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Structural and Kinetics Studies of the Enzyme Dihydropteroate Synthase and the Implications for Antibiotic Resistance Katherine A

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Structural and Kinetics Studies of the Enzyme Dihydropteroate Synthase and the Implications for Antibiotic Resistance Katherine A University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 5-2009 Structural and Kinetics Studies of the Enzyme Dihydropteroate Synthase and the Implications for Antibiotic Resistance Katherine A. Ayers University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Medical Biochemistry Commons, and the Medical Cell Biology Commons Recommended Citation Ayers, Katherine A. , "Structural and Kinetics Studies of the Enzyme Dihydropteroate Synthase and the Implications for Antibiotic Resistance" (2009). Theses and Dissertations (ETD). Paper 333. http://dx.doi.org/10.21007/etd.cghs.2009.0020. This Thesis is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. Structural and Kinetics Studies of the Enzyme Dihydropteroate Synthase and the Implications for Antibiotic Resistance Document Type Thesis Degree Name Master of Science (MS) Program Biomedical Sciences Track Cell Biology and Biochemistry Research Advisor Stephen White, PhD Committee Richard Lee, PhD Susan Senogles, PhD DOI 10.21007/etd.cghs.2009.0020 This thesis is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/333 Structural and Kinetics Studies of the Enzyme Dihydropteroate Synthase and the Implications for Antibiotic Resistance A Thesis Presented for The Graduate Studies Council The University of Tennessee Health Science Center In Partial Fulfillment Of the Requirements for the Degree Master of Science From The University of Tennessee By Katherine A. Ayers May 2009 Dedication To my beloved husband, Clay. ii Acknowledgements I would like to express my gratitude to everyone who has helped me in my endeavor of pursuing a Master of Science degree. To Dr. Stephen White, without his immense knowledge and hard work, this research project would not have been possible. To my committee members, Dr. Susan Senogles and Dr. Richard Lee for their advice and experience. To Tracey Lee and Dr. Darcie Miller, as well as the other members of the White lab, for their constant care and mentorship. Lastly, I must thank my family for their love and support. iii Abstract The goal of this study is to develop small molecule inhibitors of DHPS for the treatment of a variety of infectious diseases. According to the World Health Organization (WHO), infectious diseases kill more than 13 million people worldwide every year making it the second leading cause of death behind cardiovascular disease. The sulfonamide class of drugs has been in use since the 1930’s to treat many infectious agents and act by targeting the enzyme dihydropteroate synthase (DHPS) of the prokaryotic and lower eukaryotic folate pathway. DHPS is an ideal drug target because humans do not synthesize folate de novo and is a well validated system. However, the emergence of bacterial resistance has limited the efficacy of sulfonamides, and an increasing trend in drug resistance has heightened the need for development of new therapeutics. Although drug resistance has severely limited the clinical use of sulfonamides, the folate pathway, and DHPS in particular, remain an ideal target for therapeutic development. This is due to the fact that DHPS accommodates two substrates, para-aminobenzoic acid (pABA) and 6- hydroxymethyl-7,8-dihydropterin-pyrophosphate (DHPPP), which bind to separate and distinct regions of the protein. Sulfonamides act by binding the pABA pocket composed largely of dynamic loop regions which fold in upon substrate binding to complete the active site. In contrast, the pterin pocket is a highly conserved, rigid binding site, and is predicted to be more suitable for the development of small molecule inhibitors. Therefore, we propose targeting the pterin binding site as a means of developing novel small molecule inhibitors of DHPS. The advantages of this method are that pterin binds to a distinct region of DHPS separate from the pABA binding site and removed from areas known to accommodate sulfonamide resistance. In addition, it provides a novel approach to exploit a well validated drug target. We hypothesize that pterin-based compounds will provide a new class of antibiotics that will overcome the problems of drug resistance and provide novel therapeutics for a broad spectrum of infectious diseases. iv Table of Contents Chapter 1: Introduction ................................................................................................... 1 Discovery of Sulfonamides ............................................................................................. 1 Sulfonamides and the Treatment of Infectious Diseases ................................................ 2 Development of Antibiotic Resistance ........................................................................... 2 DHPS and the Folate Biosynthetic Pathway ................................................................... 4 Chapter 2: X-ray Crystallography .................................................................................. 6 Introduction ..................................................................................................................... 6 History............................................................................................................................. 6 Diffraction Theory .......................................................................................................... 1 Chapter 3: Structural Studies of the Dihydropteroate Synthase (DHPS) ................ 10 Background ................................................................................................................... 10 Results ........................................................................................................................... 13 Chapter 4: Kinetic Studies of DHPS ............................................................................. 20 Background ................................................................................................................... 20 Results ........................................................................................................................... 20 Chapter 5: Discussion ..................................................................................................... 27 The Conformation and Roles of Loops-1 and -2 .......................................................... 27 Implications of Sulfonamide Resistance ....................................................................... 27 The Catalytic Mechanism of DHPS .............................................................................. 29 Chapter 6: Materials and Methods ............................................................................... 32 Cloning of the folP Gene............................................................................................... 32 Protein Expression and Purification .............................................................................. 32 Crystallization and Data Collection .............................................................................. 33 Structure Determination ................................................................................................ 33 Radiometric Assay ........................................................................................................ 34 Chapter 7: Future Directions and Conclusions............................................................ 35 Developing a Robust Enzyme Assay ............................................................................ 35 Probing the Enzyme Mechanism .................................................................................. 36 Fragment-Based Virtual Screening ............................................................................... 37 Expanding the Pool of Known DHPS Structures ......................................................... 38 Conclusions ................................................................................................................... 40 List of References ............................................................................................................ 41 Vita ................................................................................................................................... 47 v List of Tables Table 1.1: Types of Sulfonamides and Therapeutic Uses ............................................... 2 Table 1.2: Resistance Mutations from Clinical Isolates ................................................. 3 Table 3.1: Crystallization Data of the DHPS Double Mutant Construct ...................... 18 Table 4.1: Kinetics Study of Mutant Alleles ................................................................ 22 Table 5.1: Sidechains Involved in Substrate Binding ................................................... 30 vi List of Figures Figure 1.1: Structure of Sulfonamides............................................................................ 1 Figure 1.2: Schematic Representation of Tetrahydrofolate Synthesis ........................... 5 Figure 3.1: Structure of the DHPS Active Site............................................................. 11 Figure 3.2: Schematic Representation of the DHPS Transition State .......................... 11 Figure 3.3: DHPS Sequence Alignment ......................................................................
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