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University Microfilms International 300 N INFORMATION TO USERS This was produced from a copy of a document sent to us for microfilming. While the most advanced technological means to photograph and reproduce this document have been used, the quality is heavily dependent upon the quality of the material submitted. The following explanation of techniques is provided to help you understand markings or notations which may appear on this reproduction. 1. The sign or “target” for pages apparently lacking from the document photographed is “ Missing Page(s)” . If it was possible to obtain the missing page(s) or section, they are spliced into the film along with adjacent pages. This may have necessitated cutting through an image and duplicating adjacent pages to assure you of complete continuity. 2. When an image on the film is obliterated with a round black mark it is an indication that the film inspector noticed either blurred copy because of movement during exposure, or duplicate copy. Unless we meant to delete copyrighted materials that should not have been film ed, you will find a good image of the page in the adjacent frame. If copyrighted materials were deleted you will find a target note listing the pages in the adjacent frame. 3. When a map, drawing or chart, etc., is part of the material being photo­ graphed the photographer has followed a definite method in “sectioning” the material. It is customary to begin filming at the upper left hand corner of a large sheet and to continue from left to right in equal sections with small overlaps. If necessary, sectioning is continued again—beginning below the first row and continuing on until complete. 4. For any illustrations that cannot be reproduced satisfactorily by xerography, photographic prints can be purchased at additional cost and tipped into your xerographic copy. Requests can be made to our Dissertations Customer Services Department. 5. Some pages in any document may have indistinct print. In all cases we have filmed the best available copy. University Microfilms International 300 N. ZEEB RD., ANN ARBOR, Ml 48106 8121868 Vargo, D onald L eslie EFFECT OF PEROXIDE ON FREE AND ENZYME-BOUND 5- DEAZAFLAVIN The Ohio State University Ph.D. 1981 University Microfilms International300 N. Zeeb Road. Ann Arbor, M I 48106 PLEASE NOTE: In all cases this material has been filmed in the best possible way from the available copy. Problems encountered with this document have been identified here with a check markV . 1. Glossy photographs or pages______ 2. Colored illustrations, paper or print______ 3. Photographs with dark background______ 4. Illustrations are poor copy______ 5. Pages with black marks, not original copy______ 6. Print shows through as there is text on both sides of page______ 7. Indistinct, broken or small print on several pages 8. Print exceeds margin requirements______ 9. Tightly bound copy with print lost in spine______ 10. Computer printout pages with indistinct print______ 11. Page(s)____________ lacking when material received, and not available from school or author. 12. Page(s)____________ seem to be missing in numbering only as text follows. 13. Two pages numbered____________ . Text follows. 14. Curling and wrinkled pages______ 15. Other_________________________________________________________________________ University Microfilms International EFFECT OF PEROXIDE ON FREE AND ENZYME-BOUND 5-DEAZAFLAVIN DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Donald Leslie Vargo, B.A. * * * * * The Ohio State University 1981 Reading Committee: Approved By Dr. M.S. Jorns Dr. M.H. KLapper Dr. R.M. Mayer Adviser Department of Chemistry To my wife, Agnes. ii ACKNOWLEDGMENTS My warmest thanks and deepest appreciation to my adviser, Dr* Marilyn Jorns, who suggested this problem and whose guidance and council were of inestimable value. To my colleague, Mr. Alex Pokora, whose parallel research with oxynitrilase has been often referred to in this text, I owe a special note of thanks. I am also indebted to Mr. Kim Calvo for performing nonlinear least squares evaluation of my data, Dr. Charles Cottrell for Fourier transform NMR spectroscopy, Mr. Dick Weisenberger for mass spectral anal­ yses, Mrs. Sylvia Dahl for isolating glycolate oxidase, and Dr. Vincent Massey for his gift of flavodoxin. I also wish to acknowledge the financial support for this research pro­ vided by a grant from the National Institutes of Health (GM 22662). iii VITA January 3, 1949*•*•...... Born - Canonsburg, Pennsylvania 1972............. • •*......B.A., California State College, California, Pennsylvania 1976-1979* ••• ............Teaching Associate, Department of Chemistry, The Ohio State Univer­ sity, Columbus, Ohio 1979-1981 •••••• *......... Research Associate, Department