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Oxidative Stress and Disease
Lester Packer, PhD
Enrique Cadenas, MD, PhD
University of Southern California School of Pharmacy
Los Angeles, California
Oxidative Stress in Cancer, AIDS, and Neurodegenerative Diseases
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Understanding the Process of Aging: The Roles of Mitochondria, Free
Radicals, and Antioxidants
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Redox Regulation of Cell Signaling and Its Clinical Application
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Antioxidants in Diabetes Management
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Mitochondria in Health and Disease
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Nutrigenomics
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Oxidative Stress, Inflammation, and Health
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Oxidative Stress and Age-Related Neurodegeneration
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Glutathione
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CRCOXISTRDIS
Glutathione
Edited by
Leopold Flohé
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Library of Congress Cataloging‑in‑Publication Data
Names: Flohé, L. (Leopold), 1938- editor.
Title: Glutathione / editor, Leopold Flohé.
Other titles: Glutathione (Flohé) | Oxidative stress and disease.
Description: Boca Raton: Taylor & Francis, 2018. | Series: Oxidative stress and
disease | Includes bibliographical references.
Identifiers: LCCN 2018017686 | ISBN 9780815365327 (hardback: alk. paper)
Subjects: | MESH: Glutathione—metabolism | Glutathione—physiology |
Glutathione—biosynthesis | Oxidative Stress
Classification: LCC QP552.G58 | NLM QU 68 | DDC 572/.65—dc23
LC record available at https://lccn.loc.gov/2018017686
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Contents
Series Preface.............................................................................................................xi
Preface.................................................................................................................... xiii
Editor.......................................................................................................................xix
List of Contributors .................................................................................................xxi
Part I Biosynthesis, Compartmentation,
and Transport of Glutathione
Chapter 1 Biosynthesis of Glutathione and Its Regulation....................................3
Henry J. Forman, Hongqiao Zhang, and Terrance J. Kavanagh
Chapter 2 Renal Glutathione Transport Systems: Roles in Redox
Homeostasis, Cytoprotection, and Bioactivation................................ 35
Lawrence H. Lash
Part II Glutathione-Dependent
Hydroperoxide Metabolism
Chapter 3 The Catalytic Mechanism of Glutathione Peroxidases....................... 53
Laura Orian, Giorgio Cozza, Matilde Maiorino,
Stefano Toppo, and Fulvio Ursini
Chapter 4 GPx1-Dependent Regulatory Processes in Health and Disease......... 67
Diane E. Handy and Joseph Loscalzo
Chapter 5 Glutathione Peroxidase 1 as a Modulator of Insulin Production
and Signaling: Implications for Its Dual Role in Diabetes................. 81
Holger Steinbrenner and Lars-Oliver Klotz
Chapter 6 GPx2: Role in Physiology and Carcinogenesis................................... 95
Anna P. Kipp
vii
viii Contents
Chapter 7 GPx4: From Prevention of Lipid Peroxidation to
Spermatogenesis and Back................................................................ 111
Matilde Maiorino, Antonella Roveri, and Fulvio Ursini
Chapter 8 Thiols, Glutathione, GPx4, and Lipid Metabolism at the
Crossroads of Cell Death and Survival............................................. 129
José Pedro Friedmann Angeli, Valerian E. Kagan,
and Marcus Conrad
Chapter 9 Peroxiredoxin 6 as Glutathione Peroxidase...................................... 143
Yefim Manevich
Chapter 10 Glutathione Peroxidases and the Thyroid Gland.............................. 161
Lutz Schomburg
Part III Conjugations and Isomerizations
Chapter 11 Glutathione Transferases: From the Test Tube to the Cell................ 175
Bengt Mannervik and Birgitta Sjödin
Chapter 12 Protein S-Glutathionylation and Glutathione S-Transferase P.......... 201
Kenneth D. Tew
Chapter 13 The Role of Glutathione in Biosynthetic Pathways and
Regulation of the Eicosanoid Metabolism........................................ 215
Ralf Morgenstern, Jesper Z. Haeggström,
Per-Johan Jakobsson, and Leopold Flohé
Chapter 14 Nitric Oxide and S-Nitrosoglutathione.............................................. 227
