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Cited by 790Neutrophil, Myeloperoxidase and Oxidative MechanismsRedox biology and oxidative stressFree Radicals and Antioxidants

Absolute Rate Constants for the Reaction of Hypochlorous Acid with Protein Side Chains and Peptide Bonds

Pattison, David I., Davies, Michael J.·2001·Chemical Research in Toxicology
DOI 10.1021/tx0155451
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Abstract

Hypochlorous acid (HOCl) is a potent oxidant, which is produced in vivo by activated phagocytes. This compound is an important antibacterial agent, but excessive or misplaced production has been implicated in a number of human diseases, including atherosclerosis, arthritis, and some cancers. Proteins are major targets for this oxidant, and such reaction results in side-chain modification, backbone fragmentation, and cross-linking. Despite a wealth of qualitative data for such reactions, little absolute kinetic data is available to rationalize the in vitro and in vivo data. In this study, absolute second-order rate constants for the reactions of HOCl with protein side chains, model compounds, and backbone amide (peptide) bonds have been determined at physiological pH values. The reactivity of HOCl with potential reactive sites in proteins is summarized by the series: Met (3.8 x 10(7) M(-1) x s(-1)) > Cys (3.0 x 10(7) M(-1) x s(-1)) >> cystine (1.6 x 10(5) M(-1) x s(-1)) approximately His (1.0 x 10(5) M(-1) x s(-1)) approximately alpha-amino (1.0 x 10(5) M(-1) x s(-1)) > Trp (1.1 x 10(4) M(-1) x s(-1)) > Lys (5.0 x 10(3) M(-1) x s(-1)) >> Tyr (44 M(-1) x s(-1)) approximately Arg (26 M(-1) x s(-1)) > backbone amides (10-10(-3) M(-1) x s(-1)) > Gln(0.03 M(-1) x s(-1)) approximately Asn (0.03 M(-1) x s(-1)). The rate constants for reaction of HOCl with backbone amides (peptide bonds) vary by 4 orders of magnitude with uncharged peptide bonds reacting more readily with HOCl than those in a charged environment. These kinetic parameters have been used in computer modeling of the reactions of HOCl with human serum albumin, apolipoprotein-A1 and free amino acids in plasma at different molar excesses. These models are useful tools for predicting, and reconciling, experimental data obtained in HOCl-induced oxidations and allow estimations to be made as to the flux of HOCl to which proteins are exposed in vivo.

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  • A large number of cytokines and hormones induce NOX2 expression, including angiotensin II, thrombin, and TNF-α.

    “A large number of cytokines and hormones have been shown to induce NOX2 expression, including angiotensin II (658, 714, 802), thrombin (725), and TNF-α (275, 964).”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [725]

  • HOCl, in equilibrium at physiological pH with its anionic form OCl−, may also induce tissue damage at sites of inflammation involving the oxidation and chlorination of biomolecules targeting peptides, proteins, lipids, and nucleic acids.

    “HOCl, in equilibrium at physiological pH with its anionic form [hypochlorite (OCl−)], may also induce tissue damage at sites of inflammation involving the oxidation and chlorination of biomolecules targeting peptides (e.g. glutathione), proteins, lipids, and nucleic acids (39, 42, 43, 47, 76, 77).”

    From Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer (2022) · cites this paper as [42]

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Authors
Pattison, D. I., & Davies, M. J.
Affiliations
The Heart Research Institute (AU)
Corresponding author
Davies, Michael J.
ORCID
Venue
Chemical Research in Toxicology
Publisher
American Chemical Society (ACS)
Published
2001-09-11
Volume
14
Issue
10
Pages
1453-1464
ISSN
  • 0893-228X (ISSN-L)
  • 1520-5010
DOI
10.1021/tx0155451
OpenAlex
W2040447429
Cited by
790
References
26
Citations by year
2026: 28 · 2025: 27 · 2024: 35 · 2023: 37 · 2022: 54 · 2021: 42 · 2020: 59 · 2019: 55 · 2018: 50 · 2017: 48 · 2016: 35 · 2015: 38 · 2014: 43 · 2013: 34 · 2012: 43
FWCI
3.02
Type
journal article
Language
en
Open access
closed
Locations
  • Chemical Research in Toxicology (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Physical Sciences › Chemistry › Organic Chemistry › Free Radicals and Antioxidants
Keywords
hypochlorous acid, protein oxidation, absolute rate constants, second-order rate constants, amino acid side chains, peptide bond, amide bond cleavage, cysteine, methionine, histidine, human serum albumin, apolipoprotein A-I, plasma amino acids, reactive oxygen species, oxidative stress, kinetic modeling, physiological pH, crosslinking
MeSH terms
Amino Acids, Computer Simulation, Forecasting, Humans, Hypochlorous Acid, Kinetics, Oxidation-Reduction, Peptides, Serum Albumin, Apolipoprotein A-I, Oxidants, Protein Structure, Secondary

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