Selenium and its Role in Biology ................................................................................................ 1 Biological Incorporation of Selenium ......................................................................................... 2 The NifS-like Protein Family ...................................................................................................... 4 A Selenocysteine Lyase in Enterococcus faecalis ...................................................................... 5 The Mechanism for Selenium-over-Sulfur Specificity ............................................................... 6 CHAPTER 2: MATERIALS AND METHODS ............................................................................ 9 Materials ...................................................................................................................................... 9 Growth Media and Bacterial Maintenance .................................................................................. 9 Sequence Alignments and Homology Modeling ...................................................................... 10 Site-directed Mutagenesis ......................................................................................................... 11 Gel Extraction and Ligation ...................................................................................................... 12 Plasmid Preparation and Sequencing ........................................................................................ 14 Expression and Purification of SclA Mutants ........................................................................... 15 Protein Analysis and Quantification ......................................................................................... 18 Lead Acetate Assay ................................................................................................................... 19 vii Methylene Blue Assay .............................................................................................................. 20 CHAPTER 3: RESULTS .............................................................................................................. 22 H100 of SclA aligns to D146 of hSCL ..................................................................................... 22 H100 point mutants of SclA were successfully generated ........................................................ 26 SclA H100 mutants can be overexpressed and purified ............................................................ 28 SclA H100 mutants demonstrate varying Michaelis-Menten kinetics for L-selenocysteine .... 31 L-Cysteine inhibits the SCL activities of H100 mutants ........................................................... 38 SclA demonstrates weak CDS activity ...................................................................................... 45 CHAPTER 4: DISCUSSION ........................................................................................................ 47 Manipulation of the catalytic cysteine may provide specificity ................................................ 47 H100 may not function as a catalytic residue ..........................................................................
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