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02 Whole.Pdf (7.606Mb) Copyright is owned by the Author of the thesis. Permission is given for a copy to be downloaded by an individual for the purpose of research and private study only. The thesis may not be reproduced elsewhere without the permission of the Author. X-RAY CRYSTALLOGRAPHIC ANALYSES OF THE STRUCTURES OF TWO HEME PROTEINS by Andrew John Sutherland-Smith A thesis submitted in partial satisfaction of th e requirements for the degree of Doctor of Philosophy . in the Institute of Molecular BioSciences at MASSEY UNIVERSITY, NEW ZEALAND June, 1998 ABSTRACT During human development three embryonic hemoglobins are synthesised prior to formation of the placenta. These hemoglobins function to scavenge oxygen from the mother's interstitial fluid enabling embryonic respiration. The human Gower 11 embry­ onic haemoglobin has been crystallized in its carbonmonoxy form, and its (a2C2) structure determined by X-ray crystallography. The structure was solved by molec­ ular replacement and refined at 2.9 A. The Gower 11 hemoglobin tetramer is interme­ diate between the adult hemoglobin R and R2 states, though closer to R2. The tertiary structure of the a subunit is essentially identical when compared to that found in the adult and fetal hemoglobins. The embryonic subunit has a very (a2�2) (a2Y2) c similar structure to the homologous adult � and fetal Y subunits, although with small differences at the N-terminus and in the A helix. Amino acid substitutions can be identified that may play a role in the altered response of the Gower II haemoglobin to allosteric effectors, in particular chloride io ns. Nitrite reductase from Pseudomonas stutzeriis a periplasmic he me enzyme respon­ sible for the reduction of nitrite to nitric oxide. This reaction is the second step in the bacterial denitrification pathway, during which nitrate acts as the terminal electron acceptor for anaerobic respiration and is consequently reduced to nitrogen gas. Ni­ trite reductase from Pseudomonas stutzeri JM300 has been crystallized in the oxi­ dised state and X-ray diffraction data collected to a resolution of 2.8 A. The structure has been solved by the method of molecular replacement. The structure of the en­ zyme is dimeric, with each monomer comprised of two domains. The smaller N-ter­ minal domain covalently binds a c heme group within an all a-helical fold similar to that of the class l e-type cytochromes. The larger C-terminal domain consists of an eight-bladed �-propeller structure that coordinates a d1 heme, a cofactor unique to this class of enzyme. The relative positions of the two domains, and hence the ori­ entations of the bound he me groups are markedly different compared to homolo­ gous enzymes from other species. ii ACKNOWLEDGMENTS Rarely in scientific research is any work done in isolation, and the studies presented here are certainly no exception. I am extremely grateful to the large number of peo­ ple who have assisted me with this work. I would like to thank very much my primary supervisor Professor Ted Baker for pro­ viding much scientific, emotional and financial help throughout the course of these studies, for introducing me to scientific research and always believing that no prob­ lem was unsurmountable. I also gratefully acknowledge the contribution of ideas and advice from my secondary supervisors Dr. Geoff Jameson and Or. Bryan Anderson. I would like to thank a number of people for both their scientific contributions to this work, and their friendship over my time spent at Massey University: Mrs. Heather Baker, Or. Stanley Moore, Dr. Richard Kingston and Dr. Max Paoli. I would also like to thank all other present and former members of the Department of Biochemistry and Structural Biology lab who have provided me with both technical assistance and friendly words of advice and encouragement over the years. I would also like to thank a number of other friends I have made during my time at Massey: Tania, Ross, Catherine, Rick, Neil, Treena, Jakki, Nick, Shaun, Matt, Maria, Heather, Michelle, Amanda, as well as numerous flat-mates and team-mates. The studies on the embryonic hemoglobins were conducted in conjunction with Dr. Tom Brittain and Dr. Oliver Hofmann from the University of Auckland. The work on the P. stutzerin it rite reductase was undertaken in collaboration with Or. Bruce Averill from the E. C. Slater Institute, University of Amsterdam. I would like to thank these people for the time and effort spent making these collaborations a success. I gratefully acknowledge financial supportfr om the award of a Massey University Doctoral Scholarship, and latterly Professor Ted Baker. Thank you to my family: Richard, Mary, Jennifer and James for all their love and en­ couragement. Finally, a special thanks to Rosemaryfor her love, understanding, patience and sup­ port. Thank you all iii TA BLE OF CONTENTS ABSTRACT ..................................................................................................... ii ACKNOWLEDGMENTS ................................................................................. iii TABLE OF CONTENTS ................................................................................. iv LIST OF FIGURES ......................................................................................... ix ABBREVIATIONS ...............................