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Information to Users INFORMATION TO USERS The most advanced technology has been used to photograph and reproduce this manuscript from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand corner and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. University Microfilms International A Bell & Howell Information Company 300 North Zeeb Road. Ann Arbor. Ml 48106-1346 USA 313/761-4700 800 521-0600 Order Number 9111825 Studies on the biosynthesis of the modified-peptide antibiotic, thiostrepton Zeng, Zhaopie, Ph.D. The Ohio State University, 1990 UMI 300 N. Zeeb Rd. Ann Arbor, MI 48106 NOTE TO USERS THE ORIGINAL DOCUMENT RECEIVED BY U.M.I. CONTAINED PAGES WITH SLANTED AND POOR PRINT. PAGES WERE FILMED AS RECEIVED. THIS REPRODUCTION IS THE BEST AVAILABLE COPY. STUDIES ON THE BIOSYNTHESIS OF THE MODIFIED-PEPTIDE ANTIBIOTIC, THIOSTREPTON DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Zhaopie Zeng, B.S. ************** The Ohio State University 1990 Dissertation Committee: Approved by Heinz G. Floss Leo A. Paquette Viresh Rawal ^Adviser Department of Chemistry To my parents ACKNOWLEDGEMENTS I would like to express my most sincere gratitude to my research advisor, Professor Heinz G. Floss, for his guidence, encouragement, and patience throughout my graduate study. I want to give special thank you to Professor John M. Beale and Dr. Ulla Mocek for their help with acquisition of NMR data, valuable suggestions and friendship. I also would like to express my appreciation to Kay Kampsen for her help during my years in Professor Floss' group. Finally, I would like to express my gratitude to my friends and family, expeciallly my parents and my brothers for their supports and encouragements. VITA March 28,1962 .............................................. Born - Shanghai, China. July 1985........................................................ B.S., Department of Chemistry, East China Normal University, Shanghai, China. Sept. 1985-June 1987 ................................ Teaching Assistant, Department of Chemistry, the Ohio State University, Columbus, Ohio. June 1987-present ...................................... Graduate Research Associate, Department of Chemistry, the Ohio State University, Ohio. PUBLICATIONS P. Zhou, D. O'Hagan, U. Mocek, Z. Zeng, L.-D. Yuen, T. Frenzel, C.J. Unkefer, J.M. Beale and H.G. Floss, "Biosynthesis of the Antibiotic Thiostrepton. Methylation of Tryptophan in the Formation of the Quinaldic Acid Moiety by Transfer of the Methionine Methyl Group with Net Retention of Configuration", J. Am. Chem. Soc., 111, 7274 (1989) FIELDS OF STUDY Major Field: Chemistry Studies in Organic Chemistry TABLE OF CONTENTS PAGE ACKNOWLEDGEMENTS................................................................................ in VITA................................................................................................................... iv LIST OF TABLES ............................................................................ vii LIST OF FIGURES............................................................................................ viii LIST OF ABBREVIATIONS.............................................................................. xii INTRODUCTION.................................................................................................. 1 RESULTS............................................................................................................ 16 Fermentation ..................................................................................... 16 Isolation of Thiostrepton .................................................................. 17 Thiostrepton Assay by HPLC and Production Curve 18 NMR Spectroscopy............................................................................ 20 D,L-[1-13C]lsoleucine Synthesis and Feeding 33 D,L-[1-13C,3-2H ]Threonine Synthesis and Feeding ................ 37 Formation of Piperideine Ring ........................................................ 44 Mode of Incorporation of Serine into Other Structural Elements ............................................................... 51 Formation of Quinaldic Acid Moiety ........................................... 62 Stereochemistry of Hydrogen Loss from the p-Carbon of Tryptophan ....................................................... 64 Role of 4-(1-Hydroxyethyl)quinoline-2-carboxylic Acid ................................................................................................ 65 Attempted 180 2 Feeding Experiment ........................................ 67 15N Precursor Feedings .................................................................. 70 DISCUSSION................................................................................................... 87 EXPERIMENTAL SECTION........................................................................... 106 Materials and General Methods ..................................................... 106 1. Materials..................................................................................... 106 2. General Methods ...................................................................... 107 Fermentation. ................................................................................... 108 Isolation of Thiostrepton .............................................................. 110 v Thiostrepton Assay by HPLC ...................................................... 110 Feeding Experiments with Labeled Precursors 111 Synthesis of D,L-[1 -13C]lsoleucine ........................................ 113 Derivatization of the Mixture of Isoleucine and Alloisoleucine .................................................................. ............... 114 Synthesis of Threonine .................................................................. 115 Synthesis of (ZS.S’RJ-P'^HjTryptophan .............................. 117 Synthesis of (ZS^'SHS'^Hp-ryptophan .......................... 118 Feeding Experiment with Mixture of (2'S,3'S)- [3'-3H]-Tryptophan and D,L-[3'-14C]Tryptophan 119 Feeding Experiment with Mixture of (2'S,3'R)- [3'-3H]-Tryptophan and D,L-[3'-14C]Tryptophan .............. 119 Feeding Experiment with Mixture of (2'S,3'S)- [3'-3H]-Tryptophan and L-[3'-14C]Tryptophan .................. 119 Feeding Experiment with Mixture of (2'S,3'R)- [3'-3H]Tryptophan and L-[3'-^4C]Tryptophan ..................... 120 Co-crystallization of a Mixture of Tryptophan ............... 120 4-(1 -Hydroxyethyl)quinaldic Acid Synthesis ........................ 121 4-(1-Hydroxy-[1 -3H]ethyl)quinaldie Acid Synthesis.... ............................................................................ 123 Feeding Experiment with the 4-(1-Hydroxy- [1 -3H]ethyl)quinaldic Acid .......................................................... 124 180 2 Experiment............................................................................. 125 Fermentation with Different Amounts of (NH4)2S 0 4 in Production Medium .................................................................. 125 15NH4CI Feeding ............................................................................. 126 15N-Glycine Feeding ............................... 126 Fermentation with Different Amounts of Serine 127 Feeding Experiment with 15NH4CI and a 3-Fold Excess of Unlabeled Serine ...................................... 127 REFERENCES........................................................................ 132 vi LIST OF TABLES TABLE PAGE 1. 13C and 1H NMR spectral data of thiostrepton ........................ 31 2. 13C-13C-Coupling patterns in thiostrepton derived from L-[1,2-13C2]- and L-[2,3-13C2]serine ............... 32 3 3 H/14c Ratios in feeding experiments with radiolabeled tryptophan ........................................................................ 66 4. 2D-NMR COSY shift correlations of thiostrepton.. .................. 82/83 5. 1H-NMR assignm ents of thiostrepton .......................................... 84/85 6. 2D-NMR 1H/15N shift correlations of thiostrepton 86 7. Required number of biosynthetic genes ...................................... 105 8. Feeding experiments with labeled precursor .......................... 112 9. HPLC system for tracing tryptophan synthesis ...................... 129 10. HPLC system for purification of tryptophan ...........................
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