GLUTATHIONE AND SULFUR AMINO ACIDS IN HUMAN HEALTH …download.e-bookshelf.de/download/0000/5734/62/L-G-0000573462... · 4.3 Evidence of Gut Sulfur Amino Acid Metabolism / 50 4.4

GLUTATHIONE ANDSULFUR AMINO ACIDSIN HUMAN HEALTHAND DISEASE

Edited by

ROBERTA MASELLAGIUSEPPE MAZZA

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Edited by

ROBERTA MASELLAGIUSEPPE MAZZA

Copyright # 2009 by John Wiley & Sons, Inc. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New JerseyPublished simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data

Masella, Roberta.Glutathione and sulfur amino acids in human health and disease / Roberta Masella, Giuseppe Mazza.p. cm.

Includes index.ISBN 978-0-470-17085-4 (cloth)1. Glutathione. 2. Sulfur amino acids. I. Mazza, Giuseppe. II. Title.QP552.G58M37 2009612.3098—dc22

2009011739

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

http://www.copyright.comhttp://www.wiley.com/go/permissionhttp://www.wiley.com

CONTENTS

PREFACE xv

CONTRIBUTORS xix

I INTRODUCTION 1

1 GLUTATHIONE AND THE SULFUR-CONTAININGAMINO ACIDS: AN OVERVIEW 3John T. Brosnan and Margaret E. Brosnan

1.1 Introduction / 3

1.2 Why Sulfur-Containing Amino Acids? / 4

1.3 S-Adenosylmethionine, Nature’s Wonder Cofactor / 7

1.4 Glutathione / 10

1.5 Taurine—the Second Essential Sulfur-Containing Amino Acid? / 13

1.6 Conclusions / 15

Acknowledgments / 15

References / 15

II CHEMISTRY AND METABOLISM OF GSH ANDSULFUR AMINO ACIDS 19

2 SULFUR AMINO ACIDS CONTENTS OF DIETARY PROTEINS:DAILY INTAKE AND REQUIREMENTS 21Cécile Bos, Jean-François Huneau, and Claire Gaudichon


2.2 Sulfur Amino Acids (SAA) Content of Dietary Protein / 21

2.3 Sulfur Amino Acid Intake / 24

v

2.4 Nutritional Requirement for Total Sulfur Amino Acids / 24


References / 30

3 CELLULAR COMPARTMENTALIZATION OFGLUTATHIONE 35Federico V. Pallardó, Jelena Markovic, and José Viña


3.2 Glutathione Content in Cells / 36

References / 42

4 INTESTINAL METABOLISM OF SULFUR AMINO ACIDS 47Nancy Benight, Douglas G. Burrin, and Barbara Stoll


4.2 Isotopic Approaches to Study Metabolism / 49

4.3 Evidence of Gut Sulfur Amino Acid Metabolism / 50

4.4 Other Key Players in Intestinal Sulfur Amino AcidMetabolism / 53

4.5 Cysteine in Redox Function and Oxidant Stressin the Gut / 58

4.6 Pathophysiology of Sulfur Amino Acid Metabolismin the GIT / 59


References / 65

5 HEPATIC SULFUR AMINO ACID METABOLISM 73Kevin L. Schalinske


5.2 Dietary Relation between Methionine and Cysteine / 73

5.3 Metabolic Relation between Hepatic Sulfur Amino Acids,B Vitamins, and Methyl Group Metabolism / 75

5.4 Regulation of Sulfur Amino Acid Metabolism and RelatedMetabolic Pathways in the Liver / 77

5.5 Impact of Physiologic and Nutritional Factors on SulfurAmino Acid Metabolism / 81


References / 84

vi CONTENTS

III ANTIOXIDANT AND DETOXIFICATIONACTIVITIES 91

6 GLUTATHIONE AND SULFUR CONTAININGAMINO ACIDS: ANTIOXIDANTANDCONJUGATION ACTIVITIES 93Nils-Erik Huseby, Elisabeth Sundkvist, and Gunbjørg Svineng


6.2 Reactive Oxygen Species and Antioxidants / 94

6.3 Glutathione Redox Cycle / 98

6.4 Regulation of GSH and Cysteine Levels / 102

6.5 Biotransformation / 106

6.6 ROS-Mediated Cellular Signaling / 109

6.7 Transcription Regulation of Antioxidant andConjugation Enzymes / 110

6.8 Oxidative Stress and Diseases / 111

References / 113

7 GLUTAREDOXIN AND THIOREDOXIN ENZYME SYSTEMS:CATALYTIC MECHANISMS AND PHYSIOLOGICALFUNCTIONS 121Elizabeth A. Sabens and John J. Mieyal