•......................................................... xii RELATED PUBLiCATION ............................................................................ xiv CHAPTER 1 HEME PROTEINS: AN INTRODUCTION 1.1 HE ME PROTEINS IN BIOLOGy ............................ ... ........................................... 1 1.1.1 OXYGEN TRANSPORT AND STORAGE ......................................................................................... 2 1.1.2 ELECTRON TRANSFER .................................................................................................................. 3 1.1.3 ENZYMATIC CATALYSIS .. ............................................................................................................... 4 CHAPTER 2 HEMOGLOBIN: AN OVERVIEW 2.1 THE IMPORTANCE OF OXYGEN IN BIOLOGy ..................... ............................ 7 2.2 HEMOGLOBIN: HISTORICAL ASPECTS......... .............................................. .... 8 2.3 THE STRUCTURE OF HEMOGLOBIN . .......... .. .................................................. 9 2.3.1 CHANGES IN THE STEREOCHEMISTRY OF THE HEME ON OXYGENATION ......................... 11 2.3.2 CHANGES ON OXYGENATION IN THE TERTIARY CONFORMATION OF THE GLOBINS. ...... 11 2.3.2.1 The a subunits ...... ............... .................... .... ............................ ........ ............... ............................. 11 2.3.2.2 The � subunits .... ................... .......... .............................. ......... ....................... ............................. 11 2.3.3 PROPOSED MECHANISM FOR THE T TO R STATE TRANSITION OF HEMOGLOBIN ............. 12 2.4 FUNCTIONAL PROPERTIES OF HEMOGLOBIN .............. ........................... ... 13 2.4.1 OXYGEN BINDING ......................................................................................................................... 13 2.5 ALLOSTERIC EFFECTS OF HEMOGLOBIN ........................................... ........ 15 2.5.1 THE BOHR EFFECT ....................................................................................................................... 15 2.5.2 ALLOSTERIC EFFECT OF 2,3·BISPHOSPHOGLYCE RATE ........................................................ 16 2.5.3 THE CHLORIDE EFFECT...... ............................. ............. ... ............................................ ........ ...... 17 2.5.4 NITRIC OXIDE BINDING ......... ................. .......... ..... .... ........................... ..... .... ..... ....... .............. 17 2.6 HUMAN HEMOGLOBINS DURING DEVELOPMENT ... .................. ................ 18 2.6.1 FETAL HEMOGLOBIN .................................................................................................................... 19 2.6.2 THE EMBRYONIC HEMOGLOBINS.......... ..................................................................................... 20 2.6.3 GENETIC CONTROL OF HEMOGLOBIN SYNTHESIS ................................................................. 24 2.7 FUNCTIONAL PROPERTIES OF EMBRYONIC RED BLOOD CELLS ............ 25 2.8 OXYGEN BINDING AND ALLOSTERIC EFFECTS OF THE HUMAN EMBRYONIC HEMOGLOBINS .......... .................. .................................. .. ........ 26 2.8.1 OXYGEN BINDING MEASUREMENTS.. ........................................................................................ 26 iv TABLE OF CONTENTS 2.8.2 ALLOSTERIC EFFECTS ................................................................................................................. 27 2.8.2.1 Binding of ;:�,3-bisphosphoglycerate ............................................................................................. 27 2.8.2.2 The Bohr e·ffect ......................... ................................................. ................................................... 28 2.8.2.3 The chlorid':l effect in the embryonic hemoglobins ....................................................................... 29 2.8.3 MEAS UREMENT OF HEME STABI LITY ........................................................................................ 30 2.8.4 KINETIC STUDIES .......................................................................................................................... 31 2.9 AIMS OF THIS STUDY ....................... ..............................................................
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