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Information to Users INFORMATION TO USERS This manuscript has been reproduced 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 comer 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 Beil & Howell information Company 300 Nortn Zeeb Road Ann Arbor. Ml 48106-1346 USA 313761-4700 800.521-0600 Order Number 9431039 Cloning, nucleotide sequence determination, and transcriptional analysis of the histidase structural gene fromStreptomyees griscus Wu, Pen-Chaur, Ph.D. The Ohio State University, 1994 UMI 300 N. Zeeb Rd. Ann Arbor. M I 48106 Cloning, Nucleotide Sequence Determination, and Tranacriptlonal Analyals of the Hiatfdaee Structural Gene from Sfrepfomycesg r lf u t DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in the Graduate School of The Ohio State University By Pen-ChaurWu, B.S., M.A. ***** The Ohio State University 1994 Dissertation Committee Approved By Charles J. Daniels Aldis Darzins Adviser Kathleen E. Kendrick Department of Microbiology William R. Strohl DEDICATION To my wife, Lily, and my parents ii ACKNOWLEDGMENTS I thank my advisor, Dr. Kathleen E. Kendrick, for her advice and guidance for the past five years. I also thank my committee members, Drs. Charles J. Daniels, Aldis Darzins, and William R. Strohl, as well as Drs. Samuel J. Black and F. Robert Tabita for their comments and suggestions about my research project. I am indebted to Dr. Peter J. White and my lab colleagues for their technical assistance and encouragement. iii VITA January 19, 1953 ........... Bom - Tainan, Taiwan, Republic of China 1977 ................................ B, S. in Biology, National Taiwan Normal University, Taipei, Taiwan, ROC 1977 - 1979 .................. Second Lieutenant ROC Army 1979 -- 1960 .................. Teaching Staff, Sun-Sun Junior High School, Tainan County, Taiwan, ROC 1964 ................................ M.A. in Microbiology, California State University, Fresno, California 1964 ~ 1966 .................. Scientist and Microbial Assay Supervisor, Cyanamid Taiwan Corp., Hsinchu, Taiwan, ROC 1986 -- present................ Graduate Teaching and Research Associate, Department of Microbiology. The Ohio State University, Columbus, Ohio PUBLICATIONS Wu. P.-C., T.A. Kroening, P.J. White, and K.E. Kendrick. 1992. Purification of histidase from Sfrepfomyces griseus and nucleotide sequence of thehutH structural gene. J. Bactehol. 174:1647*1655 Wu, P.-C., T.A. Kroening, P.J. White, and K.E. Kendrick. 1992. Histidine ammonia-lyase from Streptomyces griamua Gene 115:19-25. FIELDS OF STUDY Major Field: Microbiology Studies in gene regulation in streptomycetes, Dr. Kathleen E. Kendrick iv TABLE OF CONTENTS DEDICATION.............................................................................................. ii ACKNOWLEDGMENTS............................................................................ iii VITA.......................................................................................................... iv UST OF TABLES ..................................................................................... viii LIST OF FIGURES .................................................................................. ix CHAPTER I. INTRODUCTION.............................................................. 1 Histidine Catabolism ........................................................ 1 Biochemical Analysis of Histidase ..................................... 4 Genetic Analysis of Histidine Utilization .......................... 7 Biological Importance of Sfrepfomyces ............................ 16 Nitrogen Metabolism in Streptomyces............................... 16 CHAPTER II. MATERIALS AND METHODS.......................................... 26 Bacterial Strains, Plasmids, and Bacteriophage ............... 26 Media and Culture Conditions ......................................... 29 Recombinant DNA Techniques ......................................... 31 Isolation of DNA .................................................... 31 Generation and Manipulation of DNA Fragments . 33 Hybridization Analysis ...................................................... 38 Southern Hybridization ......................................... 38 v Plaque Hybridization .............................................. 39 Northern Hybridization ......................................... 42 Colony Hybridization .............................................. 42 Nucleotide Sequence Determination ................................. 43 Bacterial Transformations .................................................. 44 RNA Techniques ............................................................... 46 Run-off Transcription .............................................. 46 Isolation of RNA .................................................... 47 SI Mapping and Primer Extension Analysis 46 Preparation of Cell Extracts and Enzyme Assays ............. 50 CHAPTER III. RESULTS.......................................................................... 52 Cloning the hutH Gene from $. griseu s ............................ 52 Features of the Nucleotide Sequence of h u tH .................. 63 Complementation Analysis ................................................ 69 Repressor Titration Experiments ....................................... 92 Transcriptional Analysis of the hutH G en e ........................ 94 Molecular Characterization of S. griseus SKK896, a Hut* M u ta n t ................................................................... 106 CHAPTER IV. DISCUSSION ................................................................... 109 Summary .......................................................................... 129 LIST OF REFERENCES............................................................................ 130 APPENDICES A. Maps of Plasmid Vectors Used in This Study .................. 140 B. List of Plasmids Constructed in This Study ...................... 151 vi Isolation of Hut’ Mutants List ot Tables Table Page 1. Bacterial strains used ........................................................ 27 2. Plasmid vectors and bacteriophage used ......................... 28 3. Media used ....................................................................... 30 4. Hut enzyme activities in transformants of SKK821 and SKKB96 .................................................................. 93 5. Titration of a negative regulatory factor by upstream sequences in SKK821 and SKK896 ...................... 95 6. Promoter activity of the hutH upstream sequences using promoter-probe vectors plJ486 and plJ487 ......... 98 7. Promoter activity of S. griseus transformants containing the hutH upstream sequences in the promoter-probe vector pXE4 ........................................................... 100 8. Suppression of the defect in SKK896 at high copy number ............................................................................ 107 9. List of plasmids constructed ............................................. 152 10. List of Hut'Mutants of S. griseus ...................................... 164 11. Activities of the Hut enzymes in SKK821 and Hut' mutants of S. g rise u s ...................................................................... 165 viii List of Flgurss Figure Pag* 1. Pathways of L-histidine utilization in bacteria .................. 2 2. Organization and transcriptional units of the bacterial hut g e n e s ..................................................... 8 3. Life cycle of Streptomyces................................. 17 4. Metabolism of L-histidine in streptomycetes ..................... 21 5. Degenerate oligonucleotide probe used for cloning hutH 40 6. Southern analysis of total genomic DNA from S. griseus SKK821 probed with oligonucleotides specific to the N-terminus of hutH ................................ 53 7. Identification of hutH from a library of genomic DNA from S. griseus SKK821 .............................................. 55 8. Southern analysis of AKK500 and AKK501 with the oligonucleotide probe ............................ 57 9. Restriction maps of pKKSOO and pKK501 ......................... 59 10. Strategy used to clone hutH from S. griseus SKKB21 . 61 11. Determination of the direction of transcription of hutH in pK K 501 .................................................. 64 ix 12. Construction
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