Lipases and Phospholipases in Drug Development: From Biochemistry to Molecular Pharmacology

, by Editor: Günter Müller (Department of Metabolic Diseases, Aventis Pharma, Frankfurt, Germany); Editor: Stefan Petry (Department of Chemistry, Aventis Pharma, Frankfurt, Germany)

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ISBN: 9783527306770 | 3527306773
Cover: Hardcover
Copyright: 4/1/2004

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Lipases and Phospholipases are key control elements in mammalian metabolism. They share many common features that set them apart from other metabolic enzyme classes, most importantly their association with biological membranes. Their potential as drug targets for the treatment of metabolic diseases is widely recognized, and the first lipase inhibitor drugs have been successfully introduced. Providing drug developers with a firm foundation for lipase-centered drug design, the editors of this volume have assembled experts from different scientific disciplines to create a comprehensive handbook for all pharmaceutical chemists, biochemists and physiologists working with lipases. The authors examine fundamental aspects of lipase function in vitro and in vivo, explaining how this knowledge may be used to develop lipase assays. They also treat the physiological roles of lipases in normal and disordered metabolism, as well as strategies to target lipases for the treatment of diabetes, obesity and related disorders. Additional topics include the application of phospholipases for liposome-based drug delivery and their use as diagnostic tools.

Preface

xiii

List of Contributors

1 Purification of Lipase

(22)

Palligarnai T. Vasudevan

1.1 Introduction

(1)

1.2 Pre-purification Steps

(1)

1.3 Chromatographic Steps

(4)

1.4 Unique Purification Strategies

(2)

1.5 Theoretical Modeling

(10)

1.5.1 Model Formulation

(1)

1.5.1.1 Mobile Phase

(1)

1.5.1.2 Stationary Phase

(1)

1.5.1.3 Boundary Conditions

(1)

1.5.2 Solution

(2)

1.5.3 Method of Moments

(2)

1.5.4 Model Evaluation

(1)

1.5.5 Simulation Results

(1)

1.5.5.1 Effect of Feed Angle

(1)

1.5.5.2 Effect of Flow Rate

(1)

1.5.5.3 Effect of Rotation Rate

(1)

1.5.5.4 Effect of Column Height

(1)

1.6 Conclusions

(1)

1.7 Acknowledgements

(1)

1.8 References

(3)

2 Phospholipase A1 Structures, Physiological and Patho-physiological Roles in Mammals

(18)

Keizo Inoue, Hiroyuki Arai, and Junken Aoki

2.1 Introduction

(4)

2.2 Phosphatidylserine-specific Phospholipase Al (PS-PLA1)

(5)

2.2.1 Historical Aspects

(1)

2.2.2 Biochemical Characterization and Tissue Distribution

(2)

2.2.3 Structural Characteristics

(1)

2.2.4 Substrate Specificity

(1)

2.2.5 Possible Functions

(2)

2.3 Membrane-associated Phosphatidic Acid-selective Phospholipase A1s (mPA-PLA1α and mPA-PLA1β)

(3)

2.3.1 Historical Aspects

(1)

2.3.2 Characterization and Distribution

(1)

2.3.3 Structural Characteristics

(1)

2.3.4 Function

(1)

2.4 Phosphatidic Acid-preferring Phospholipase Al (PA-PLA1)

(2)

2.4.1 Historical Aspects

(1)

2.4.2 Characterization and Distribution

(1)

2.4.3 Substrate Specificity

(1)

2.4.4 Function

(1)

2.5 KIAA0725P, a Novel PLA1 with Sequence Homology to a Mammalian Sec23p-interacting Protein, p125

(1)

2.5.1 Historical Aspects

(1)

2.5.2 Characterization and Distribution

(1)

2.6 References

(3)

3 Rational Design of a Liposomal Drug Delivery System Based on Biophysical Studies of Phospholipase A2 Activity on Model Lipid Membranes

(14)

Kent Jørgensen, Jesper Davidsen, Thomas L. Andresen, and Ole G. Mouritsen

3.1 Introduction

(2)

3.2 Role for Secretory Phospholipase A2 (sPLA2) in Liposomal Drug Delivery

(1)

3.3 Lateral Microstructure of Lipid Bilayers and its Influence on sPLA2

(3)

3.4 sPLA2 Degradation of Drug-delivery Liposomes: A New Drug-delivery Principle

(5)

3.4.1 Liposomes Protected by Polymer Coating

(1)

3.4.2 Biophysical Model Drug-delivery System to Study sPLA2 Activity

(1)

3.4.3 Effect of Lipid Composition on sPLA2-triggered Drug Release and Absorption

(1)

3.4.4 Effect of Temperature on Liposomal Drug Release and Absorption by sPLA2

(1)

3.4.5 Liposomal Drug Release as a Function of sPLA2 Concentration

(1)

