Regulation of Redox Signaling by Selenoproteins |
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Authors: | Wayne Chris Hawkes Zeynep Alkan |
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Institution: | (1) USDA Agricultural Research Service, Western Human Nutrition Research Center, University of California at Davis, Davis, USA |
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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 (five to six 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 (three genes) use nicotinamide adenine
dinucleotide phosphate 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 the 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. |
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