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Tài liệu Lipases and Phospholipases in Drug Development pptx
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Edited by
Günter Müller and Stefan Petry
Lipases and Phospholipases
in Drug Development
From Biochemistry
to Molecular Pharmacology
Lipases and Phospholipases in Drug Development
Edited by
Günter Müller and Stefan Petry
Further Titles of Interest
J. Östman, M. Britton, E. Jonsson (Eds.)
Treating and Preventing Obesity
2004. ISBN 3-527-30818-0
T. Dingermann, D. Steinhilber, G. Folkers (Eds.)
Molecular Biology in Medicinal Chemistry
2004. ISBN 3-527-30431-2
A. K. Duttaroy, F. Spener (Eds.)
Cellular Proteins and Their Fatty Acids in Health and Disease
2003. ISBN 3-527-30437-1
H. Buschmann et al. (Eds.)
Analgesics –
From Chemistry and Pharmacology to Clinical Application
2002. ISBN 3-527-30403-7
G. Molema, D. K. F. Meijer (Eds.)
Drug Targeting
2001. ISBN 3-527-29989-0
Edited by
Günter Müller and Stefan Petry
Lipases and Phospholipases
in Drug Development
From Biochemistry
to Molecular Pharmacology
Dr. Günter Müller
Dr. Stefan Petry
Aventis Pharma Germany
Industrial Park Höchst
65926 Frankfurt am Main
Germany
Library of Congress Card No.: applied for
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from
the British Library.
Bibliographic information published
by Die Deutsche Bibliothek
Die Deutsche Bibliothek lists this publication
in the Deutsche Nationalbibliografie; detailed
bibliographic data is available in the Internet at
<http://dnb.ddb.de>
© 2004 WILEY-VCH Verlag GmbH & Co. KGaA,
Weinheim, Germany
All rights reserved (including those of translation
in other languages). No part of this book may be
reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or
translated into machine language without written
permission from the publishers. Registered names,
trademarks, etc. used in this book, even when not
specifically marked as such, are not to be considered unprotected by law.
Printed in the Federal Republic of Germany
Printed on acid-free paper
Composition K+V Fotosatz GmbH, Beerfelden
Printing Strauss Offsetdruck GmbH, Mörlenbach
Bookbinding Litges & Dopf Buchbinderei GmbH,
Heppenheim
ISBN 3-527-30677-3
This book was carefully produced. Nevertheless,
editors, authors and publisher do not warrant the
information contained therein to be free of errors.
Readers are advised to keep in mind that statements, data, illustrations, procedural details or
other items may inadvertently be inaccurate.
Preface XIII
List of Contributors XV
1 Purification of Lipase 1
Palligarnai T. Vasudevan
1.1 Introduction 2
1.2 Pre-purification Steps 2
1.3 Chromatographic Steps 3
1.4 Unique Purification Strategies 7
1.5 Theoretical Modeling 9
1.5.1 Model Formulation 9
1.5.1.1 Mobile Phase 9
1.5.1.2 Stationary Phase 10
1.5.1.3 Boundary Conditions 10
1.5.2 Solution 11
1.5.3 Method of Moments 13
1.5.4 Model Evaluation 15
1.5.5 Simulation Results 16
1.5.5.1 Effect of Feed Angle 16
1.5.5.2 Effect of Flow Rate 17
1.5.5.3 Effect of Rotation Rate 17
1.5.5.4 Effect of Column Height 19
1.6 Conclusions 19
1.7 Acknowledgements 20
1.8 References 20
2 Phospholipase A1 Structures, Physiological and Patho-physiological Roles
in Mammals 23
Keizo Inoue, Hiroyuki Arai, and Junken Aoki
2.1 Introduction 23
2.2 Phosphatidylserine-specific Phospholipase A1 (PS-PLA1) 27
2.2.1 Historical Aspects 27
V
Contents
2.2.2 Biochemical Characterization and Tissue Distribution 27
2.2.3 Structural Characteristics 29
2.2.4 Substrate Specificity 29
2.2.5 Possible Functions 30
2.3 Membrane-associated Phosphatidic Acid-selective Phospholipase A1s