7.2 General Characteristics of Glutaredoxins / 124

7.3 General Characteristics of Thioredoxins / 126

7.4 Glutaredoxin Mechanism of Action / 128

7.5 Thioredoxin Mechanism of Action / 132

7.6 Control of Grx Expression / 133

7.7 Control of Trx Expression in MammalianSystems / 134

7.8 Cellular Functions of Grx / 135

7.9 Cellular Functions of Trx / 139

7.10 Reversible Sulfhydryl Oxidation andDisease / 142


References / 146

CONTENTS vii

8 METHIONINE SULFOXIDE REDUCTASES: A PROTECTIVESYSTEM AGAINST OXIDATIVE DAMAGE 157Herbert Weissbach and Nathan Brot


8.2 History of the Msr System / 158

8.3 MsrA and MsrB Protein Structure and Mechanism of Action / 160

8.4 Msr Reducing Requirement / 162

8.5 Other Members of the Msr Family / 165

8.6 The Msr System: Both a Repair Enzyme and aScavenger of ROS / 166

8.7 Genetic Studies on the Role of the Msr System in ProtectingCells Against Oxidative Damage / 167

8.8 Evidence that Oxidative Damage is a Major Factor in Aging:Role of Mitochondria and the Msr System / 170

8.9 How can the Msr System be Utilized for Drug Development? / 174

8.10 Methionine Sulfoxide and Disease / 176

Acknowledgment / 180

References / 181

IV BIOACTIVITY OF GSH AND SULFUR AMINOACIDS AS REGULATORS OF CELLULARPROCESSES 189

9 REGULATION OF PROTEIN FUNCTION BYGLUTATHIONYLATION 191Pietro Ghezzi and Paolo Di Simplicio


9.2 Glutathione and Redox Regulation in Immunity / 192

9.3 Protein Cysteine Oxidation / 193

9.4 Mechanisms for PSSG Formation and the ComplexScenario of Protein Glutathionylation / 196

9.5 Deglutathionylation / 199

9.6 Identification of Proteins UndergoingGlutathionylation / 200

9.7 Functional Consequences of Protein Glutathionylation / 202

9.8 Structural Changes Induced by Protein Glutathionylation / 203


References / 203

viii CONTENTS

10 GSH, SULFUR AMINO ACIDS, AND APOPTOSIS 211Giuseppe Filomeni, Katia Aquilano, and Maria Rosa Ciriolo


10.2 Synthesis and Functions of GSH / 213

10.3 Apoptosis: A Programmed Mode to Die / 221

10.4 Role of GSH and Cysteine in Apoptosis / 224

10.5 Sulfur Amino Acids in Apoptosis / 239

10.6 Concluding Remarks and Recent Progress / 241


References / 242

11 METHIONINE OXIDATION: IMPLICATION INPROTEIN REGULATION, AGING, AND AGING-ASSOCIATEDDISEASES 257Jackob Moskovitz and Derek B. Oien


11.2 The Methionine Sulfoxide Reductase System / 258

11.3 Methionine Sulfoxide Reductase and Selenium / 259

11.4 Methionine Sulfoxide Reductase: A Knockout Mouse as a Modelfor Neurodegenerative Diseases / 262

11.5 Regulation of Protein Expression/Function by the MethionineSulfoxide Reductase System / 264


References / 267

12 SULFUR AMINO ACIDS, GLUTATHIONE, AND IMMUNEFUNCTION 273Robert Grimble

12.1 The Biochemistry of Sulfur Amino Acids / 273

12.2 Sulfur Amino Acid and Glutathione Metabolism Following Infectionand Injury / 275

12.3 Glutathione and the Immune System / 278

12.4 Mechanism of the Effect of Oxidants and Antioxidants onInflammation and Immune Function / 280

12.5 Strategies for Modulating Tissue Glutathione Content andInfluencing Immune Function / 282

12.6 Taurine and Immune Function / 284


References / 285

CONTENTS ix

V GSH AND SULFUR AMINO ACIDS INPATHOLOGICAL PROCESSES 289

13 SULFUR AMINO ACID DEFICIENCYANDTOXICITY: RESEARCH WITH ANIMAL MODELS 291David H. Baker and Ryan N. Dilger


13.2 Sulfur Amino Acid Deficiency / 291

13.3 Sulfur Amino Acid Toxicity / 299

References / 305

14 HUMAN PATHOLOGIES AND ABERRANTSULFUR METABOLISM 317Danyelle M. Townsend, Haim Tapiero, and Kenneth D. Tew


14.2 Biosynthesis and Metabolism of Methionine andCysteine / 317

14.3 Defects in the Transulfuration Pathway / 319

14.4 Inherited Defects in Membrane Transport / 321

14.5 Pathologies Associated with Folic AcidMetabolizing Enzymes / 323

14.6 Heterogeneity of GSH Metabolizing Enzymes andAssociated Human Pathologies / 326

References / 333

15 INBORN ERRORS OF GSH METABOLISM 343Ellinor Ristoff


15.2 Definitions / 345

15.3 The g-Glutamyl Cycle / 345

15.4 Inborn Errors in the Metabolism ofGSH / 346

15.5 Animal Models / 355


References / 356

x CONTENTS

16 HOMOCYSTEINE METABOLISM AND PATHOLOGICALIMPLICATIONS: THE HOMOCYSTEINE THIOLACTONEHYPOTHESIS OF VASCULAR DISEASE 363Hieronim Jakubowski