Iain L. O. Buxton and Scott D. Barnett
Part IV The Glutaredoxins
Chapter 15 The Catalytic Mechanism of Glutaredoxins..................................... 251
Linda Liedgens and Marcel Deponte
Contents ix
Chapter 16 The Role of Glutaredoxins in the Brain............................................ 263
Carsten Berndt, Anna Dorothee Engelke, Klaudia Lepka, and
Lars Bräutigam
Part V Glutathione Derivatives and
Substitutes in Pathogenic Microorganisms
Chapter 17 Biosynthesis of Polyamine–Glutathione Derivatives in
Enterobacteria and Kinetoplastida................................................... 285
Marcelo A. Comini
Chapter 18 Trypanothione Functions in Kinetoplastida......................................307
Martín Hugo, Madia Trujillo, Lucía Piacenza, and Rafael Radi
Chapter 19 Mycothiol, a Low-Molecular-Weight Thiol Drafted for
Oxidative Stress Defense Duty......................................................... 331
Leonardo Astolfi Rosado, Brandán Pedre, and Joris Messens
Chapter 20 Biosynthesis and Functions of Bacillithiol in Firmicutes................. 357
Quach Ngoc Tung, Nico Linzner, Vu Van Loi,
and Haike Antelmann
Index....................................................................................................................... 379
Series Preface
GLUTATHIONE
The editor, Professor Leopold Flohé – Redox Pioneer 2010 (Antioxidants & Redox
Signaling 13, 1617–1622) – is an eminent scientist who opened the field of selenium
biochemistry by proving that this trace element is an integral moiety of the enzyme
glutathione peroxidase. His seminal studies on glutathione peroxidase and its
catalytic mechanism preceded the discoveries of other glutathione peroxidases
and of peroxiredoxins. This pioneer work on glutathione peroxidase branched out
to a myriad of topics of significance for redox biology, of which two are worth
mentioning. First, it challenged the dogma of hydroperoxide metabolism being only
the domain of heme-containing enzymes, thus placing glutathione peroxidase(s)
at the center stage of peroxide metabolism. Second, it established the basis for an
ever-developing integrated redox network with implications for the regulation of
signaling and transcriptional pathways. Dr. Flohé also pioneered several studies
on hydroperoxide metabolism (it may be viewed also as ‘antioxidant defense’) in
pathogens of the genera Trypanosoma, Leishmania, and Mycobacterium, with the
goal of identifying suitable drug targets, thus lending a translational value to the
knowledge and technology in the field.
To edit a book on glutathione and glutathione-dependent biological phenomena is
not an easy task because of the abundance of reviews and books on these subjects.
To the editor’s credit, Glutathione compiles state-of-the-art glutathione-dependent
biological processes. Following an editor’s introduction and historical perspective on
glutathione, the book consists of five parts: biosynthesis, compartmentalization and
transport of glutathione, glutathione-dependent hydroperoxide metabolism, roles of
glutathione derivatives and substitutes in conjugations and isomerization, glutare-
doxins, and glutathione in pathogenic microorganisms. Each section or part contains
several chapters written by highly esteemed experts in the field.
In bringing Glutathione to fruition in the series Oxidative Stress and Disease,
credit must be given to the editor, Professor Leopold Flohé, and to the experts in
the various aspects of glutathione and glutathione-dependent biological processes,
whose thorough and innovative work is the basis for this book.
Lester Packer
Enrique Cadenas
xi
Preface
Glutathione was detected as a thiol-containing compound in 1888 by J. de Ray-
Pailhade (de Rey-Pailhade, 1888) and named “philothion,” a term composed of the
Greek words for love and sulfur. The elucidation of its structure did not start but
in the early 1920s and kept some Nobel laureates and others busy for more than a
decade. It was Sir Frederick Gowland Hopkins who started with the isolation of phi-
lothion and renamed it glutathione, yet the chemical analysis of the isolated material
led him to conclude that it was a dipeptide consisting of glutamic acid and cysteine
(Hopkins, 1921; Hopkins and Dixon, 1922). The addition of the missing third amino
acid, glycine, goes back to Hunter and Eagles (1927a,b), Pirie and Pinhey (1929), and
Kendall et al. (1929). Its structure as γ-glutamyl-cysteinyl-glycine, however, had to
wait for final proof by chemical synthesis in 1935 (Harrington and Mead, 1935) and
1936 (du Vigneaud and Miller, 1936), respectively.