(mPA-PLA1 and mPA-PLA1) 32
2.3.1 Historical Aspects 32
2.3.2 Characterization and Distribution 33
2.3.3 Structural Characteristics 34
2.3.4 Function 34
2.4 Phosphatidic Acid-preferring Phospholipase A1 (PA-PLA1) 35
2.4.1 Historical Aspects 35
2.4.2 Characterization and Distribution 36
2.4.3 Substrate Specificity 36
2.4.4 Function 37
2.5 KIAA0725P, a Novel PLA1 with Sequence Homology to a Mammalian
Sec23p-interacting Protein, p125 37
2.5.1 Historical Aspects 37
2.5.2 Characterization and Distribution 37
2.6 References 38
3 Rational Design of a Liposomal Drug Delivery System Based on Biophysical
Studies of Phospholipase A2 Activity on Model Lipid Membranes 41
Kent Jørgensen, Jesper Davidsen, Thomas L. Andresen,
and Ole G. Mouritsen
3.1 Introduction 41
3.2 Role for Secretory Phospholipase A2 (sPLA2) in Liposomal
Drug Delivery 43
3.3 Lateral Microstructure of Lipid Bilayers and its Influence
on sPLA2 43
3.4 sPLA2 Degradation of Drug-delivery Liposomes: A New Drug-delivery
Principle 46
3.4.1 Liposomes Protected by Polymer Coating 46
3.4.2 Biophysical Model Drug-delivery System to Study sPLA2 Activity 47
3.4.3 Effect of Lipid Composition on sPLA2-triggered Drug Release
and Absorption 48
3.4.4 Effect of Temperature on Liposomal Drug Release and Absorption
by sPLA2 49
3.4.5 Liposomal Drug Release as a Function of sPLA2 Concentration 50
3.5 Conclusion 51
3.6 Acknowledgments 51
3.7 References 52
VI Contents
4 Phospholipase D 55
John H. Exton
4.1 Introduction 55
4.2 Structure and Catalytic Mechanism of Mammalian
Phospholipase D 56
4.3 Cellular Locations of PLD1 and PLD2 58
4.4 Post-translational Modification of PLD 59
4.5 Regulation of PLD1 and PLD2 60
4.5.1 Role of PIP2 60
4.5.2 Role of PKC 61
4.6 Role of Rho Family GTPases 64
4.7 Role of Arf Family GTPases 65
4.8 Role of Tyrosine Kinase 66
4.9 Role of Ral 66
4.10 Cellular Functions of PLD 66
4.11 Role of PLD in Growth and Differentiation 67
4.12 Role of PLD in Vesicle Trafficking in Golgi 68
4.13 Role of PLD in Exocytosis and Endocytosis 68
4.14 Role of PLD in Superoxide Formation 69
4.15 Role in Actin Cytoskeleton Rearrangements 70
4.16 Role in Lysophosphatidic Acid Formation 71
4.17 Role of PA in Other Cellular Systems 71
4.18 References 72
5 Sphingomyelinases and Their Interaction with Membrane Lipids 79
Félix M. Goñi and Alicia Alonso
5.1 Introduction and Scope
5.2 Sphingomyelinases 80
5.2.1 Types of Sphingomyelinases 80
5.2.1.1 Acid Sphingomyelinase (aSMase) 80
5.2.1.2 Secretory Sphingomyelinase (sSMase) 81
5.2.1.3 Neutral, Mg2+-dependent Sphingomyelinases (nSMase) 81
5.2.1.4 Mg2+-independent Neutral Sphingomyelinases 84
5.2.1.5 Alkaline Sphingomyelinase from the Intestinal Tract 85
5.2.1.6 Bacterial Sphingomyelinase-phospholipase C 85
5.2.2 Sphingomyelinase Mechanism 85
5.2.2.1 Binding of Magnesium Ions 85
5.2.2.2 Binding of Substrate 85
5.2.2.3 Mechanism of Catalysis 86
5.2.3 Sphingomyelinase Assay 88
5.2.4 Sphingomyelinase Inhibitors 89
5.3 Sphingomyelinase–Membrane Interactions 89
5.3.1 Lipid Effects on Sphingomyelinase Activity 90
5.3.2 Effects of Sphingomyelinase Activity on Membrane Properties 91
5.3.2.1 Effects on Membrane Lateral Organization 91
Contents VII
5.3.2.2 Effects on Membrane Permeability 93
5.3.2.3 Effects on Membrane Aggregation and Fusion 94
5.4 Acknowledgments 96
5.5 References 96
6 Glycosyl-phosphatidylinositol Cleavage Products
in Signal Transduction 101
Yolanda León and Isabel Varela-Nieto
6.1 Introduction 101
6.2 GPI Structure and Hydrolysis by Specific Phospholipases 102
6.3 Diffusible Factors and the Regulation of GPI Levels 104
6.4 IPG Structure and Biological Activities 106