16.2 An Overview of Hcy Metabolism / 365

16.3 Toxicity of Hcy and Its Metabolites / 366

16.4 Physical-Chemical Properties of Hcy-Thiolactone / 369

16.5 The Mechanism of Hcy-Thiolactone Biosynthesis / 374

16.6 Structural and Functional Consequences of ProteinModification by Hcy-Thiolactone / 378

16.7 The Hcy-Thiolactone Hypothesis of VascularDisease / 382

16.8 Pathophysiologic Consequences of ProteinN-Homocysteinylation / 387

16.9 Urinary Elimination of Hcy-Thiolactone / 393

16.10 Enzymatic Elimination of Hcy-Thiolactone / 395


References / 397

17 HOMOCYSTEINE AND CARDIOVASCULAR DISEASE 413Jayanta R. Das and Sanjay Kaul


17.2 Homocysteine Metabolism / 414

17.3 Homocysteine Forms In Vivo / 415

17.4 Homocysteine Measurement / 415

17.5 Causes of Hyperhomocysteinemia / 417

17.6 Therapeutic Options for Lowering Elevated Homocysteine / 418

17.7 Epidemiologic Evidence Linking Homocysteine andAtherothrombotic Vascular Disease / 418

17.8 Homocysteine and Atherothrombosis: PathophysiologicMechanisms / 422

17.9 Impact of Homocysteine-Lowering Therapy onAtherothrombotic Vascular Disease / 424


References / 432

CONTENTS xi

18 HOMOCYSTEINE AND NEUROLOGICAL DISORDERS 441Rodica E. Petrea and Sudha Seshadri


18.2 What is an “Abnormal” Plasma Homocysteine Level in ClinicalStudies of Neurological Disease? / 443

18.3 Elevated Plasma Homocysteine and the Risk of CarotidAtherosclerosis / 444

18.4 Hyperhomocysteinemia and the Risk of Stroke / 444

18.5 Elevated Plasma Homocysteine Levels are Associated with theRisk of Dementia and Alzheimer’s Disease / 447

18.6 Parkinson’s Disease / 455

18.7 Epilepsy / 456


18.9 Acknowledgments / 456

References / 456

19 GLUTATHIONE, SULFUR AMINO ACIDS, AND CANCER 471José M. Estrela, Julian Carretero, and Angel Ortega


19.2 Carcinogenesis, Tumor Growth, and Cell Death / 472

19.3 Intercellular and Interorgan Transport of GSH in Tumor-BearingMammals / 479

19.4 GSH and the Interaction of Metastatic Cells with the VascularEndothelium / 480

19.5 Adaptive Response in Invasive Cells / 483

19.6 GSH Depletion and the Sensitization of CancerCells to Therapy / 484

References / 487

VI GSH AND SULFUR AMINO ACIDS ASDRUGS AND NUTRACEUTICALS 501

20 GSH, GSH DERIVATIVES, AND ANTIVIRAL ACTIVITY 503Anna Teresa Palamara, Lucia Nencioni, Rossella Sgarbanti,and Enrico Garaci


20.2 Intracellular GSH Status during Viral Infection / 504

20.3 Mechanism of Virus-Induced GSH Depletion / 506

xii CONTENTS

20.4 Role of Constitutive GSH Levels in Controlling CellSusceptibility to Viral Infection / 506

20.5 Effect of Intracellular GSH Depletion on Viral Replication / 508

20.6 Effect of Exogenous GSH and GSH Derivatives on ViralReplication / 511

20.7 In Vivo Effects of Systemic and Topic GSHAdministration / 513

References / 515

21 N-ACETYL CYSTEINE AND CYTOPROTECTIVE EFFECTSAGAINST BRONCHOPULMONARY DAMAGE: FROM IN VITROSTUDIES TO CLINICAL APPLICATION 519Richard Dekhuijzen