3.5 Conclusion

(1)

3.6 Acknowledgments

(1)

3.7 References

(3)

4 Phospholipase D

(24)

John H. Exton

4.1 Introduction

(1)

4.2 Structure and Catalytic Mechanism of Mammalian Phospholipase D

(2)

4.3 Cellular Locations of PLD1 and PLD2

(1)

4.4 Post-translational Modification of PLD

(1)

4.5 Regulation of PLD1 and PLD2

(4)

4.5.1 Role of PIP2

(1)

4.5.2 Role of PKC

(3)

4.6 Role of Rho Family GTPases

(1)

4.7 Role of Arf Family GTPases

(1)

4.8 Role of Tyrosine Kinase

(1)

4.9 Role of Ral

(1)

4.10 Cellular Functions of PLD

(1)

4.11 Role of PLD in Growth and Differentiation

(1)

4.12 Role of PLD in Vesicle Trafficking in Golgi

(1)

4.13 Role of PLD in Exocytosis and Endocytosis

(1)

4.14 Role of PLD in Superoxide Formation

(1)

4.15 Role in Actin Cytoskeleton Rearrangements

(1)

4.16 Role in Lysophosphatidic Acid Formation

(1)

4.17 Role of PA in Other Cellular Systems

(1)

4.18 References

(7)

5 Sphingomyelinases and Their Interaction with Membrane Lipids

(22)

Félix M. Goñi and Alicia Alonso

5.1 Introduction and Scope

5.2 Sphingomyelinases

(9)

5.2.1 Types of Sphingomyelinases

(1)

5.2.1.1 Acid Sphingomyelinase (aSMase)

(1)

5.2.1.2 Secretory Sphingomyelinase (sSMase)

(1)

5.2.1.3 Neutral, Mg²+-dependent Sphingomyelinases (nSMase)

(1)

5.2.1.4 Mg²-independent Neutral Sphingomyelinases

(1)

5.2.1.5 Alkaline Sphingomyelinase from the Intestinal Tract

(1)

5.2.1.6 Bacterial Sphingomyelinase-phospholipase C

(1)

5.2.2 Sphingomyelinase Mechanism

(1)

5.2.2.1 Binding of Magnesium Ions

(1)

5.2.2.2 Binding of Substrate

(1)

5.2.2.3 Mechanism of Catalysis

(2)

5.2.3 Sphingomyelinase Assay

(1)

5.2.4 Sphingomyelinase Inhibitors

(1)

5.3 Sphingomyelinase-Membrane Interactions

(7)

5.3.1 Lipid Effects on Sphingomyelinase Activity

(1)

5.3.2 Effects of Sphingomyelinase Activity on Membrane Properties

(1)

5.3.2.1 Effects on Membrane Lateral Organization

(1)

5.3.2.2 Effects on Membrane Permeability

(1)

5.3.2.3 Effects on Membrane Aggregation and Fusion

(2)

5.4 Acknowledgments

(1)

5.5 References

(5)

6 Glycosyl-phosphatidylinositol Cleavage Products in Signal Transduction

101

(20)

Yolanda Leon and Isabel Varela-Nieto

6.1 Introduction

101

(1)

6.2 GPI Structure and Hydrolysis by Specific Phospholipases

102

(2)

6.3 Diffusible Factors and the Regulation of GPI Levels

104

(2)

6.4 IPG Structure and Biological Activities

106

(3)

6.5 GPI/IPG Pathway and the Intracellular Signaling Circuit

109

(3)

6.6 Acknowledgments

112

(1)

6.7 References

113

(8)

7 High-throughput Screening of Hormone-sensitive Lipase and Subsequent Computer-assisted Compound Optimization

121

(18)

Stefan Petry, Karl-Heinz Baringhaus, Karl Schoenafinger, Christian Jung, Horst Kleine, and Günter Müller

7.1 Introduction

121

(1)

7.1.1 Lipases in Metabolism

121

(1)

7.2 Lipases Show Unique Differences in Comparison to Other Drug Targets

122

(1)

7.3 Lipase Assays

123

(2)

7.4 Hormone-sensitive Lipase (HSL) as a Drug Target in Diabetes

125

(9)

7.4.1 Biological Role of HSL

125

(1)

7.4.2 Characteristics of HSL

126

(2)

7.4.3 Inhibitors of HSL

128

(6)

7.5 Perspective

134

(1)

7.6 References

134

(5)

8 Endothelial Lipase: A Novel Drug Target for HDL and Atherosclerosis?

139

(16)

Karen Badellino, Weijun Jin, and Daniel J. Rader

8.1 Introduction

139

(1)

8.2 Structure of Endothelial Lipase

140

(1)

8.3 Tissue Expression of Endothelial Lipase and Its Implications

141

(1)