6.5 GPI/IPG Pathway and the Intracellular Signaling Circuit 109
6.6 Acknowledgments 112
6.7 References 113
7 High-throughput Screening of Hormone-sensitive Lipase
and Subsequent Computer-assisted Compound Optimization 121
Stefan Petry, Karl-Heinz Baringhaus, Karl Schoenafinger, Christian Jung,
Horst Kleine, and Günter Müller
7.1 Introduction 121
7.1.1 Lipases in Metabolism 121
7.2 Lipases Show Unique Differences in Comparison
to Other Drug Targets 122
7.3 Lipase Assays 123
7.4 Hormone-sensitive Lipase (HSL) as a Drug Target in Diabetes 125
7.4.1 Biological Role of HSL 125
7.4.2 Characteristics of HSL 126
7.4.3 Inhibitors of HSL 128
7.5 Perspective 134
7.6 References 134
8 Endothelial Lipase: A Novel Drug Target for HDL and Atherosclerosis? 139
Karen Badellino, Weijun Jin, and Daniel J. Rader
8.1 Introduction 139
8.2 Structure of Endothelial Lipase 140
8.3 Tissue Expression of Endothelial Lipase and Its Implications 141
8.4 Enzymatic Activity and Effects on Cellular Lipid Metabolism
of Endothelial Lipase 142
8.5 Regulation of Endothelial Lipase Expression 145
8.6 Physiology of Endothelial Lipase 146
8.7 Variation in the Human Endothelial Lipase Gene 149
8.8 Endothelial Lipase as a Potential Pharmacologic Target 151
8.9 References 151
VIII Contents
9 Digestive Lipases Inhibition: an In vitro Study 155
Ali Tiss, Nabil Miled, Robert Verger, Youssef Gargouri,
and Abdelkarim Abousalham
9.1 Introduction 155
9.1.1 3-D Structure of Human Pancreatic Lipase 156
9.1.2 3-D Structure of Human Gastric Lipase 158
9.2 Methods for Lipase Inhibition 159
9.2.1 Method A: Lipase/Inhibitor Pre-incubation 162
9.2.2 Method B: Inhibition During Lipolysis 162
9.2.3 “Pre-poisoned” Interfaces 163
9.2.3.1 Method C 163
9.2.3.2 Method D 163
9.3 Inhibition of Lipases by E600 and Various Phosphonates 164
9.3.1 Inhibition of PPL, HGL and RGL by Radiolabeled E600 165
9.3.2 Interfacial Binding to Tributyrin Emulsion of Native
and Chemically Modified Digestive Lipases 167
9.3.3 Inhibition of Lipases by Phosphonates and the 3-D Structures
of Lipase-inhibitor Complexes 167
9.3.3.1 Synthesis of New Chiral Organophosphorus Compounds Analogous
to TAG 167
9.3.3.2 The 2.46 Å Resolution Structure of the Pancreatic/Procolipase
Complex Inhibited by a C11 Alkylphosphonate 170
9.3.3.3 Crystal Structure of the Open Form of DGL in Complex
with a Phosphonate Inhibitor 173
9.4 Inhibition of Digestive Lipases by Orlistat 174
9.4.1 Introduction 174
9.4.2 Inhibition of Digestive Lipases by Pre-incubation
with Orlistat (Method A) 175
9.4.2.1 Inhibition of Gastric Lipases 175
9.4.2.2 Inhibition of Pancreatic Lipases 176
9.4.2.3 Kinetic Model Illustrating the Covalent Inhibition of HPL
in the Aqueous Phase 180
9.4.3 Inhibition of Digestive Lipases During Lipolysis (Method B) 181
9.4.4 Inhibition of Digestive Lipases on Oil Emulsions “Poisoned”
with Orlistat (Method C) 181
9.4.5 Inhibition of Digestive Lipases on Oil Substrate “Poisoned”
with Orlistat (Method D) 184
9.4.5.1 Inhibition of Pancreatic Lipase on Emulsion “Pre-poisoned”
with Orlistat 184
9.4.5.2 Inhibition of Gastric and Pancreatic Lipases on Mixed Films
Containing Orlistat 185
9.4.5.3 Inhibition of Pancreatic Lipase on Oil Drop “Pre-poisoned”
with Orlistat 185
9.5 References 187
Contents IX
10 Physiology of Gastrointestinal Lipolysis and Therapeutical Use
of Lipases and Digestive Lipase Inhibitors 195
Hans Lengsfeld, Gabrielle Beaumier-Gallon, Henri Chahinian,
Alain De Caro, Robert Verger, René Laugier, and Frédéric Carrière
10.1 Introduction 195
10.2 Tissular and Cellular Origins of HGL and HPL 196