21.2 Oxidative Stress in COPD / 520

21.3 Pharmacology of N-Acetylcysteine / 522

21.4 Pulmonary Antioxidant and Anti-Inflammatory Effects / 524

21.5 Nonpulmonary Effects / 526

21.6 Clinical Efficacy of N-Acetylcysteine in COPD / 528

21.7 Idiopathic Pulmonary Fibrosis / 531

21.8 Other Disorders / 532


References / 534

22 TAURINE AS DRUG AND FUNCTIONAL FOOD COMPONENT 543Ramesh C. Gupta, Massimo D’Archivio, and Roberta Masella


22.2 The Unique Character of Taurine: Basis for DistinguishedBehavior / 544

22.3 Functional Properties of Taurine / 546

22.4 Taurine Deficiency / 549

22.5 Taurine Concentration in Fetal Development and NeonatalGrowth / 549

22.6 Beneficial Actions of Taurine / 551

22.7 Taurine and Diabetes / 554

22.8 Taurine and the Cardiovascular System / 555

22.9 Taurine and Endothelial Dysfunction / 557

22.10 Taurine and Lung Dysfunction / 558

22.11 Taurine and the Kidney / 559

CONTENTS xiii

22.12 Retinal Protection / 559

22.13 Anticancer Activity of Taurine / 560

22.14 Taurine in Bone Tissue Formation and Inhibitionof Bone Loss / 561

22.15 Taurine and Smoking / 562

22.16 Taurine as an Antialcohol Molecule / 563

22.17 Taurine as Functional Food and Supplement / 564


References / 566

SUBJECT INDEX 581

xiv CONTENTS

PREFACE

Oxidative stress and antioxidant deficiency have been implicated in the pathogenesisof many diseases and conditions, including atherosclerosis, cancer, aging, and respir-atory disease. Glutathione (L-g-glutamyl-L-cysteinyl-glycine, GSH) is a major anti-oxidant acting as a free radical scavenger that protects the cell from reactive oxygenspecies (ROS). In addition, GSH is involved in nutrient metabolism and regulationof cellular metabolic functions ranging from DNA and protein synthesis to signaltransduction, cell proliferation, and apoptosis.

By affecting the cellular reduction/oxidation status, GSH may also modulate geneexpression and other cellular mechanisms. Glutathione depletion is linked to a numberof disease states, including liver cirrhosis, various pulmonary diseases, myocardialischemia and reperfusion injury, aging, Parkinson’s disease, Alzheimer’s disease,and sepsis, also called a systemic inflammatory response syndrome. Low intracellularlevels of GSHmay contribute to the immunodeficiency observed in later stages of HIVinfection, as adequate concentrations of GSH are needed for proper lymphocytefunction.

Virtually all mammalian cells have capacity to synthesize GSH de novo from glu-tamate, cysteine, and glycine by two sequential ATP-dependent reactions catalyzed byg-glutamylcysteine synthetase (g-GCS), recently renamed glutamate-cysteine ligase,and GSH synthetase. Furthermore, compelling evidence shows that the synthesisdepends on g-GCS activity, cysteine availability, and GSH feedback regulation.The chemical structure of glutathione provides special characteristics ranging frominsusceptibility to proteolysis to redox thiols catalysis. These features, together withits high intracellular concentration, make GSH the most important redox-active thiol.

Methionine, cysteine, taurine, and homocysteine are the four common sulfur-containing amino acids. Methionine is nutritionally essential due to the inability ofmammals to synthesize its carbon skeleton. It is required for protein synthesis,while its activated form, S-adenosylmethionine, serves as a methyl donor in numerousbiological reactions. Methionine is one of the most sensitive amino acids to ROSdamage, being converted to methionine sulfoxide [Met(o)]. Since the sulfur atom ofMet(o) is a chiral center, oxidation of methionine by ROS results in an equal mixtureof both the R and S epimers of Met(o). Further oxidation yields methionine sulfone,which has been detected in tissues, although the mechanism by which it is formed orits relevance remains unknown. One of the recently discovered systems that cells use toprotect against oxidative damage is the methionine sulfoxide reductase system (Msr),which can reduce Met(o) in proteins back to methionine.

xv

Cysteine is considered to be semiessential because it is synthesized frommethionine, provided that the dietary supply of the latter is sufficient. Methioninecatabolism to generate cysteine begins with its activation to S-adenosylmethionine,followed by transmethylation and the eventual formation of homocysteine. Thus,homocysteine is synthesized in vivo as an intermediate in methionine metabolism.Elevated plasma homocysteine has been associated with such chronic diseasesas atherosclerosis, Alzheimer’s disease, and osteoporosis. Homocysteine has beenproposed as an additional risk factor related to cardiovascular illness. The theoryof a relationship between the sulfur moiety and cardiovascular disease has beenpresent since the late 1960s. However, the evidence presented in this volume indicatesthat the role of homocysteine as either a mediator or marker of cardiovascular riskremains unclear.

Taurine is synthesized from cysteine by most mammals, but the ability to do sovaries markedly. Its synthetic activity is very low in humans and there is evidencethat taurine is a conditionally essential nutrient, particularly in premature infants, inpatients who are on very long term parenteral nutrition, and possibly in those whoare vegans, since fruits, vegetables, grains, legumes, and nuts do not contain measur-able amounts of taurine. Taurine is the most abundant free nitrogenous compoundin cells, and it has a variety of functions, including its role as a membrane stabilizer,calcium flux regulator, and immune function modulator.

