Title: Regulation of Redox Signaling by Selenoproteins Authors
Submitted to: Biological Trace Element Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: February 12, 2010
Publication Date: March 20, 2010
Repository URL: http://www.springerlink.com/content/k2393p2175452837/fulltext.pdf
Citation: Hawkes, W.C., Alkan, Z. 2010. Regulation of Redox Signaling by Selenoproteins. Biological Trace Element Research. 134(3): 235-251, 2010. Interpretive Summary: Since the discovery that selenium has its own genetic codeword, 25 human selenium-containing proteins have been discovered. However, the biological functions of the majority are unknown. All animals depend on oxygen, yet oxygen can be very reactive and cause damage to proteins and genetic material. Selenium has been seen mainly as an antioxidant that protects against the harmful effects of oxygen. New research is revealing that the side reactions of oxygen are used to convey important biological information as signals within and between cells. This review summarizes the current state of knowledge of the role of selenoproteins in transmitting and regulating reactive oxygen signals. We make the case that these functions are the reason selenoproteins have been conserved throughout evolution. This hypothesis provides a new framework for predicting and understanding the biological functions of uncharacterized selenoproteins.
Technical Abstract: The unique chemistry of oxygen has been both a resource and threat for life on Earth for at least the last 2.4 billion years. Reduction of oxygen to water allows extraction of more metabolic energy from organic fuels than is possible through anaerobic glycolysis. On the other hand, partially reduced oxygen can react indiscriminately with biomolecules to cause genetic damage, disease, and even death. Organisms in all three superkingdoms of life have developed elaborate mechanisms to protect against such oxidative damage and to exploit reactive oxygen species as sensors and signals in myriad processes. The sulfur amino acids, cysteine and methionine, are the main targets of reactive oxygen species in proteins. Oxidative modifications to cysteine and methionine can have profound effects on a protein’s activity, structure, stability, and subcellular localization. Non-reversible oxidative modifications (oxidative damage) may contribute to molecular, cellular, and organismal aging and serve as signals for repair, removal, or programmed cell death. Reversible oxidation events can function as transient signals of physiological status, extracellular environment, nutrient availability, metabolic state, cell cycle phase, immune function, or sensory stimuli. Because of its chemical similarity to sulfur and stronger nucleophilicity and acidity, selenium is an extremely efficient catalyst of reactions between sulfur and oxygen. Most of the biological activity of selenium is due to selenoproteins containing selenocysteine, the 21st genetically encoded protein amino acid. The most abundant selenoproteins in mammals are the glutathione peroxidases (5-6 genes) that reduce hydrogen peroxide and lipid hydroperoxides at the expense of glutathione and serve to limit the strength and duration of reactive oxygen signals. Thioredoxin reductases (3 genes) use NADPH to reduce oxidized thioredoxin and its homologs, which regulate a plethora of redox signaling events. Methionine sulfoxide reductase B1 reduces methionine sulfoxide back to methionine using thioredoxin as a reductant. Several selenoproteins in the endoplasmic reticulum are involved in regulation of protein disulfide formation and unfolded protein response signaling, although their precise biological activities have not been determined. The most widely distributed selenoprotein family in Nature is represented by the highly conserved thioredoxin-like selenoprotein W and its homologs that have not yet been assigned specific biological functions. Recent evidence suggests selenoprotein W and the six other small thioredoxin-like mammalian selenoproteins may serve to transduce hydrogen peroxide signals into regulatory disulfide bonds in specific target proteins.