10.3 Hydrolysis of Acylglycerols by HGL and HPL 199
10.3.1 Substrate Specificity 199
10.3.2 Specific Activities of HGL and HPL 200
10.3.3 Lipase Activity as a Function of pH 202
10.3.4 Effects of Bile Salts on the Activity of HGL and HPL 202
10.4 Gastrointestinal Lipolysis of Test Meals in Healthy Human
Volunteers 204
10.4.1 Test Meals 205
10.4.2 Experimental Device for Collecting Samples in vivo 207
10.4.3 Gastric and Duodenal pH Variations 207
10.4.4 Lipase Concentrations and Outputs 207
10.4.5 Lipolysis Levels 211
10.5 HGL and HPL Stability 213
10.6 Potential Use of Gastric Lipase in the Treatment of Pancreatic
Insufficiency 215
10.7 Inhibition of Gastrointestinal Lipolysis by Orlistat for Obesity
Treatment 216
10.7.1 The Lipase Inhibitor Orlistat 216
10.7.2 Design of Clinical Studies for Quantification of Lipase and Lipolysis
Inhibition 217
10.7.3 HGL Inhibition by Orlistat 218
10.7.4 HPL Inhibition by Orlistat 219
10.7.5 Effects of Orlistat on Gastric Lipolysis 220
10.7.6 Effects of Orlistat on Duodenal Lipolysis 221
10.7.7 Effects of Orlistat on Overall Lipolysis 221
10.7.8 Effects of Orlistat on Fat Excretion 221
10.7.9 Weight Management by Orlistat in Obese Patients 222
10.7.10 Conclusions 224
10.8 References 224
11 Physiological and Pharmacological Regulation of Triacylglycerol Storage
and Mobilization 231
Günter Müller
11.1 Metabolic Role of Triacylglycerol 231
11.1.1 Triacylglycerol and Energy Storage 231
11.1.2 Lipolysis and Re-esterification 234
11.1.3 TAG Storage/Mobilization and Disease 236
11.1.3.1 Diabetes Mellitus and Metabolic Syndrome 236
11.1.3.2 Lipotoxicity 238
X Contents
11.1.3.2.1 -Cells 238
11.1.3.2.2 Cardiac Myocytes 239
11.1.3.2.3 Molecular Mechanisms 240
11.1.3.3 Inborn Errors of TAG Storage and Metabolism 241
11.2 Components for TAG Storage and Mobilization 242
11.2.1 TAG in Lipoproteins 242
11.2.2 TAG in Adipose Cells 243
11.2.2.1 Enzymes of TAG Synthesis 244
11.2.2.2 Lipid Droplets 246
11.2.2.2.1 Morphology and Lipid Composition 246
11.2.2.2.2 Protein Composition 248
11.2.2.2.3 Biogenesis 252
11.3 Mechanism and Regulation of TAG Mobilization 259
11.3.1 cAMP 259
11.3.2 Phosphorylation of HSL 260
11.3.3 Dephosphorylation of HSL 263
11.3.4 Intrinsic HSL Activity 263
11.3.5 Translocation of HSL 264
11.3.5.1 Mechanism 264
11.3.5.2 Involvement of Perilipins 266
11.3.5.3 Involvement of Lipotransin 268
11.3.6 Intrinsic Activity of HSL 270
11.3.6.1 Feedback Inhibition 270
11.3.6.2 Adipocyte Lipid-binding Protein 272
11.3.7 Expression of HSL 274
11.3.8 Release of Lipolytic Products 275
11.3.8.1 FA Transport 275
11.3.8.2 Glycerol Transport 276
11.3.8.3 Cholesterol Transport 277
11.4 Physiological, Pharmacological and Genetic Modulation
of TAG Mobilization 278
11.4.1 Muscle Contraction 278
11.4.2 Nutritional State 279
11.4.3 Hormones and Cytokines 279
11.4.3.1 Insulin 279
11.4.3.1.1 Molecular Mechanisms 279
11.4.3.1.2 Desensitization 281
11.4.3.2 Leptin 282
11.4.3.3 Growth Hormone 283
11.4.3.4 Glucose-dependent Insulinotropic Polypeptide 283
11.4.3.5 TNF- 283
11.4.4 ASP 285
11.4.5 Acipimox and Nicotinic Acid 286
11.4.5.1 Mode of Action 287
11.4.5.2 Molecular Mechanism 288
Contents XI
11.4.5.3 Desensitization 289
11.4.6 Glimepiride and Phosphoinositolglycans 290
11.4.7 Differences in Regulation of TAG Storage and Mobilization between
Visceral and Subcutaneous Adipocytes 292
11.4.8 Up-/Down-regulation of Components of TAG Storage
and Mobilization 294
11.4.8.1 HSL 294
11.4.8.2 ALBP 296
11.4.8.3 Perilipin 297
11.4.8.4 PKA 299
11.4.8.5 ASP 300
11.4.8.6 Caveolin 301
11.5 Concluding Remarks 302
11.6 References 303
Subject Index 333
XII Contents