Finally, the nutritional aspects of sulfur compounds must be considered. Aminoacid deficiency remains a significant nutritional problem, so new knowledge regardingthe utilization and metabolism of dietary amino acids is essential for the developmentof nutritional strategies. In this regard, the deleterious effects exerted by sulfur aminoacids at high intakes must be addressed.

This complex network of roles, functions, and effects makes GSH and sulfuramino acids a fascinating subject for protein chemists, biochemists, nutritionists,and pathologists. However, few publications are targeted at giving a multifacetedview highlighting their biological significance by different focal points.

This book, written by an international panel of experts, is a primary referencebook that provides a comprehensive, state-of-the-science, in-depth review of the bio-chemistry, absorption, metabolism, biological activities, disease prevention, and healthpromotion of glutathione and sulfur amino acids. The complexity of the relationshipbetween GSH and sulfur amino acids, their physiological role, as well as the possiblerole exerted by their principal metabolites, in the pathogenesis of chronic-degenerativediseases have been addressed and extensively discussed. In 22 outstanding chapters,this book provides up-to-date information on the following topics:

1. Chemistry, absorption, transport, and metabolism of GSH and sulfur aminoacids

2. Antioxidant and detoxification properties of GSH and sulfur amino acids,highlighting the enzymatic systems involved in antioxidant defenses

3. Biological activities of GSH and sulfur amino acids and their role in modulatingcell processes

xvi PREFACE

4. Role of GSH and sulfur amino acid deficiency and alteration in the onset ofdiseases and in aging

5. Protective effects exerted by GSH and sulfur amino acids when used as drugs,functional foods and nutraceuticals in humans and animals

Special attention has been paid to the molecular mechanisms by which sulfuramino acids and GSH can regulate cell processes through the modulation of transcrip-tion factors and enzyme activities; and the nutritional and therapeutic significance ofdietary sulfur amino acids has been carefully addressed through studies in humans andanimal models.

With over 2000 scientific references, this book provides our readers (food scien-tists, nutritionists, biochemists, food technologists, chemists, molecular biologists,and public health professionals) with a most comprehensive and up-to-date publi-cation on glutathione and sulfur amino acids in human health and disease.

We express our sincere thanks and appreciation to all the contributors who by freelyand willingly giving their knowledge and expertise have made this book possible.Our gratitude is also extended to colleagues who have reviewed various chapters,and the editorial staff and publishers at Wiley for their contribution in bringing thiswork to publication.

We hope that this book will serve to further stimulate the understanding of the roleof glutathione and sulfur amino acids in human health and disease, stimulate thedevelopment of functional foods and nutraceuticals rich in these important biochemi-cals and provide consumers worldwide with products that prevent diseases andmaintain a healthier life.

G. MAZZAR. MASELLA

PREFACE xvii

CONTRIBUTORS

KATIA AQUILANO, Department of Biology, University of Rome “Tor Vergata,” Rome,Italy

DAVID H. BAKER, Department of Animal Sciences and Division of NutritionalSciences, University of Illinois, Urbana, IL

NANCY BENIGHT, USDA/ARS Children’s Nutrition Research Center, Department ofPediatrics, Baylor College of Medicine, Houston, TX

CÉCILE BOS, INRA, AgroParisTech, Nutrition Physiology and Ingestive Behavior,Paris, France

JOHN T. BROSNAN, Department of Biochemistry, Memorial University ofNewfoundland, St. John’s, Newfoundland, Canada

MARGARET E. BROSNAN, Department of Biochemistry, Memorial University ofNewfoundland, St. John’s, Newfoundland, Canada

NATHAN BROT, Center for Molecular Biology and Biotechnology, Florida AtlanticUniversity, Boca Raton, FL and Department of Microbiology and Immunology,Weill Medical College of Cornell University, New York, NY

DOUGLAS G. BURRIN, USDA/ARS Children’s Nutrition Research Center, Departmentof Pediatrics, Baylor College of Medicine, Houston, TX

JULIAN CARRETERO, Department of Physiology, Faculty of Medicine and Odontology,University of Valencia, Spain

MARIA ROSA CIRIOLO, Department of Biology, University of Rome “Tor Vergata,”Rome, Italy

MASSIMO D’ARCHIVIO, Department of Veterinary Public Health and Food Safety,Istituto Superiore di Sanità, Rome, Italy

JAYANTA R. DAS, Division of Cardiology, Cedars-Sinai Medical Center, and DavidGeffen School of Medicine, University of California, Los Angeles, CA

RICHARD DEKHUIJZEN, Department of Pulmonary Diseases, Radboud University,Nijmegen, The Netherlands

