Superoxide Reaction with Tyrosyl Radicals Generates para-Hydroperoxy and para-Hydroxy Derivatives of Tyrosine

Möller, Matías N.; Hatch, Duane M.; Kim, Hye-Young H.; Porter, Ned A.

doi:10.1021/ja307215z

Cited by 50Redox biology and oxidative stressFree Radicals and AntioxidantsMetal-Catalyzed Oxygenation Mechanisms

Superoxide Reaction with Tyrosyl Radicals Generates para-Hydroperoxy and para-Hydroxy Derivatives of Tyrosine

Möller, Matías N., Hatch, Duane M., Kim, Hye-Young H., Porter, Ned A.·2012·Journal of the American Chemical Society

DOI 10.1021/ja307215z

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Abstract

Tyrosine-derived hydroperoxides are formed in peptides and proteins exposed to enzymatic or cellular sources of superoxide and oxidizing species as a result of the nearly diffusion-limited reaction between tyrosyl radical and superoxide. However, the structure of these products, which informs their reactivity in biology, has not been unequivocally established. We report here the complete characterization of the products formed in the addition of superoxide, generated from xanthine oxidase, to several peptide-derived tyrosyl radicals, formed from horseradish peroxidase. RP-HPLC, LC-MS, and NMR experiments indicate that the primary stable products of superoxide addition to tyrosyl radical are para-hydroperoxide derivatives (para relative to the position of the OH in tyrosine) that can be reduced to the corresponding para-alcohol. In the case of glycyl-tyrosine, a stable 3-(1-hydroperoxy-4-oxocyclohexa-2,5-dien-1-yl)-L-alanine was formed. In tyrosyl-glycine and Leu-enkephalin, which have N-terminal tyrosines, bicyclic indolic para-hydroperoxide derivatives were formed ((2S,3aR,7aR)-3a-hydroperoxy-6-oxo-2,3,3a,6,7,7a-hexahydro-1H-indole-2-carboxylic acid) by the conjugate addition of the free amine to the cyclohexadienone. It was also found that significant amounts of the para-OH derivative were generated from the hydroxyl radical, formed on exposure of tyrosine-containing peptides to Fenton conditions. The para-OOH and para-OH derivatives are much more reactive than other tyrosine oxidation products and may play important roles in physiology and disease.

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The tyrosine hydroperoxide can be formed in the ortho or para position relative to the phenoxyl radical due to resonant forms of Tyr.
“The hydroperoxide, due to the resonant forms of Tyr, can be formed in the ortho or para position with respect to the phenoxyl radical [138,139,140], Figure 51 and Figure 52.”
From Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity (2023) · cites this paper as [140]

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Authors: Möller, M. N., Hatch, D. M., Kim, H.-Y. H., & Porter, N. A.
Affiliations: Universidad de la República de Uruguay (UY)
Vanderbilt University (US)
Corresponding author: Porter, Ned A.
ORCID: Möller, Matías N.
Kim, Hye-Young H.
Porter, Ned A.
Venue: Journal of the American Chemical Society
Publisher: American Chemical Society (ACS)
Published: 2012-09-28
Volume: 134
Issue: 40
Pages: 16773-16780
ISSN: 0002-7863 (ISSN-L)
1520-5126
DOI: 10.1021/ja307215z
OpenAlex: W2315794577
Cited by: 50
References: 44
Citations by year: 2026: 1 · 2025: 3 · 2024: 5 · 2023: 6 · 2022: 4 · 2021: 4 · 2020: 2 · 2019: 6 · 2018: 5 · 2017: 1 · 2016: 3 · 2015: 1 · 2014: 5 · 2013: 4
FWCI: 1.28
Type: journal article
Language: en
Open access: closed
Locations: Journal of the American Chemical Society (publishedVersion)
PubMed (publishedVersion)
Funders: National Science Foundation
Vanderbilt University
National Institute of Environmental Health Sciences (P01ES013125)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Physical Sciences › Chemistry › Organic Chemistry › Free Radicals and Antioxidants
Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
Keywords: superoxide, tyrosyl radical, xanthine oxidase, horseradish peroxidase, peptide oxidation, leu-enkephalin, hydroxyl radicals, Fenton reaction, protein oxidation, cyclohexadienones
MeSH terms: Animals, Cattle, Enkephalin, Leucine, Horseradish Peroxidase, Hydrogen Peroxide, Models, Molecular, Oxidation-Reduction, Peptides, Superoxides, Superoxide Dismutase, Tyrosine, Xanthine Oxidase, Armoracia

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Superoxide Reaction with Tyrosyl Radicals Generates para-Hydroperoxy and para-Hydroxy Derivatives of Tyrosine

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