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Published September 1, 2015 | Published + Supplemental Material
Journal Article Open

Hole hopping through tyrosine/tryptophan chains protects proteins from oxidative damage


Living organisms have adapted to atmospheric dioxygen by exploiting its oxidizing power while protecting themselves against toxic side effects. Reactive oxygen and nitrogen species formed during oxidative stress, as well as high-potential reactive intermediates formed during enzymatic catalysis, could rapidly and irreversibly damage polypeptides were protective mechanisms not available. Chains of redox-active tyrosine and tryptophan residues can transport potentially damaging oxidizing equivalents (holes) away from fragile active sites and toward protein surfaces where they can be scavenged by cellular reductants. Precise positioning of these chains is required to provide effective protection without inhibiting normal function. A search of the structural database reveals that about one third of all proteins contain Tyr/Trp chains composed of three or more residues. Although these chains are distributed among all enzyme classes, they appear with greatest frequency in the oxidoreductases and hydrolases. Consistent with a redox-protective role, approximately half of the dioxygen-using oxidoreductases have Tyr/Trp chain lengths ≥3 residues. Among the hydrolases, long Tyr/Trp chains appear almost exclusively in the glycoside hydrolases. These chains likely are important for substrate binding and positioning, but a secondary redox role also is a possibility.

Additional Information

© 2015 National Academy of Sciences. Contributed by Harry B. Gray, June 29, 2015 (sent for review June 10, 2015; reviewed by David Beratan and Peter Brzezinski). Published online before print July 20, 2015. For many years we enjoyed collaborative work with the late John H. (Jack) Richards; discussions with him influenced our current view of the roles of hole hopping in biology. Research reported in this publication was supported by The National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award R01DK019038 (to H.B.G. and J.R.W.). Additional support was provided by the Arnold and Mabel Beckman Foundation. Author contributions: J.R.W. designed research; J.R.W. performed research; H.B.G. and J.R.W. analyzed data; and H.B.G. and J.R.W. wrote the paper. Reviewers: D.B., Duke University; and P.B., Stockholm University. The authors declare no conflict of interest. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1512704112/-/DCSupplemental.

Attached Files

Published - PNAS-2015-Gray-10920-5.pdf

Supplemental Material - pnas.1512704112.sapp.pdf


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August 22, 2023
August 22, 2023