RYAN N. DILGER, Department of Animal Sciences and Division of NutritionalSciences, University of Illinois, Urbana, IL

xix

PAOLO DI SIMPLICIO, Department of Neuroscience, Pharmacology Unit, University ofSiena 53100 Siena, Italy

JOSÉ M. ESTRELA, Department of Physiology, Faculty of Medicine and Odontology,University of Valencia, Spain

GIUSEPPE FILOMENI, Department of Biology, University of Rome “Tor Vergata,”Rome, Italy

ENRICO GARACI, Department of Experimental Medicine and Biochemical Sciences,University of Rome “Tor Vergata,” Rome, Italy

CLAIRE GAUDICHON, INRA, AgroParisTech, Nutrition Physiology and IngestiveBehavior, Paris, France

PIETRO GHEZZI, Chair in Experimental Medicine, Trafford Centre, Brighton & SussexMedical School, Brighton, UK

ROBERT GRIMBLE, B.SC., PH.D., R.NUTR., Professor of Nutrition, Institute of HumanNutrition, Institute of Developmental Sciences Building, School of Medicine,University of Southampton, Southampton, UK

RAMESH C. GUPTA, Department of Chemistry, SASRD, Nagaland University,Nagaland, India

JEAN-FRANÇOIS HUNEAU, INRA, AgroParisTech, Nutrition Physiology and IngestiveBehavior, Paris, France

NILS-ERIK HUSEBY, Institute of Medical Biology and Department of Pharmacy,University of Tromsø, Norway

HIERONIM JAKUBOWSKI, Department of Microbiology and Molecular GeneticsUMDNJ-New Jersey Medical School, International Center for Public Health,Newark, NJ, and Institute of Bioorganic Chemistry, Polish Academy ofSciences, Poznań, Poland

SANJAY KAUL, Division of Cardiology, Cedars-Sinai Medical Center, and DavidGeffen School of Medicine, University of California, Los Angeles, CA

JELENA MARKOVIC, Department of Physiology, Faculty of Medicine, University ofValencia, Valencia, Spain

ROBERTA MASELLA, Department of Veterinary Public Health and Food Safety, IstitutoSuperiore di Sanità, Rome, Italy.

JOHN J. MIEYAL, Department of Pharmacology, Case Western Reserve University,School of Medicine, Cleveland, OH

JACKOB MOSKOVITZ, University of Kansas, School of Pharmacy, Department ofPharmacology and Toxicology, Lawrence, KS

LUCIA NENCIONI, Department of Public Health Sciences, University of Rome “LaSapienza,” Rome, Italy

xx CONTRIBUTORS

DEREK B. OIEN, University of Kansas, School of Pharmacy, Department ofPharmacology and Toxicology, Lawrence, KS

ANGEL ORTEGA, Department of Physiology, University of Valencia, Valencia, Spain

ANNA TERESA PALAMARA, Department of Public Health Sciences, University of Rome“La Sapienza,” Rome, Italy

FEDERICO V. PALLARDÒ, Department of Physiology, Faculty of Medicine, University ofValencia, Valencia, Spain

RODICA E. PETREA, Alzheimer Disease Center, Boston University, Boston, MA

ELLINOR RISTOFF, Department of Pediatrics, Children’s Hospital, KarolinskaUniversity Hospital Huddinge, Stockholm, Sweden

ELIZABETH A. SABENS, Department of Pharmacology, Case Western ReserveUniversity School of Medicine, Cleveland, OH

KEVIN L. SCHALINSKE, Department of Food Science and Human Nutrition, Iowa StateUniversity, Ames, IA

SUDHA SESHADRI, Alzheimer Disease Center, Boston University, Boston, MA

ROSSELLA SGARBANTI, Department of Public Health Sciences, PharmaceuticalMicrobiology Section, University of Rome “La Sapienza,” Rome, Italy

BARBARA STOLL, USDA/ARS Children’s Nutrition Research Center, Department ofPediatrics, Baylor College of Medicine, Houston, TX

ELISABETH SUNDKVIST, Institute of Medical Biology and Department of Pharmacy,University of Tromsø, Norway

GUNBJØRG SVINENG, Institute of Medical Biology and Department of Pharmacy,University of Tromsø, Norway

HAIM TAPIERO, Universite de Paris—Faculté de Pharmacie CNRS UMR 8612,Chatenay Malabry, France

KENNETH D. TEW, Department of Cell and Molecular Pharmacology, MedicalUniversity of South Carolina, Charleston, SC

DANYELLEM. TOWNSEND, Department of Pharmaceutical SciencesMedical Universityof South Carolina, Charleston, SC

JOSÉ VIÑA, Department of Physiology, Faculty of Medicine, University of Valencia,Valencia, Spain

HERBERT WEISSBACH, Center for Molecular Biology and Biotechnology, FloridaAtlantic University, Boca Raton, FL