In the 1950s, the state of the art, up to the biosynthesis of glutathione and its
enzymatic regeneration from the disulfide form, was compiled in symposia held at
Ridgefield (Colowik et al., 1954) and London (Crook, 1958). In 1972, a bunch of
impecunious youngsters dared to invite the most famous glutathione researchers
from all over the world to a small meeting to be held in the German university village
of Tübingen, and, to their great surprise, they all showed up and appeared to enjoy
the modest hospitality the “organizers” could afford. Despite a strong chemical
touch, the clinical implications of genetic errors relevant to the r egeneration of
reduced glutathione were a major focus of this conference (Flohé et al., 1974).
Highlights were contributed by the Kosowers, demonstrating the influence of the
redox state of the glutathione system on seemingly unrelated cellular functions
such as ion transport, and by Wolfgang A. Günzler providing the first unequivocal
proof of the selenoprotein nature of glutathione peroxidase, now addressed to as
GPx1 (Flohé, 2009). At this meeting, Alton Meister also presented his γ-glutamyl
cycle, at that time still claimed to be responsible for amino acid transport in gen-
eral. The meeting at the Kroc Foundation in the Santa Inez Valley in California
focused on the role of glutathione S-transferases in the metabolism of xenobiotics
(Arias and Jakoby, 1976). The following meeting at the Reißensburg near Ulm in
Germany dealt with the function of glutathione in the liver and kidney (Sies and
Wendel, 1978). At this meeting, Alton Meister seemed still to defend his original
idea of a major role of the γ-glutamyl cycle in amino acid transport. Although
his statements were already less apodictic, he was heavily challenged by Norman
Curthoys and his colleagues from the University of Pittsburgh and my former stu-
dents Rolf Hahn, Helmut Heinle, and Albrecht Wendel, whom I had left behind in
Tübingen when taking a break from academia to work for a drug company. In the
meantime, it had become clear from localization and organ perfusion studies that
the original concept of the γ-glutamyl cycle was no longer tenable, but it had been
heuristic in fertilizing the work on s alvage and inter-organ trafficking of glutathi-
one via extracellular degradation and resynthesis, as well as clarifying the bio-
synthesis of mercapturic acids and leukotrienes via cooperation of different cells,
xiii
xiv Preface
tissues and organs. Transport, turnover, and storage of glutathione then became
the central issue of the 1981 meeting in Osaka (Sakamoto et al., 1983), and in
1982, glutathione even made its career as subject of the Fifth Karolinska Nobel
Conference, which tried to bridge the gap between toxicologists and clinicians
interested in glutathione-related inborn errors of metabolism (Larsson et al., 1983).
Finally, the discovery of philothion by de Rey-Pailhade was celebrated in Osaka in
December 1988, and the proceedings of this meeting were published one year later
as “Glutathione Centennial” (Taniguchi et al., 1989).
Also in 1989, an extensive monograph on glutathione appeared in two parts of
the series Coenzymes and Cofactors (Dolphin et al., 1989). It starts with a “brief”
history of glutathione comprising 34 pages plus 427 references masterly written
by the late Alton Meister. These two volumes also contain chapters dealing with
the physicochemical properties of glutathione and related thiols, its chemical and
biochemical syntheses, and detailed updates on glutathione-dependent enzymatic
systems. The book remains an invaluable access to the first 100 years of glutathione
research.
Surprisingly, no serious attempts to compile the state of the art in the field
have since been made. This does not mean that the interest in the compound is
fading away. On the contrary, the lay press has knighted glutathione as “the most
important antioxidant of the organism,” a label that is to characterize it as being
always beneficial and indispensable for well-being. In strict chemical terms, how-
ever, this label is wrong and, in biological terms, at least an oversimplification.
The mislabeling of glutathione as an antioxidant originates from the discovery of
glutathione peroxidases, which efficiently reduce all kind of hydroperoxides. Yet
without the aid of these enzymes, glutathione reacts with hydroperoxides only
in a biologically irrelevant speed. It rather tends to react with the most abundant
radical, molecular dioxygen, thereby forming superoxide radicals, initiating free
radical chain reactions and oxidative tissue destruction. Moreover, hydrogen per-
oxide and other hydroperoxides meanwhile adopted new roles in living systems:
They abandoned their ugly image as oxidative poisons and became mediators or
modulators of signaling cascades, and accordingly, many of the glutathione per-
oxidases acquired unexpected novel functions as sensors, regulators, or modula-
tors in metabolic regulation and differentiation. Another honor often conferred
to glutathione is “the key detoxifying agent.” It is based on the assumption that
nature anticipated the ingenuity of industrial chemists to create uncountable toxic
compounds and prophylactically developed the realm of glutathione S-transferases
just to conjugate and excrete the chemical waste via the mercapturic acid pathway.
