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Biochemical Characterization of Human Serine Racemase: Substrates, Inhibitors and Allosteric Effectors

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Biochemical Characterization of Human Serine Racemase: Substrates, Inhibitors and Allosteric Effectors Department of Pharmacy Laboratories of Biochemistry and Molecular Biology PhD Program in Biochemistry and Molecular Biology XXVII cycle Biochemical characterization of human serine racemase: substrates, inhibitors and allosteric effectors Coordinator: Prof. Andrea Mozzarelli Tutor: Prof. Alessio Peracchi PhD student: MARIALAURA MARCHETTI 2012-2014 Index INDEX INTRODUCTION D-serine: origin, localization and functions ........................................................................ 1 Biological role of D-amino acids in mammals .................................................................. 1 Localization of D-serine and its functions ........................................................................ 1 NMDA receptors ............................................................................................................... 2 Origin and brain distribution of D-serine: neurons versus astroglia ............................... 2 Human Serine Racemase .................................................................................................... 6 Structure ........................................................................................................................... 6 Catalysis ............................................................................................................................ 8 Regulation of SR ............................................................................................................. 10 ATP and cations .................................................................................................... 11 Nitrosylation ......................................................................................................... 11 Interacting proteins .............................................................................................. 12 Phosphorylation and translocation to the membrane ........................................ 14 D-serine and neuropathologies ........................................................................................ 15 hSR as a therapeutic target ............................................................................................... 16 hSR inhibitors .................................................................................................................... 17 References ........................................................................................................................ 19 AIMS OF THE RESEARCH Aims of the research ......................................................................................................... 27 COOPERATIVE BINDING OF ATP ATP binding to human serine racemase is cooperative and modulated by glycine Abstract .......................................................................................................................... 29 Introduction .................................................................................................................... 30 Results and discussion .................................................................................................... 33 Catalytic parameters of hSR for the β-elimination and racemization reactions . 33 ATP binding affinity to hSR measured in the presence of saturating concentration of either L-or D-serine .................................................................. 36 ATP binding to hSR detected by fluorescence measurements ............................ 37 I Index Analyzing ATP binding according to the Monod, Wyman, Changeux model ...... 40 Conclusions ..................................................................................................................... 42 Materials and Methods .................................................................................................. 44 References ...................................................................................................................... 48 ACTIVITY REGULATION BY LIGANDS Regulation of human serine racemase activity and dynamics by halides, ATP and malonate Abstract .......................................................................................................................... 53 Introduction .................................................................................................................... 54 Results and discussion .................................................................................................... 57 hSR stability .......................................................................................................... 58 Effects of phosphates on hSR activity .................................................................. 59 Effects of halides on hSR activity ......................................................................... 60 Active site accessibility by fluorescence quenching ............................................ 67 Effects of malonate on ATP binding ..................................................................... 68 Conclusions ..................................................................................................................... 71 Materials and Methods .................................................................................................. 72 References ...................................................................................................................... 75 INHIBITION STUDIES: RATIONAL DRUG DESIGN Identification and screening of novel malonate-based human serine racemase inhibitors Abstract .......................................................................................................................... 81 Introduction .................................................................................................................... 82 Results and discussion .................................................................................................... 84 Design of substituted cyclopropanes ................................................................... 84 Design of malonate derivatives ............................................................................ 86 Compound library screening ................................................................................ 88 Substituted cyclopropanes ................................................................................... 91 Malonate derivatives ........................................................................................... 92 Conclusions ..................................................................................................................... 93 Materials and Methods .................................................................................................. 95 References ...................................................................................................................... 98 II Index INHIBITION STUDIES: STRUCTURE-BASED VIRTUAL SCREENING Application of structure-based virtual screening for the development of novel human serine racemase inhibitors Abstract ........................................................................................................................ 100 Introduction .................................................................................................................. 101 Results and discussion .................................................................................................. 103 Conclusions ................................................................................................................... 108 Materials and Methods ................................................................................................ 110 References .................................................................................................................... 115 CROWDING AGENTS Dependence of hSR β-eliminase activity on crowding agents Introduction .................................................................................................................. 119 Results and discussion .................................................................................................. 120 Materials and Methods ................................................................................................ 123 References .................................................................................................................... 125 DIVALENT CATIONS Dependence of hSR β-eliminase activity on divalent cations Introduction .................................................................................................................. 126 Results and discussion .................................................................................................. 128 Materials and Methods ................................................................................................ 131 References .................................................................................................................... 134 CONCLUSIONS Conclusions ..................................................................................................................... 135 OTHER RESEARCH ACTIVITIES Human aspartate racemase ............................................................................................ 136 Amino deoxychorismate lyase of Plasmodium falciparum ............................................. 137 References ...................................................................................................................... 138 III INTRODUCTION Introduction D-SERINE: ORIGIN, LOCALIZATION AND FUNCTIONS Biological
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