CONTRIBUTORS xxi

PART I

INTRODUCTION

CHAPTER 1

GLUTATHIONE AND THESULFUR-CONTAINING AMINOACIDS: AN OVERVIEW

JOHN T. BROSNAN and MARGARET E. BROSNAN

1.1 INTRODUCTION

Methionine and cysteine are two of the canonical amino acids that are incorporatedinto proteins, where they can be quite abundant. According to the MassachusettsNutrient Data Bank, the sulfur amino acid content (methionine plus cysteine) foranimal proteins, cereals, and nuts is between 37 and 41 mg/g protein. Legumes andfruits/vegetables average 25 and 23 mg/g protein, respectively [1]. Taurine, a non-protein b-amino sulfonic acid, is present in many animal tissues but is absent frommost plants [2]. In addition, homocysteine is synthesized in vivo as an intermediatein methionine metabolism. Elevated plasma homocysteine has been associatedwith such chronic diseases as atherosclerosis, Alzheimer’s disease, and osteoporosis[3–5]. Homocysteine thiolactone is synthesized by methionyl-tRNA synthetasewhen an elevated concentration of homocysteine leads to its selection for chargingof tRNAmet in place of methionine [6]. Structures of these amino acids are shownin Fig. 1.1.

The names of these amino acids recall their structure or discovery. Methioninereflects the fact that this amino acid contains a methyl group attached to a sulfuratom. The history of cysteine and cystine is particularly interesting. We first meet iton July 5, 1810 when William Hyde Wollaston, MD, secretary to the Royal Society,read a paper entitled “On Cystic Oxide, a New Species of Urinary Calculus,” to thataugust body [7]. The bladder stone, which had been removed from a five-year-oldboy, was named cystic oxide from the Greek word for bladder, kystis. We nowknow that such stones are largely comprised of cystine, which is quite insoluble,particularly at low pH. Subsequent work revealed that the substance was not anoxide and the terms cysteine (for the reduced form) and cystine (for the disulfide)

Glutathione and Sulfur Amino Acids in Human Health and Disease. Edited by R. Masella and G. MazzaCopyright # 2009 John Wiley & Sons, Inc.

3

came into use. Cysteine (or more accurately, cystine) has the distinction of being ouroldest known amino acid.

Homocysteine is a homolog of cysteine. Its discovery dates from 1932, whenduVigneaud was examining the nature of the sulfur in insulin. He found that treatmentof methionine with strong acid yielded homocysteine [8]. Subsequent work showedthat homocysteine fed to animals could produce cysteine and that homocysteinecould be produced after ingestion of methionine [9]. Taurine was discovered in1824, just a few years after cystine, by Tiedemann and Gmelin [10]. Since it was orig-inally isolated from ox bile, the name taurine reflects its bovine origin (Bos taurus).

Methionine cannot be produced, de novo, by animals and is therefore a dietaryessential amino acid. Cysteine is not an essential amino acid, as it may be readilyproduced from methionine [11]. Taurine is an essential nutrient, during development,in some species [12].

1.2 WHY SULFUR-CONTAINING AMINO ACIDS?

Perhaps the most fundamental question that can be asked about these compounds iswhy they contain sulfur. The question may be better stated as: what properties ofsulfur are fundamental to the functions of these amino acids? Methionine and cysteineare incorporated into proteins and also play important metabolic roles. However, weconsider their roles in proteins to be primary and key to their selection; the metabolicroles are likely to have evolved subsequently. Sulfur belongs to group VIA of theperiodic table. This group also includes oxygen and selenium. An appreciation ofthe importance of sulfur chemistry to the function of these amino acids is revealedby considering the roles of these amino acids in proteins and how these roles wouldbe affected if the sulfur atom were replaced by an oxygen atom.

Cysteine’s most distinctive role in proteins lies in its ability to form a disulfidelinkage with another cysteine residue, thus providing a readily reversible covalentbond in vivo. Extracellular proteins are particularly rich in these disulfide linkages,which may be either intrachain or interchain and which play a fundamental role indetermining the stability of proteins [13]. In fact, one of the earliest examples of

Figure 1.1 Structures of the common, sulfur-containing amino acids.

4 GLUTATHIONE AND THE SULFUR-CONTAINING AMINO ACIDS: AN OVERVIEW

bioengineering involved cysteine. It occurred in 1906 when Karl Nessler designed amachine to curl a woman’s hair by reducing the disulfide bonds in keratin. If thehair was then twisted around a series of rods and the disulfide bonds allowed toreform, the hair would be “curled.” The original design was less than satisfactory(his wife lost considerable hair) but eventually the design was so improved thatevery woman could afford a “Toni” permanent at home if she wished.