Again, we have meanwhile learned that the S-transferases may also increase the
toxicity of xenobiotics, they also have distinct endogenous substrates and cata-
lyze processes, such as cis-trans isomerization, leukotriene biosynthesis, or protein
glutathionylation, which have little in common with detoxification reactions that
fascinated researchers in the past century. What we are experiencing is a profound
change in paradigms: Glutathione is no longer just an antioxidant and detoxifying
compound but a redox-active one that dominates many and highly diversified bio-
logical processes (Flohé, 2010).
Preface xv
It is not the aim of this book to reiterate what has meanwhile become text-
book knowledge. As mentioned, the history of glutathione research has been
described in detail, and the chemical properties of glutathione, as presented in
the 1989 monograph (Dolphin et al., 1989), are still valid. The editor tried to
select the topics in which substantial progress has been made over the past three
decades. He admits that his selection is biased by the conviction that most, if
not all, glutathione-dependent reactions of physiological relevance are catalyzed
by enzymes or due to other specific interactions with proteins (Flohé, 2013;
Berndt et al., 2014).
Accordingly, the first part of the book contains an update of glutathione
biosynthesis with special emphasis on its regulation in the context of adaptive stress
response (Chapter 1). It further reviews glutathione transport systems, which together
with de novo synthesis determine the cellular and subcellular pools (Chapter 2).
Part II covers the glutathione peroxidases (Chapters 3–10), which in principle
catalyze similar reactions. It starts with the attempt to solve the enigma how these
enzymes can accelerate the reaction of glutathione with hydroperoxides by orders
of magnitude irrespective of the involvement of a selenocysteine or cysteine in
the catalytic process (Chapter 3). The remaining articles will reveal how discrete
differences in substrate specificities, localization, and substrate availability modify
their biological roles in most surprising ways. In fact, one and the same glutathione
peroxidase gene (gpx4), depending on the mode and site of its expression, may inter-
fere with unrelated phenomena such as spermiogenesis, chromatin compaction, and
ferroptosis (Chapters 7 and 8).
Part III centers on the diversified roles of the different glutathione S-transferases,
which for sure can detoxify xenobiotics but are gaining increasing interest as a
means for synthesis of powerful mediators or hormones or as catalysts of specific
glutathionylation in redox regulation (Chapters 11–14). The part ends with a chapter
on nitrosoglutathione, which apparently plays a pivotal role in metabolic regulation
by the NO radical (Chapter 14).
Part IV deals with the glutaredoxins, a subfamily of the redoxins, long believed
to catalyze the reduction of protein disulfides by glutathione promiscuously or con-
sidered to back up the thioredoxin systems in the synthesis of deoxyribonucleotides
and in protecting proteins with sensitive thiol groups (Chapters 15–16). Although
their glutathione binding sites are similar or identical, the diverse surroundings of
the reaction centers enable them to interact with defined proteins selectively. Inverse
genetics revealed that the role of a particular glutaredoxin, e.g., in the brain, cannot
be substituted by another glutaredoxin or by any of the thioredoxins.
Part V seemingly breaks with the aim to limit the scope of the book to the role
of glutathione to human health and disease. The thiol metabolism in the pathogens
addressed is largely analogous to that of mammalian organisms. The differences,
however, are pronounced enough to qualify the analogous or homologous enzymes
as potential drug targets and, thus, have attracted considerable interest for the
development of drugs to treat human and veterinary diseases such as t rypanosomiasis,
leishmaniasis (Chapters 17 and 18), tuberculosis (Chapter 19), and other bacterial
infections (Chapter 20).
xvi Preface
With some interruptions, the editor spent 50 years of his life with research on
glutathione and did not get bored. His hope is to infect the next generation with his
enthusiasm for this fascinating molecule, and he closes this introduction with the
often-quoted reminder of the Kosowers: “Lest I forget thee, glutathione” (Kosower
and Kosower, 1969).
Leopold Flohé
Potsdam, Germany
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