Forum GLUTATHIONE AND ITS ROLE IN CELLULAR FUNCTIONS HELMUT SIES Institut fu ¨r Physiologische Chemie I, Heinrich-Heine-Universita ¨t Du ¨sseldorf, Du ¨sseldorf, Germany Abstract—Glutathione (GSH) is the major cellular thiol participating in cellular redox reactions and thioether formation. This article serves as introduction to the FRBM Forum on glutathione and emphasizes cellular functions: What is GSH? Where does it come from? Where does it go? What does it do? What is new and noteworthy? Research tools, historical remarks, and links to current trends. © 1999 Elsevier Science Inc. Keywords—Glutathione, Free radicals, Glutathionylation, Redox state, Thiols, Glutathione conjugation, Subcellular compartmentation, Apoptosis, Gene expression INTRODUCTION Glutathione (GSH) has generated waves of activity raging through different scientific fields. Currently, we are in one such wave, related to the role of thiols in gene expression, apoptosis, signaling, etc.; this Forum on GSH focuses on these areas. There are well over 40,000 entries under “glutathione” found at the Medline data- base, reflecting the importance of this biomolecule. In the following, the field is highlighted, with the hope of conveying a feel for where future developments may go. GLUTATHIONE What is it? The tripeptide, L--glutamyl-L-cysteinyl-glycine, or GSH, mol.wt. 307, is the major low-molecular-mass thiol compound in plants and animals [1]. GSH lacks the toxicity associated with cysteine [2], making this com- pound suitable as a cellular thiol “redox buffer” to main- tain a given thiol/disulfide redox potential. The excep- tional peptidic -linkage is thought to protect the tripeptide from degradation by aminopeptidases. In cells, tissues, and plasma, glutathione is present in several additional forms. Glutathione disulfide (GSSG), is formed upon oxidation; sometimes, this species is re- ferred to as “oxidized glutathione,” but further oxidation products are also formed from GSH, e.g., sulfonates. Other forms of disulfide are of the mixed type, GSSR, a major class of biologically interesting ones being gluta- thione-cysteinyl disulfides on proteins. Thus, proteins can be glutathionylated or, as sometimes referred to, thiolated. When speaking of “total glutathione,” all free or bound glutathione moieties would be included; however, usage has it that only GSH plus twice the GSSG levels are denoted as total glutathione, expressed in “GSH equivalents.” Of note, this operative definition neglects important pool(s) of bound glutathione that are not nor- mally included in this definition. Bound glutathione, however, can make up a considerable amount of the cellular glutathione present, so an update of the definition and usage of “total cellular glutathione” is suitable, par- Address correspondence to: Helmut Sies, Institut fu ¨r Physiologische Chemie I, Heinrich-Heine-Universita ¨t Du ¨sseldorf, Postfach 101007, D-40001-Du ¨sseldorf, Germany; Tel: +49 (211) 811-2707; Fax: +49 (211) 811-3029; E-Mail: helmut.sies@uni-duesseldorf.de. Helmut Sies, M.D., Ph.D. (hon.), is Professor and Chairman, De- partment of Physiological Chemistry I, at the Faculty of Medicine, Heinrich-Heine University at Du ¨sseldorf, Germany. He held this posi- tion since 1979. After studying medicine at Tu ¨bingen, Paris, and Munich (he received his doctorate in medicine in 1967), he received his Habilitation for Physiological Chemistry and Physical Biochemistry at the University of Munich in 1972. He received an Honorary PhD from the University of Buenos Aires, Argentina, in 1996. He worked with Britton Chance, Johnson Research Foundation (Philadelphia, 1969 – 1970) and was Visiting Professor at the University of California at Berkeley, Department of Biochemistry (Bruce Ames, 1984 –1985) and Department of Molecular and Cell Biology as Miller Visiting Professor (Lester Packer, 1992), and at the Heart Research Institute, Sydney (Roland Stocker, 1993). He is President of the Society for Free Radical Research (International) 1998 –2000. His research interests in biologi- cal oxidations include oxidative stress, oxidants, and antioxidants (glu- tathione, tocopherols, carotenoids, peroxynitrite and selenium). Free Radical Biology & Medicine, Vol. 27, Nos. 9/10, pp. 916 –921, 1999 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0891-5849/99/$–see front matter PII S0891-5849(99)00177-X 916