The amino acid serine is a structural analogue of cysteine in which the sulfur atomis replaced by oxygen but serine shows no comparable tendency to form dioxides.This important difference may be explained by the acid dissociation of H2O andH2S since serine and cysteine may be regarded as derivatives of these compounds(Fig. 1.2). H2S is a much stronger acid than is H2O (pKa 7.04 and 15.74, respectively)(Fig. 1.2a), which means that, of the two conjugate bases, SH2 will be formed muchmore readily than OH2. The reason for the difference in these dissociation constants isstraightforward. Although both oxygen and sulfur share the same number of electronsin their outer orbitals (2p4 and 3p4, respectively), because of oxygen’s much smallersize these electrons are held muchmore closely and, therefore, more tightly to the posi-tive nucleus in an oxygen atom than in a sulfur atom. Indeed, oxygen is much moreelectronegative than sulfur (3.44 and 2.58, respectively, on the Pauling scale).Applying these considerations to cysteine and serine, it is evident that cysteine willdissociate to Hþ and the corresponding thiolate anion much more readily thanserine will dissociate to Hþ and the corresponding oxide (pKSH of cysteine 8.3and pKOH of serine �13) (Fig. 1.2b). The pK values for these amino acids in proteinsmay vary somewhat but the principle remains. Since the formation of disulfidelinkages first requires the dissociation of two cysteines, followed by the reaction ofthe two thiolate anions, we can appreciate that the formation of interchain linkagesbetween two cysteine residues is feasible, whereas the formation of comparable inter-chain linkages between serine residues is highly unfavored. The same argumentapplies to other functions of cysteine, which require thiol dissociation. For example,

Figure 1.2 The importance of the sulfur atom to the chemistry of cysteine.

1.2 WHY SULFUR-CONTAINING AMINO ACIDS? 5

substitution of serine for cysteine in glutathione would provide a molecule that wouldessentially be incapable of becoming oxidized and unable to play a physiological rolein oxidation-reduction reactions.

There are many other roles played by cysteine in proteins and they all rely on theunique chemistry of sulfur. Giles et al. [14] draw our attention to the multiple rolesplayed by cysteine in biocatalysis, which include disulfide formation, metal binding,electron donation, and redox catalysis. Beinert and coworkers [15, 16] emphasizethe role of iron-sulfur clusters in proteins, including their involvement in nitrogenfixation, electron transfer, the catalysis of homolytic reactions, and acting as sensorsof iron and oxygen.

We may also enquire about the effects of substitution of methionine’s sulfur withoxygen and how this would affect methionine’s role in proteins. Methionine is amongthe most hydrophobic of amino acids; substitution of its sulfur with the much moreelectronegative oxygen would result in a d2 charge at the oxygen atom, making theside chain much less hydrophobic. This would affect methionine’s function in anumber of ways. For example, methionine is the initiating amino acid in the synthesisof eukaryotic proteins. N-formylmethionine serves the same function in prokaryotes.As most of these methionine residues are subsequently removed, it is evident that theirfunction lies in the initiation of translation rather than in the structure of the matureprotein. In eukaryotic cells, the initiation of translation requires the association ofthe charged initiator tRNA (met-tRNAmet) with the initiation factor, eIF-2, and the40S ribosomal subunit, together with a molecule of the mRNA that is to be translated.Drabkin and RajBhandary [17] have studied this reaction in detail and suggest that thehydrophobic nature of methionine is key to the binding of the initiator tRNA to eIF-2.Using appropriate double mutations (in codon and anticodon), they were able to showthat the hydrophobic valine could be effective for initiation in mammalian cells butthat the polar glutamine was very poor. The hydrophobicity of methionine also hasan important effect on the role played by this amino acid in protein structure. Mostof the methionine residues in globular proteins are found in the interior hydrophobiccore; in membrane-spanning protein domains, methionine is often found to interactwith the lipid bilayer [18]. The sulfur atom of methionine is key to its hydrophobicityand, therefore, to its functions in protein structure.

Not all methionine residues are buried in the interiors of proteins. In Escherichiacoli glutamine synthetase, as much as one third of them are found on the protein sur-face, many clustered around the active site. These residues are susceptible to oxidationby certain reactive oxygen species (ROS), producing methionine sulfoxide. Figures1.3a and 1.3b show the reaction of such a methionine residue with hydrogen peroxide.Levine et al. [19] view these methionine residues as playing the role of molecularlightning rods, in that they protect access of ROS to the active site. In line with thisview is the fact that they report that oxidation of these residues has little effect onthe catalytic activity of the enzyme. These oxidized methionine residues may bereduced to methionine by the enzyme methionine sulfoxide reductase. This is dealtwith, in detail, in the chapters by Weissbach and by Moskovitz, including the rolesplayed by this system in age-related diseases. What concerns us here, however, isthe suitability of sulfur for this role. The production of the sulfoxide employs a

6 GLUTATHIONE AND THE SULFUR-CONTAINING AMINO ACIDS: AN OVERVIEW

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