8.4 Enzymatic Activity and Effects on Cellular Lipid Metabolism of Endothelial Lipase

142

(3)

8.5 Regulation of Endothelial Lipase Expression

145

(1)

8.6 Physiology of Endothelial Lipase

146

(3)

8.7 Variation in the Human Endothelial Lipase Gene

149

(2)

8.8 Endothelial Lipase as a Potential Pharmacologic Target

151

(1)

8.9 References

151

(4)

9 Digestive Lipases Inhibition: an In vitro Study

155

(40)

Ali Tiss, Nabil Miled, Robert Verger, Youssef Gargouri, and Abdelkarim Abousalham

9.1 Introduction

155

(4)

9.1.1 3-D Structure of Human Pancreatic Lipase

156

(2)

9.1.2 3-D Structure of Human Gastric Lipase

158

(1)

9.2 Methods for Lipase Inhibition

159

(5)

9.2.1 Method A: Lipase/Inhibitor Pre-incubation

162

(1)

9.2.2 Method B: Inhibition During Lipolysis

162

(1)

9.2.3 "Pre-poisoned" Interfaces

163

(1)

9.2.3.1 Method C

163

(1)

9.2.3.2 Method D

163

(1)

9.3 Inhibition of Lipases by E600 and Various Phosphonates

164

(23)

9.3.1 Inhibition of PPL, HGL and RGL by Radiolabcled E600

165

(2)

9.3.2 Interfacial Binding to Tributyrin Emulsion of Native and Chemically Modified Digestive Lipases

167

(1)

9.3.3 Inhibition of Lipases by Phosphonates and the 3-D Structures of Lipase-inhibitor Complexes

167

(1)

9.3.3.1 Synthesis of New Chiral Organophosphorus Compounds Analogous to TAG

167

(1)

9.3.3.2 The 2.46 Å Resolution Structure of the Pancreatic/Procolipase Complex Inhibited by a C11 Alkylphosphonate

170

(1)

9.3.3.3 tive Lipases by Orlistat

174

(1)

9.4.1 Introduction

174

(1)

9.4.2 Inhibition of Digestive Lipases by Pre-incubation with Orlistat (Method A)

175

(1)

9.4.2.1 Inhibition of Gastric Lipases

175

(1)

9.4.2.2 Inhibition of Pancreatic Lipases

176

(1)

9.4.2.3 Kinetic Model Illustrating the Covalent Inhibition of HPL in the Aqueous Phase

180

(1)

9.4.3 Inhibition of Digestive Lipases During Lipolysis (Method B)

181

(1)

9.4.4 Inhibition of Digestive Lipases on Oil Emulsions "Poisoned" with Orlistat (Method C)

181

(3)

9.4.5 Inhibition of Digestive Lipases on Oil Substrate "Poisoned" with Orlistat (Method D)

184

(1)

9.4.5.1 Inhibition of Pancreatic Lipase on Emulsion "Pre-poisoned" with Orlistat

184

(1)

9.4.5.2 Inhibition of Gastric and Pancreatic Lipases on Mixed Films Containing Orlistat

185

(1)

9.4.5.3 Inhibition of Pancreatic Lipase on Oil Drop "Pre-poisoned" with Orlistat

185

(2)

9.5 References

187

(8)

10 Physiology of Gastrointestinal Lipolysis and Therapeutical Use of Lipases and Digestive Lipase Inhibitors

195

(36)

Hans Lengsfeld, Gabrielle Beaumier-Gallon, Henri Chahinian, Alain De Caro, Robert Verger, Rene Laugier, and Frédéric Carrière

10.1 Introduction

195

(1)

10.2 Tissular and Cellular Origins of HGL and HPL

196

(1)

10.3 Hydrolysis of Acylglycerols by HGL and HPL

199

(1)

10.3.1 Substrate Specificity

199

(1)

10.3.2 Specific Activities of HGL and HPL

200

(2)

10.3.3 Lipase Activity as a Function of pH

202

(1)

10.3.4 Effects of Bile Salts on the Activity of HGL and HPL

202

(2)

10.4 Gastrointestinal Lipolysis of Test Meals in Healthy Human Volunteers

204

(1)

10.4.1 Test Meals

205

(2)

10.4.2 Experimental Device for Collecting Samples in vivo

207

(1)

10.4.3 Gastric and Duodenal pH Variations

207

(1)

10.4.4 Lipase Concentrations and Outputs

207

(4)

10.4.5 Lipolysis Levels

211

(2)

10.5 HGL and HPL Stability

213

(1)

10.6 Potential Use of Gastric Lipase in the Treatment of Pancreatic Insufficiency

215

(1)

10.7 Inhibition of Gastrointestinal Lipolysis by Orlistat for Obesity Treatment

216

(1)

10.7.1 The Lipase Inhibitor Orlistat

216

(1)

