Redox biology is a rapidly expanding area of research. Recent studies have shown that the major cellular processes are regulated by redox, yet specific mechanisnns are poorly understood. With the exception of several exannples, the molecular targets of redox control, specificity of redox regulation, and the sets of proteins that maintain cellular redox homeostasis are not known. Thiol-based redox regulation has emerged as a prevalent mechanism to regulate cellular processes. Its major components, thioredoxin (Trx) and thioredoxin reductase (TR), are present in nearly all organisms. TRs control the redox state of Trxs, which in turn regulate cellular processes by controlling the redox state of cysteine (Cys) residues in proteins. Mammals have three TRs, and all three contain catalytic selenocysteine (Sec) residues; therefore, the mammalian Trx system is dependent on dietary selenium. Besides TRs and Trxs, numerous Trx-like proteins and other thiol oxidoreductases (i.e., proteins that use catalytic redox Cys) exist, but their functions are mostly unknown. It is also unknown which proteins are targeted by these enzymes. We would like to characterize TRs, Trxs, thiol oxidoreductases and protein targets regulated by these proteins to define the major pathways of thiol-based redox regulation in mammals. Specifically, we will carry out the following studies: (1) Characterize organismal sets of thiol oxidoreductases and their protein targets using bioinformatics, proteomics, and biochemical methods; (2) Analyze general features of thiol-based redox regulation; (3) Characterize interplay between cysteine and selenocysteine in the active sites of oxidoreductases; and (4) Examine interrelationship between hydrogen peroxide metabolism and thiol-based redox control.

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Thioredoxin reductase and thioredoxin are the main redox regulators of cysteines in proteins, whereby controlling cellular processes. This system has been implicated in cell signaling, apoptosis, cancer development, and many other physiological processes. We propose to characterize functions of thioredoxin reductases, thiol oxidoreductases and their targets to define mechanisms of thiol-based redox regulation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Barski, Oleg
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Brigham and Women's Hospital
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Seluanov, Andrei; Gladyshev, Vadim N; Vijg, Jan et al. (2018) Mechanisms of cancer resistance in long-lived mammals. Nat Rev Cancer 18:433-441
Golubev, Alexey; Hanson, Andrew D; Gladyshev, Vadim N (2018) A Tale of Two Concepts: Harmonizing the Free Radical and Antagonistic Pleiotropy Theories of Aging. Antioxid Redox Signal 29:1003-1017
Samokhin, Andriy O; Stephens, Thomas; Wertheim, Bradley M et al. (2018) NEDD9 targets COL3A1 to promote endothelial fibrosis and pulmonary arterial hypertension. Sci Transl Med 10:
Zhou, Xuming; Sun, Di; Guang, Xuanmin et al. (2018) Molecular Footprints of Aquatic Adaptation Including Bone Mass Changes in Cetaceans. Genome Biol Evol 10:967-975
Zhang, Yichong; Lee, Ji-Hoon; Paull, Tanya T et al. (2018) Mitochondrial redox sensing by the kinase ATM maintains cellular antioxidant capacity. Sci Signal 11:
Carlson, Bradley A; Lee, Byeong Jae; Tsuji, Petra A et al. (2018) Selenocysteine tRNA[Ser]Sec, the Central Component of Selenoprotein Biosynthesis: Isolation, Identification, Modification, and Sequencing. Methods Mol Biol 1661:43-60
Ke, Zhonghe; Mallik, Pramit; Johnson, Adam B et al. (2017) Translation fidelity coevolves with longevity. Aging Cell 16:988-993
Moskalev, Alexey; Anisimov, Vladimir; Aliper, Aleksander et al. (2017) A review of the biomedical innovations for healthy longevity. Aging (Albany NY) 9:7-25
Kaya, Alaattin; Mariotti, Marco; Gladyshev, Vadim N (2017) Cytochrome c peroxidase facilitates the beneficial use of H2O2 in prokaryotes. Proc Natl Acad Sci U S A 114:8678-8680
Lobanov, Alexei V; Heaphy, Stephen M; Turanov, Anton A et al. (2017) Position-dependent termination and widespread obligatory frameshifting in Euplotes translation. Nat Struct Mol Biol 24:61-68

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