of Chemistry, The Ohio State Univer­ sity, Columbus, Ohio FIELD OF STUDY Biochemistry TABLE OF CONTENTS Page ID EL X C ATX ON ©ooo©©©©©®©©©®®®®®©©©©®®©®®®©®®®®®*®®©©©©®©* XX ACKNOWLEDGMENTS ooo®®®®©®©®©©©®®®®®©©©®®®®®©©©©©©©©*©** XXX VXTAa9ooo9OO90O9Qoeooocooo00eoo««oo«eo0tt*eoeftQoooaeeoa i V L I ST OF TABLES ©oooo©®®©®®©©®®©®©®©®©®®©©®®©©©0©0©®®©©0 VXX L 1ST OF FIGURESQooooe®©©®©©©©©©©®©©©®©®*©®©®©0©©®®©®®© VXXX Chapter X o INTRODUCTION ©©©ooo®®®©®®*©®*®*®©®®®®®©®®®®®©®®© 1 A. Deazaflavin as an analogue for flavin«0oo 1 B® Oxygen intermediates of flavin and deaZaflaVXno0©0©0®©©0®«®®®©0©©®©®#0®©®©®® 11 11 o MAT ERIALS AND MiiiTHODS ©ooooooo®®®®®®®®®®©®©®©®®© 17 A« Reagents and solutions©oooo©©©®®®®©®©®©©® 17 1 © Chemicals and supplierso®©®®©©©®®©®®© 17 2© Reagent purification and solutions,,®* 18 Bo Synthesis© 0 ©®©©©®©©®®©©®©©®©©©®©©©©©©®©©® 20 1 © lO-Methyl-5-deazaisoalloxazine® © ® * * © © 20 2® 3 ,10-Dimethyl~5“deazaisoalloxazine© 0® 22 3 o 5-Beazariboflavino©o®©®©®®®®®©©©©©©®® 2if if« if a, 5-Epoxy- 10-me thyl-5-deazaiso- alloxazine©e®e©®©©9©«©®®oo©o©©®©©©®®© 28 5® if a, 3-Epoxy-3, IO-dimethyl-5-deaza- xsoalloxazineo©o©®®®®®®®©©®®®®®®®®®®® 29 6 ® ifa,5“Epoxy-5-deazariboflavin®....... 30 C© Preparation of glycolate oxidase and flavodoxin reconstituted with 5-deazaFMN0 31 1 © General procedure© ©eo®®®®®©®®®®®®©®®® 31 2o Glycolate oxidase© ©©ooo®®®®®®®®®®©*©© 31 3• Flavodoxxnoa©®®®®©®®©©®©®®®®®©©®®®©©® 32 Do Instruments© © ®© ©................ 33 E© Statistics© •©•••©••••©•••••••©•©•••a®®®©® 3 if v TABLE OF CONTENTS (CON*T) Page III. RESULTS AND DISCUSSION......................... 35 A. The identification of a 4a»5-*epoxy- 5-deazaflavin............................ 35 B. Reaction of 4as5-epoxy-5*-deazaiso- alloxazine with iodide . • • • 61 C. Kinetic studies of the epoxidation of 3.10-dimethyl-5-deazaisoalloxazine with HOOH m aqueous h u f f o r s « 66 D. The epoxidation of 5~deazaisoalloxazine with HOOH in carbonate buffer...........• 75 E. Kinetic studies of the epoxidation of 3.10-dimethyl-5-deazaisoalloxazine with ra-chloroperoxybenzoic acid in aqueous buffersc......................... 31 F. Kinetic studies of the epoxidation of 3»IO-dimethyl-5-deazaisoalloxazine with m-chloroperoxybenzoic acid in chloroform. 87 G. Studies with 5-deazariboflavin......... 90 H. Relationship of 4a} 5-epoxide to deazaFAD-X.ooeeoo.eo«eoo0 ooe....e.eo..o.o 101 I. Studies with Glycolate Oxidase........... 104 1. Reaction of 5-deazaFMN glycolate oxidase with HOOH.o.................. 104 2. Reaction of 5-deazaFMN glycolate oxidase with m-chloroperoxybenzoic acid....ooo.......................... 106 3. Characterizing the first intermediate 108 4. Characterizing the second inter­ mediate. ........ 90. 0 ..............0 O. 1 13 5. Characterization of the product....... 116 6. Kinetics of the reaction of EdeazaFMN with H O O H . 116 7. Theoretical absorption spectra... 121 J. Studies with Flavodoxin............. 127 LIST OF REFERENCES...................... ............. 132 vi LIST OF TABLES Table Page 1. Reactivity of the if a, 5-Epoxides of 1O-Methyl-5-deazaisoalloxazine (III), 3.10-Dimethyl-5-deazaisoalloxazine (IV), and 5-deazariboflavin (VI) with Iodide and Thioxane in Methanol at 25 C„.... 65 2, Effect of pH on the Epoxidation of 3.10-Dimethyl-5-deazaisoalloxazine with Hydrogen Peroxideo..o..0 oo....o.o..o...oo.. 74 3. Effect of pH on the Epoxidation of 3,10-Dimethyl-5-deazaisoalloxazine with m-Chloroperoxybenzoic acid................. 8if if. Epoxidation of 3, IO-Dimethyl-5-deaza- isoalloxazine with m-Chloroperoxyben- zoic acid in Chloroform................... 88 5. Calculated composition of the reaction mixture during the recording of curve 2, Figure 3 5....................... 124 6. Calculated composition of the reaction mixture during the recording of curve 3, Figure 35................ •...................... 125 vii LIST OF FIGURES Figure Page 1. Reaction of 10-methyl-5-deazaisoalloxazine with HOOH in acetonitrile................ 36 2. Reaction of 3 910-dimethyl-5-deazaisoalloxazine with HOOH in acetonitrile.................oo.o 37 3. Titration of 3,IO-dimethyl-5-deazaisoalloxazine With SUlfite. o o o a e . o e o o . e . e . o e o o o o . o o . o . o . ooo 4^ If. Reaction of 10-methyl-5-deazaisoalloxazine with cyanide.oo.eoo.o.ooo..00.0.00.00.00.000.. 41 5. Reaction of IO-methyl-5-deazaisoalloxazine with t-butyl hydroperoxide in acetonitrile.... 43 6. Thin layer chromatography of the product formed with 10-methyl»5“deazaisoalloxazine and t-butyl hydroperoxide..o .0.0000.0.00.00.....o.oeooo... 46 7. Reaction of 4a»5-epoxy-3,10-dimethyl-5-deaza- isoalloxazine tlV) with morpholine.........o.. 51 8. Reaction of 3*IO-dimethyl-5-deazaisoalloxazine with m-chloroperoxybenzoic acid in chloroform.
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