10.7.2 Design of Clinical Studies for Quantification of Lipase and Lipolysis Inhibition

217

(1)

10.7.3 HGL Inhibition by Orlistat

218

(1)

10.7.4 HPL Inhibition by Orlistat

219

(1)

10.7.5 Effects of Orlistat on Gastric Lipolysis

220

(1)

10.7.6 Effects of Orlistat on Duodenal Lipolysis

221

(1)

10.7.7 Effects of Orlistat on Overall Lipolysis

221

(1)

10.7.8 Effects of Orlistat on Fat Excretion

221

(1)

10.7.9 Weight Management by Orlistat in Obese Patients

222

(2)

10.7.10 Conclusions

224

(1)

10.8 References

224

(7)

11 Physiological and Pharmacological Regulation of Triacylglycerol Storage and Mobilization

231

(102)

Günter Müller

11.1 Metabolic Role of Triacylglycerol

231

(1)

11.1.1 Triacylglycerol and Energy Storage

231

(3)

11.1.2 Lipolysis and Re-esterification

234

(2)

11.1.3 TAG Storage/Mobilization and Disease

236

(1)

11.1.3.1 Diabetes Mellitus and Metabolic Syndrome

236

(2)

11.1.3.2 Lipotoxicity

238

(1)

11.1.3.2.1 β-Cells

238

(1)

11.1.3.2.2 Cardiac Myocytes

239

(1)

11.1.3.2.3 Molecular Mechanisms

240

(1)

11.1.3.3 Inborn Errors of TAG Storage and Metabolism

241

(1)

11.2 Components for TAG Storage and Mobilization

242

(1)

11.2.1 TAG in lipoproteins

242

(1)

11.2.2 TAG in Adipose Cells

243

(1)

11.2.2.1 Enzymes of TAG Synthesis

244

(2)

11.2.2.2 Lipid Droplets

246

(1)

11.2.2.2.1 Morphology and Lipid Composition

246

(2)

11.2.2.2.2 Protein Composition

248

(4)

11.2.2.2.3 Biogenesis

252

(7)

11.3 Mechanism and Regulation of TAG Mobilization

259

(1)

11.3.1 cAMP

259

(1)

11.3.2 Phosphorylation of HSL

260

(3)

11.3.3 Dephosphorylation of HSL

263

(1)

11.3.4 Intrinsic HSL Activity

263

(1)

11.3.5 Translocation of HSL

264

(1)

11.3.5.1 Mechanism

264

(2)

11.3.5.2 Involvement of Perilipins

266

(2)

11.3.5.3 Involvement of Lipotransin

268

(2)

11.3.6 Intrinsic Activity of HSL

270

(1)

11.3.6.1 Feedback Inhibition

270

(2)

11.3.6.2 Adipocyte Lipid-binding Protein

272

(2)

11.3.7 Expression of HSL

274

(1)

11.3.8 Release of Lipolytic Products

275

(1)

11.3.8.1 FA Transport

275

(1)

11.3.8.2 Glycerol Transport

276

(1)

11.3.8.3 Cholesterol Transport

277

(1)

11.4 Physiological, Pharmacological and Genetic Modulation of TAG Mobilization

278

(1)

11.4.1 Muscle Contraction

278

(1)

11.4.2 Nutritional State

279

(1)

11.4.3 Hormones and Cytokines

279

(1)

11.4.3.1 Insulin

279

(1)

11.4.3.1.1 Molecular Mechanisms

279

(2)

11.4.3.1.2 Desensitization

281

(1)

11.4.3.2 Leptin

282

(1)

11.4.3.3 Growth Hormone

283

(1)

11.4.3.4 Glucose-dependent Insulinotropic Polypeptide

283

(1)

11.4.3.5 TNF-α

283

(2)

11.4.4 ASP

285

(1)

11.4.5 Acipimox and Nicotinic Acid

286

(1)

11.4.5.1 Mode of Action

287

(1)

11.4.5.2 Molecular Mechanism

288

(1)

11.4.5.3 Desensitization

289

(1)

11.4.6 Glimepiride and Phosphoinositolglycans

290

(2)

11.4.7 Differences in Regulation of TAG Storage and Mobilization between Visceral and Subcutaneous Adipocytes

292

(2)

11.4.8 Up-/Down-regulation of Components of TAG Storage and Mobilization

294

(1)

11.4.8.1 HSL

294

(2)

11.4.8.2 ALBP

296

(1)

11.4.8.3 Perilipin

297

(2)

11.4.8.4 PKA

299

(1)

11.4.8.5 ASP

300

(1)

11.4.8.6 Caveolin

301

(1)

11.5 Concluding Remarks

302

(1)

11.6 References

303

(30)

Subject Index

333

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Lipases and Phospholipases in Drug Development: From Biochemistry to Molecular Pharmacology

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Author Biography

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