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Biochemical Characterization of Human Matrix Metalloproteinases and Their Newly Designed Inhibitors Related to Stroke Qiang Cao

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Biochemical Characterization of Human Matrix Metalloproteinases and Their Newly Designed Inhibitors Related to Stroke Qiang Cao Florida State University Libraries Electronic Theses, Treatises and Dissertations The Graduate School 2010 Biochemical Characterization of Human Matrix Metalloproteinases and Their Newly Designed Inhibitors Related to Stroke Qiang Cao Follow this and additional works at the FSU Digital Library. For more information, please contact [email protected] THE FLORIDA STATE UNIVERSITY COLLEGE OF ARTS AND SCIENCES BIOCHEMICAL CHARACTERIZATION OF HUMAN MATRIX METALLOPROTEINASES AND THEIR NEWLY DESIGNED INHIBITORS RELATED TO STROKE By QIANG CAO A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy Degree Awarded: Fall Semester, 2010 The members of the committee approve the dissertation of Qiang Cao defended on July 14, 2010. Qing-Xiang Amy Sang Professor Directing Dissertation Yan-Chang Wang University Representative Hong Li Committee Member Igor Alabugin Committee Member Approved: Joseph B. Schlenoff, Chair, Department of Chemistry and Biochemistry The Graduate School has verified and approved the above-named committee members. ii This dissertation is dedicated to my parents, Shi-De Cao & Mu-Dan Li. iii ACKNOWLEDGEMENTS There are many people to thank for their support and guidance during the past years. My wife, Juan Zhou, has shown a great deal of patience and personal support through difficult times. Professor Qing-Xiang Amy Sang has provided outstanding scientific guidance and truly developed my interest in cancer research and cardiovascular disease research. A special thanks is given to Drs. Martin Schwartz, Yonghao Jin and Wei Yang for the many discussions about inhibitor interactions the synthesis and modeling of the compounds. I especially thank Mark Dru Roycik for his help on English writing and organizing through the past years and Douglas R. Hurst, Robert Newcomer and Seakoo Lee for their expert guidance throughout my training. I thank the Sang lab members, Chi Ben, Manuel H. Constantino, Suzan Semaan, Dale B. Bosco, Zahraa Khamis, Paul Steward, and other members for their numerous scientific discussions and helps. Last but not least, I would like to thank my family and my friend, Qin Li, for their love and support. Without them, I would not have been able to finish the dissertation on time. iv TABLE OF CONTENTS List of Tables .................................................................................. vii List of Figures ............................................................................... viii List of Abbreviations .................................................................... x Abstract ..................................................................................... xii 1. INTRODUCTION ...................................................................... 1 1.1 Introduction of stroke and how MMPs are involved ............. 1 1.2 Matrix metalloproteinases and their inhibitors...................... 5 2. MATERIALS AND METHODS .............................................. 25 Materials .................................................................................. 25 Total hydrolysis of Quenched Fluorescent Peptide ................... 25 Time Dependence Experiments ............................................... 26 Estimation of the Michaelis constant (Km) Value........................ 26 Competitive inhibition determination .......................................... 27 app ’ The determination of apparent dissociation constant (Ki or Ki ) 27 MMPI stability in HEPES buffer ............................................... 28 MMPI stability in EGM-2 MV ...................................................... 28 Human Brain Microvascular Endothelial (hBMEC) Growth ...... 29 Human Mesenchymal Stem Cell (hMSC) Growth...................... 29 The assay of inhibition on Endothelial cells migration .............. 29 hBMEC Culture & hMSC Co-Culture ......................................... 31 MMPI cytotoxicity in EGM-2MV ................................................. 31 Protease inhibitor preparation ................................................... 31 The inhibitor treatment on hBMEC, protein extraction preparation 32 Cell sample homogenization using the bead beater .................. 32 TCA/Acetone Precipitation ........................................................ 32 Two-dimensional gel electrophoresis ........................................ 32 Analysis of Proteins ................................................................... 33 LC- MS/MS ................................................................................ 33 Protein Search Algorithm ........................................................... 