Redox-dependent processes substantially influence the functional activity of many proteins and participate in regulation of the most important vital processes of the cell such as proliferation, differentiation, and apoptosis. Considerable recent attention of researchers has been focused on thiol–disulfide regulation, which is realized by redox proteins, whose activities depend of a redox- active site in the form of amino acid sequence containing one or two active thiols. Among these proteins, two thiol–disulfide reductases stand out: thioredoxin (Trx) and glutaredoxin (Grx), which are the members of thiore- doxin superfamily. These enzymes are multifunctional and comprise thioredoxin- and glutaredoxin-dependent systems playing an important role in maintenance of intracellular redox homeostasis. The first system con- tains, apart from thioredoxin, a NADPH-dependent thioredoxin reductase (TrxR), which reduces the oxidized form of thioredoxin. The second system includes glu- tathione (GSH) as an agent reducing the oxidized glutaredoxin and glutathione reductase reducing glu- tathione from its oxidized form (GSSG). Both of these systems contribute to the antioxidant defense of cells from destructive influence of oxidative stress, which causes formation of intra- and intermolecu- ISSN 0006-2979, Biochemistry (Moscow), 2008, Vol. 73, No. 13, pp. 1493-1510. © Pleiades Publishing, Ltd., 2008. Original Russian Text © E. V. Kalinina, N. N. Chernov, A. N. Saprin, 2008, published in Uspekhi Biologicheskoi Khimii, 2008, Vol. 48, pp. 319-358. REVIEW 1493 Abbreviations: AP-1, activator protein 1; ARE, antioxidant- responsive element; ASK-1, apoptosis signal-regulating kinase 1; Cdc2, cyclin-dependent kinase 2; ERK, extracellular signal regulated kinase; Grx, glutaredoxin; GSH and GSSG, glu- tathione reduced and oxidized, respectively; GST P1-1, glu- tathione transferase P1-1; IκB, inhibitor of κB; iNOS, inducible NO-synthase; JNK, c-Jun-N-terminal kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; Mn-SOD, Mn-dependent superoxide dismutase; NF- κB, nuclear factor κB; Nrf2, NF-E2-dependent factor 2; PDI, protein disulfide isomerase; PKC, protein kinase C; Prx, perox- iredoxin; ROS, reactive oxygen species; SAPK, stress-activated protein kinase; Sec, selenocysteine; SEK, SAPK/ERK kinase; Trx, thioredoxin; Trx1 and Trx2, cytoplasmic and mitochondr- ial Trx forms, respectively; TrxR, thioredoxin reductase. * To whom correspondence should be addressed. Involvement of Thio-, Peroxi-, and Glutaredoxins in Cellular Redox-Dependent Processes E. V. Kalinina 1,2 , N. N. Chernov 3 , and A. N. Saprin 1 * 1 Center for Theoretical Problems of Physico-Chemical Pharmacology, Russian Academy of Sciences, ul. Kosygina 4, 119991 Moscow, Russia; fax: (495) 938-2533; E-mail: kevsan@orc.ru 2 Institute of Cytochemistry and Molecular Pharmacology, 6-ya Radial’naya ul. 24/14, 115404 Moscow, Russia 3 Peoples’ Friendship University of Russia, ul. Miklukho-Maklaya 8, 117198 Moscow, Russia Received November 7, 2007 Revision received July 24, 2008 Abstract—Among the key antioxidant enzymes, thioredoxin and glutaredoxin systems play an important role in cell defense against oxidative stress and maintenance of redox homeostasis owing to the regulation of thiol–disulfide exchange. The thioredoxin isoforms Trx1 (cytoplasmic form) and Trx2 (mitochondrial form) can reduce inter- and intramolecular disul- fide bonds in proteins, in particular, in oxidized peroxiredoxins, which disrupt organic hydroperoxides, H 2 O 2 , and perox- ynitrite. NADPH-dependent thioredoxin reductase, which reduces a broad range of substrates including oxidized form of thioredoxin, can also directly reduce lipid hydroperoxides, H 2 O 2 , and dehydroascorbic and lipoic acids. Glutaredoxin, whose major isoforms in mammals are Grx1, Grx2, and Grx5, as well as thioredoxin, catalyzes S-glutathionylation and deg- lutathionylation of proteins to protect SH-groups from oxidation and restore functionally active thiols. However, in contrast to thioredoxin, glutaredoxin reduces GSH-mixed disulfides and catalyzes the reaction not only via a dithiol mechanism but also via monothiol reduction. In addition to the role in cellular antioxidant defense, all of the reviewed redox proteins (thioredoxin, thioredoxin reductase, peroxiredoxin, and glutaredoxin) have a number of significant functions required for cell viability: they regulate transcription factor activities, play the role of growth factors, serve as enzyme cofactors, take part in regulation of cell cycle, and are involved in antiapoptotic mechanisms. DOI: 10.1134/S0006297908130099 Key words: oxidative stress, thioredoxin, thioredoxin reductase, peroxiredoxin, glutaredoxin, redox-dependent processes