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Aspects of Glycogen Phosphorylase Catalysis and Regulation Ronald Joseph Uhing Iowa State University

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Aspects of Glycogen Phosphorylase Catalysis and Regulation Ronald Joseph Uhing Iowa State University Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 1980 Aspects of glycogen phosphorylase catalysis and regulation Ronald Joseph Uhing Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Biochemistry Commons Recommended Citation Uhing, Ronald Joseph, "Aspects of glycogen phosphorylase catalysis and regulation " (1980). Retrospective Theses and Dissertations. 7140. https://lib.dr.iastate.edu/rtd/7140 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. INFORMATION TO USERS This was produced from a copy of a document sent to us for microHlming. 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 filmed, you will find a good image of the page 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 comer 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. Universi^ Micrdllnns International 300 N. ZEEB ROAD, ANN ARBOR. Ml 48106 18 BEDFORD ROW, LONDON WC1R 4EJ, ENGLAND 8106065 UHING, RONALD JOSEPH ASPECTS OF GLYCOGEN PHOSPHORYLASE CATALYSIS AND REGULATION Iowa Stale University PH.D. 1980 University Microfilms I ntern Stio nsi 300 N. Zeeb Road, Ann Arbor, MI 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 mark . 1. Glossy photographs \/^ 2. Colored illustrations 3. Photographs with dark background '4. Illustrations are poor copy 5. °rint shows through as there is text on both sides of page 6. Indistinct, broken or small print on several pages 7. Tightly bound copy with print lost in spine 8. Computer printout pages with indistinct print 9. Page(s) lacking when material received, and not available from school or author 10. Page(s) seem to be missing in numbering only as text follows n. Poor carbon copy 12. Not original copy, several pages with blurred type 13. Appendix pages are poor copy 14. Original copy with light type 15. Curling and wrinkled pages 16. Other Universiw Micrailms Internationa! 300 N 25== no., ANN AR30B Ml J8106'3131 761-47Q0 Aspects of glycogen phosphorylase catalysis and regulation by Ronald Joseph Uhing A Dissertation Submitted to the Graduate Faculty in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Department: Biochemistry and Biophysics Major: Biochemistry Approved: Signature was redacted for privacy. In Charge of(^jor Work Signature was redacted for privacy. Signature was redacted for privacy. Iowa State University Ames, Iowa 1980 il TABLE OF CONTENTS Page DEDICATION ill ABBREVIATIONS iv HISTORICAL BACKGROUND 1 PART I. THE EFFECTS OF ORGANIC SOLVENTS ON THE 14 CATALYTIC AND COENZYME PROPERTIES OF GLYCOGEN PHOSPHORYLASE INTRODUCTION 15 EXPERIMENTAL PROCEDURES 17 RESULTS 22 DISCUSSION 76 CONCLUSION 89 ACKNOWLEDGEMENTS 91 PART II. THE EFFECT OF DIETARY PYRIDOXINE ON GLYCOGEN 92 METABOLISM IN THE MOUSE INTRODUCTION 93 EXPERIMENTAL PROCEDURES 95 RESULTS 99 DISCUSSION 117 CONCLUSION 123 ACKNOWLEDGEMENTS 124 LITERATURE CITED 125 OVERALL ACKNOWLEDGEMENTS 134 iii DEDICATION To my parents, for a lifetime of support and encouragement. iv ABBREVIATIONS AMP Adenosine 5'-monophosphate AMPS Adenosine 5'-thiophosphate ATP Adenosine 5'-triphosphate cAMP Adenosine 35'-monophosphate EDTA Ethylenediaminetetraacetate glucose-l-P glucose-l-phosphate IMP Inosine 5'-monophosphate MES 2(N-Morpholino)ethane sulfonic acid P^ Orthophosphate Tris Tris(hydroxymethyl)aminomethane UDPG Uridine 5'-diphosphoglucose 1 HISTORICAL BACKGROUND Glycogen phosphorylase (a-l,4-glucan : orthophosphate glycosyl transferase, E.