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Structural and Functional Characterization of the Lantibiotic Mutacin 1140

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Structural and Functional Characterization of the Lantibiotic Mutacin 1140 STRUCTURAL AND FUNCTIONAL CHARACTERIZATION OF THE LANTIBIOTIC MUTACIN 1140 By JAMES LEIF SMITH A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2002 Copyright 2002 by James Leif Smith This work is dedicated to all my family and friends. Finishing this Ph.D. has come down to two traits that my family instilled in me. One is to never give up, and the other is the lack of good common sense. My friends for standing by my side while I complained moaned and groaned about my life over the last five years. ACKNOWLEDGMENTS First and foremost, I am thankful to my parents for all the love and guidance they have given me throughout my life. I would like to thank my lab mates Cherian Zachariah, Eduardo Espinoza, Matt Carrigan, Ramanan Thirumoorthy, Steve Thomas, Terry Green, and Alexis Harrison for their help and most of all for their friendship. I would like to thank my mentor Arthur S. Edison for teaching me patience. I am very thankful to him for all that he has done for me and for his patience with me. I have learned very much in the time I spent in his lab. I would like to thank my committee members Nancy Denslow, Ben Dunn, Jeff Hillman, and Gerry Shaw for all their help with my project. In particular I would like to thank the Department of Oral Biology and Jeffrey Hillman for supporting my work. I would also like to thank all of my committee members for supporting my decision to enter the MBA program. I would like to thank Jim Rocca for his tutelage and friendship over the years. He was always available to me when I had questions and his enthusiasm for science has been very motivating for me. I would also like to thank everyone who has helped me along the way! Lastly, I would like to thank my friends for all their support. iv TABLE OF CONTENTS page LIST OF TABLES............................................................................................................ vii LIST OF FIGURES ......................................................................................................... viii ABSTRACT.........................................................................................................................x CHAPTER 1 THE WONDERFUL WORLD OF LANTIBIOTICS ...................................................1 Introduction................................................................................................................... 1 Biosynthesis of Lantibiotics.......................................................................................... 2 Methods for Determining Lantibiotic Structure. .......................................................... 7 Covalent Structures of Lantibiotics. ........................................................................... 11 Three-Dimensional Structures of Lantibiotics............................................................ 14 Mutagenesis of Lantibiotics........................................................................................ 17 Bactericidal Function of Lantibiotics.......................................................................... 23 Commercial Applications of Lantibiotics................................................................... 25 2 STRUCTURAL CHARACTERIZATION OF MUTACIN 1140 AND A NOVEL METHOD FOR THE RAPID IDENTIFICATION OF LANTIBIOTICS ..................51 Note............................................................................................................................. 51 Introduction................................................................................................................. 51 Experimental Procedures ............................................................................................ 53 Production and Purification of Mutacin 1140........................................................ 53 Chemical Sequencing............................................................................................. 55 Mass Spectrometry................................................................................................. 56 Nuclear Magnetic Resonance (NMR) Spectroscopy. ............................................ 57 Results......................................................................................................................... 58 Chemical Sequencing............................................................................................. 58 Mass Spectrometry................................................................................................. 60 NMR Spectroscopy................................................................................................ 62 Discussion................................................................................................................... 65 v 3 THREE DIMENSIONAL STRUCTURE CHARACTERIZATION OF MUTACIN 1140 AND THE POSSIBLE ORIENTATION OF THE LIPID BOUND MOLECULE................................................................................................................82 Introduction................................................................................................................. 82 Experimental Procedures ............................................................................................ 84 NMR Spectroscopy ................................................................................................ 84 Computer-Assisted Molecular Modeling (CAMM) .............................................. 85 Results......................................................................................................................... 88 Nuclear Magnetic Resonance................................................................................. 88 Restrained Molecular Dynamics Simulations........................................................ 88 Global Structure of Mutacin 1140.......................................................................... 90 Structural Elements of Mutacin 1140 .................................................................... 91 Discussion................................................................................................................... 95 4 MECHANISTIC STUDIES OF MUTACIN 1140 INDUCED PERMEABILIZATION OF PHOSPHOLIPID VESICLES .....................................121 Introduction............................................................................................................... 121 Experimental Procedures .......................................................................................... 122 Vesicle Preparation (Avanti Polar Lipids Protocol)............................................. 122 Carboxyfluorescein (CF) Leakage Experiments (65, 81). ................................... 123 Determination of Total Phosphorus (Avanti Polar Lipids Inc. Protocol, (126)).. 124 Transmission Electron Microscopy...................................................................... 125 Results....................................................................................................................... 126 CF Release. .......................................................................................................... 126 Transmission Electron Microscopy...................................................................... 127 Discussion................................................................................................................. 128 5 CONCLUSIONS AND FUTURE DIRECTIONS.....................................................139 LIST OF REFERENCES.................................................................................................145 BIOGRAPHICAL SKETCH ...........................................................................................159 vi LIST OF TABLES Table page 1-1. Type A lantibiotics Characterized as of January 2002..............................................29 1-2. Edman Sequencing of Mutacin 1140.........................................................................30 2-1. Amino acid sequence of mutacin 1140 and daughter ions ........................................68 2-2. NMR chemical shift values .......................................................................................70 3-1. Protocol for the Structural Determination of Mutacin 1140....................................101 3-2. PROCHECK-NMR software results .......................................................................102 3-3. Determined scalar coupling values..........................................................................105 3-4. The total differences between scalar couplings…………………………………...106 vii LIST OF FIGURES Figure page 1-1. Schematic of Lantibiotic prepropeptide modification...............................................31 1-2. The structure of the modified residues in Type A lantibiotics. .................................33 1-3. Cellular maturation processing of Lantibiotics. ........................................................34 1-4. Comparison of lantibiotic leader sequences. .............................................................36 1-5. Sequence alignment of Type A lantibiotics...............................................................37 1-6. Representative covalent structures ............................................................................39 1-7. Schematic of ethanethiol derivatization of lantibiotic residues.................................41 1-8. Covalent structure of mutacin 1140...........................................................................42
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