34 3. RESULTS AND DISCUSSION ................................................. 35 3.1 Enzyme kinetics ................................................................... 35 3.2 Inhibitor application and characterization in cellular system 67 3.3 Proteomic studies after hBMEC treated with YHJ-6-43 ....... 77 4. CONCLUSION AND FUTURE WORK ..................................... 86 v REFERENCES ............................................................................. 88 BIOGRAPHICAL SKETCH ............................................................. 107 vi LIST OF TABLES 1.1 Selected Variable Residues in the Active Site of MMPs ...................... 20 1.2. MMP Inhibitors with a Mercaptosulfide Zinc Binding Group ............... 23 1.3. MMP comparison with deep and shallow P1' substituent ................ 41 3.1 The apparent Ki for YHJ-6-43 and YHJ-6-45 against eight members of MMP family ............................................................................................... 54 3.2 The apparent Ki of inhibitor modified with fluoride replacement. ......... 56 3.3 The apparent Ki of inhibitors with Modification on para & meta position at the biphenyl ester ...................................................................................... 57 3.4 The apparent Ki values of inhibitors with modification for increasing rigidity ........................................................................................................ 59 3.5 The apparent Ki of pyrrolidine-based mercaptosulfonamide inhibitors 60 3.6 The apparent Ki of different types inhibitors ........................................ 62 3.7 Table of identified proteins by LC MS-MS ........................................... 81 vii LIST OF FIGURES 1.1 The Structure of Blood Brain Barrier .................................................... 4 1.2 Zinc metalloproteinase classification scheme ...................................... 6 1.3 The conserved amino acid coordinating with catalytic zinc for the metzicin proteases family .......................................................................... 7 1.4 Domain structures of the MMPs.......................................................... 8 1.5 Nomenclature of the peptide substrate ................................................ 11 1.6 The proposed Reaction mechanism for proteolysis by MMPs ............. 12 1.7 The activation network of MMP-9 by MMPs ........................................ 14 1.8 The activation of proMMP-2 involving MT1-MMP and TIMP-2 ............ 15 1.9 Relationship between enzyme and peptide-based inhibitor structure .. 16 1.10 Common zinc binding groups ............................................................ 18 1.11 Inhibitor zinc binding group ................................................................ 20 1.12 Concept and rationale of novel thiol MMPIs proposed in this study ... 21 1.13 Structures and predicted bindings of mercaptosulfide inhibitor MAG-182 and proposed mercaptosulfonamide inhibitors .......................................... 23 3.1 Binding and hydrolyzation between enzyme and substrate ................. 35 3.2 Michaelis-Menten hyperbolic curve ..................................................... 38 3.3 The full structure of substrate used in this study .................................. 39 3.4 Intensity of cleaved substrate .............................................................. 39 3.5 Km of MMP-2 determination ................................................................. 40 3.6 Km of MMP-9 determination ................................................................. 41 3.7 Time dependence study of YHJ-6-43 against MMP-2 ......................... 42 3.8 Time dependence study of YHJ-6-43 against MMP-9 ......................... 42 3.9 Time dependence study of YHJ-6-286 against MMP-2 ....................... 43 3.10 Time dependence study of YHJ-6-286 against MMP-9 ..................... 44 3.11 Enzyme-inhibitor association and dissociation .................................. 44 3.12 The three conditions for a reversible, competitive inhibition .............. 45 3.13 Mechanisms of inhibition ................................................................... 50 3.14 Competitive inhibition of YHJ-6-43 .................................................... 51 app 3.15 The replot of the Ki s ....................................................................... 51 3.16 Competitive inhibition of YHJ-6-286 .................................................. 52 app 3.17 The replot of the Ki s ....................................................................... 52 3.18 The structures of YHJ-6-43(trans) Vs YHJ-6-45(Cis) ........................ 54 3.19 The structures for inhibitors modified with fluoride replacement ........ 55 3.20 The structures for inhibitors with Modification on para & meta position at the biphenyl ester
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