Thioredoxins, Glutaredoxins, and Peroxiredoxins—Molecular Mechanisms and Health Significance: from Cofactors to Antioxidants to Redox Signaling

Abstract

Thioredoxins (Trxs), glutaredoxins (Grxs), and peroxiredoxins (Prxs) have been characterized as electron donors, guards of the intracellular redox state, and “antioxidants”. Today, these redox catalysts are increasingly recognized for their specific role in redox signaling. The number of publications published on the functions of these proteins continues to increase exponentially. The field is experiencing an exciting transformation, from looking at a general redox homeostasis and the pathological oxidative stress model to realizing redox changes as a part of localized, rapid, specific, and reversible redox-regulated signaling events. This review summarizes the almost 50 years of research on these proteins, focusing primarily on data from vertebrates and mammals. The role of Trx fold proteins in redox signaling is discussed by looking at reaction mechanisms, reversible oxidative post-translational modifications of proteins, and characterized interaction partners. On the basis of this analysis, the specific regulatory functions are exemplified for the cellular processes of apoptosis, proliferation, and iron metabolism. The importance of Trxs, Grxs, and Prxs for human health is addressed in the second part of this review, that is, their potential impact and functions in different cell types, tissues, and various pathological conditions. Antioxid. Redox Signal. 19, 1539–1605. I. Introduction A. Trx family of proteins 1. Structure and reaction mechanisms 2. Trx, Grx, and Prx family proteins in mammals a. Trx systems b. Grx systems c. Peroxiredoxins d. Trx-like proteins B. The concept of redox signaling C. Reversible post-translational redox modifications of protein thiols 1. Sulfenylation 2. Protein disulfides 3. Glutathionylation and cysteinylation 4. S-nitrosylation 5. Other reversible redox modifications a. Persulfide formation b. Methionine sulfoxidation D. Oxidative stress in the concept of redox signaling II. Mammalian Trx Family Proteins in Health and Disease A. Specific pathways 1. Apoptosis a. Cytosolic pathways b. Mitochondrial pathways 2. Proliferation 3. Iron metabolism a. Iron sulfur Grxs b. Biogenesis of iron-sulfur centers c. Regulation of iron metabolism d. Intracellular iron distribution B. Tissues, organ systems, and diseases 1. Development 2. Central nervous system a. Expression profile of Trxs, Grxs, Prxs, and related proteins in the CNS b. Trxs, Grxs, Prxs, and pathologies of the CNS 3. Sensory organs a. Expression profile of Trx-related proteins in sensory organs b. Pathologies of the eye c. Pathologies related to tongue, olfactory system, and ear 4. Cardiovascular system a. Expression pattern of Trxs, Grxs, and Prxs in cardiovascular tissue b. Trxs, Grxs, and Prxs in pathologies of the cardiovascular system 5. Skin 6. Skeletal muscle 7. Respiratory system a. Expression of Trx family proteins in the respiratory system b. Trxs, Grxs, and Prxs in pathologies of the lung—interplay between ROS and inflammation 8. Infection, inflammation, and immune response a. Expression pattern of Trx-related proteins in lymphoid tissues b. Immune system c. Infectious diseases 9. Metabolic and digestive system a. Diabetes mellitus 10. Urinary tract and reproductive systems a. Kidney b. Urinary bladder c. Male reproductive system d. Female reproductive system 11. Ischemia and hypoxia 12. Cancer a. Carcinogenesis 13. Aging C. Therapeutic approaches III. Concluding Remarks