(.2.4.1.1) catalyzes the Initial step in the degradation of glycogen; (a-l,4-glueoside)^ + $ (a-l,4-glucoside)^_^ + glucose-1-P. Although the equilibrium constant for this reaction is 0.3 at pH 6.8 (1), the enzyme acts in the direction of glycogen degradation in the cell due to the high ratio of inorganic phosphate to glucose-1-P (2). In muscle,the breakdown of glycogen is coupled to the energy needs of contraction, whereas in liver it is linked primarily to blood glucose homeostasis. The reaction sequence outlined above is an important control step in carbohydrate metabolism and glycogen phosphorylase has been shown to be part of a complex regulatory system involving several enzymes and the levels of substrates, divalent cations, nucleotides, and hormones. In addition, skeletal muscle phosphorylase has been suggested to be a reservoir for pyridoxal phosphate (3), which is an indispensable part of the enzyme (4), so that glycogen metabolism may also be affected by the nutritional intake of this vitamin. In 1943, Cori and Green reported that rabbit skeletal muscle glycogen phosphorylase exists in two forms, phosphorylase _a and phosphorylase ^ (5). Subsequent studies have elucidated an interconversion mechanism involving the following phosphorylation-dephosphorylation sequence; 2 4 ATP phosphoxylasé b kinase 2 phosphorylase ^ phosphorylase a phosphorylase phosphatase Phosphorylase a from skeletal muscle is a tetrameric enzyme composed of identical subunits (6). From sequence studies a monomeric molecular weight of 97,412 daltons has been determined (7). The phosphorylation site on the enzyme is a seryl residue located fourteen amino acids from the amino terminus (8). The £i form of the enzyme exhibits activity in the absence of an allosteric effector, although the activity is stimulated about 25% by AMP (9). The ^ form of the enzyme is a dimer (10), and exhibits an absolute requirement for a nucleotide activator (9). Although in the absence of any effectors phosphorylase a exists as a tetramer and phosphorylase ^ as a dimer, there exists a significant dimer-tetramer equilibrium for both forms. This equilibrium is dependent upon various factors including ionic strength, pH, temperature, and the presence of substrates and allosteric effectors (11). Huang and Graves have shown that the dimeric form of phosphorylase ^ is several fold more active than the tetramer (12). Under normal 3 physiological conditions both phosphorylases ^ and ^ exist as dimers. Phosphorylases a^ from several sources, e.g. lobster (13) and rabbit liver (14), exist only as dimers. Both the phosphorylation and dephosphorylation reactions are rigidly controlled. Fhosphorylase kinases from both skeletal muscle and liver have been shown to be activated via phosphorylation by cAMP-dependent protein kinase (15,16). Physiologically, this phosphor­ ylation is a result of hormonal stimulation. Fhosphorylase kinase can also be activated through an autophosphorylation mechanism initiated by the presence of calcium ions (17). This may be an important regulatory mechanism in skeletal muscle where nervous stimulation results in the release of calcium into the cytoplasm from the sarcoplasmic reticuluum. The controls on phosphorylase phosphatase activity have not been resolved to the same extent as those on the kinase. The substrate specificity of the phosphatase is apparently broader than that of phosphorylase kinase (18). Thus, one set of controls appears to be substrate competition for the enzyme. Hers and colleagues have suggested that this is important in the simultaneous inactlvation of phosphorylase and activation of glycogen synthase in vivo (19), and Witters and Avruch have also found evidence for this from studies utilizing perfused liver (20). Phosphatase activity is also regulated by the presence of various heat stable protein inhibitors (21-24). The presence of type I heat stable inhibitor is increased by epinephrine (25), suggesting that 4 both the phosphorylation and dephosphorylation of phosphorylase may be regulated by cAMP-dependent
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