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Cited by 166Neutrophil, Myeloperoxidase and Oxidative MechanismsRedox biology and oxidative stressAntioxidant Activity and Oxidative Stress

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Hypochlorous Acid Chemistry in Mammalian Cells—Influence on Infection and Role in Various Pathologies

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Andrés, Celia María Curieses, Pérez de la Lastra, José Manuel, Juan, Celia Andrés, Plou, Francisco J., Pérez-Lebeña, Eduardo·2022·International Journal of Molecular Sciences
DOI 10.3390/ijms231810735PMC PMC9504810
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Abstract

This review discusses the formation of hypochlorous acid HOCl and the role of reactive chlorinated species (RCS), which are catalysed by the enzyme myeloperoxidase MPO, mainly located in leukocytes and which in turn contribute to cellular oxidative stress. The reactions of RCS with various organic molecules such as amines, amino acids, proteins, lipids, carbohydrates, nucleic acids, and DNA are described, and an attempt is made to explain the chemical mechanisms of the formation of the various chlorinated derivatives and the data available so far on the effects of MPO, RCS and halogenative stress. Their presence in numerous pathologies such as atherosclerosis, arthritis, neurological and renal diseases, diabetes, and obesity is reviewed and were found to be a feature of debilitating diseases.

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Figures

Figure 1 Chemical and enzymatic reactions generating ROS and main antioxidant systems.
Figure 1 Chemical and enzymatic reactions generating ROS and main antioxidant systems.CC BY · PubMed Central
Figure 2 Schematic representation of HOCl production during the respiratory burst. The cell uses molecular oxygen (O2) to produce H2O2, using the enzyme NADPH oxidase. MPO deposited on the azurophilic granules catalyses the reaction of H2O2 and the chloride anion Cl− to form hypochlorous acid HOCl.
Figure 2 Schematic representation of HOCl production during the respiratory burst. The cell uses molecular oxygen (O2) to produce H2O2, using the enzyme NADPH oxidase. MPO deposited on the azurophilic granules catalyses the reaction of H2O2 and the chloride anion Cl− to form hypochlorous acid HOCl.CC BY · PubMed Central
Figure 3 Normal catalytic cycling of myeloperoxidase. The native state of the enzyme, ferric MPO, reacts with hydrogen peroxide to form the redox intermediate Compound I. Compound I oxidises chloride to regenerate ferric MPO via the halogenation cycle.
Figure 3 Normal catalytic cycling of myeloperoxidase. The native state of the enzyme, ferric MPO, reacts with hydrogen peroxide to form the redox intermediate Compound I. Compound I oxidises chloride to regenerate ferric MPO via the halogenation cycle.CC BY · PubMed Central
Figure 4 Catalysed conversion of Cl−, Br−, I−, and SCN− by MPO, with second-order constants K.
Figure 4 Catalysed conversion of Cl−, Br−, I−, and SCN− by MPO, with second-order constants K.CC BY · PubMed Central
Figure 5 In hypochlorous acid, the chlorine–oxygen bond is polarised as shown in the figure, so Cl+ will act as an electrophilic reactant.
Figure 5 In hypochlorous acid, the chlorine–oxygen bond is polarised as shown in the figure, so Cl+ will act as an electrophilic reactant.CC BY · PubMed Central
Figure 6 Production of hypochlorous acid from hydrogen peroxide and chloride.
Figure 6 Production of hypochlorous acid from hydrogen peroxide and chloride.CC BY · PubMed Central
Figure 7 Electrophilic addition of HOCl to unsaturated fatty acids.
Figure 7 Electrophilic addition of HOCl to unsaturated fatty acids.CC BY · PubMed Central
Figure 8 Electrophilic addition of HOCl to cholesterol. Mechanism of formation of cholesterol chlorohydrins.
Figure 8 Electrophilic addition of HOCl to cholesterol. Mechanism of formation of cholesterol chlorohydrins.CC BY · PubMed Central
Figure 9 Synthesis of epoxy-cholesterol by intramolecular Williamson reaction via an intramolecular SN2 reaction.
Figure 9 Synthesis of epoxy-cholesterol by intramolecular Williamson reaction via an intramolecular SN2 reaction.CC BY · PubMed Central
Figure 10 Plasmalogen modification by HOCl or MPO/H2O2/Cl−. (a) Acid-catalysed hydrolysis of hemiacetal. The vinyl ether bond of plasmalogens is targeted by HOCl resulting in the release of the masked aldehyde as an α-chloro-fatty aldehyde. The other product of this reaction is an unsaturated molecular species of lysophosphatidylcholine.
Figure 10 Plasmalogen modification by HOCl or MPO/H2O2/Cl−. (a) Acid-catalysed hydrolysis of hemiacetal. The vinyl ether bond of plasmalogens is targeted by HOCl resulting in the release of the masked aldehyde as an α-chloro-fatty aldehyde. The other product of this reaction is an unsaturated molecular species of lysophosphatidylcholine.CC BY · PubMed Central
Figure 11 The alkene bond in the unsaturated molecular species of lysophosphatidylcholine is targeted by HOCl to yield a chlorohydrin molecular species.
Figure 11 The alkene bond in the unsaturated molecular species of lysophosphatidylcholine is targeted by HOCl to yield a chlorohydrin molecular species.CC BY · PubMed Central
Figure 12 Sphingomyelin modification by HOCl or H2O2/MPO/Cl−. Chlorinated sphingomyelin derivatives produce significant deleterious effects on cells, including apoptosis and DNA damage.
Figure 12 Sphingomyelin modification by HOCl or H2O2/MPO/Cl−. Chlorinated sphingomyelin derivatives produce significant deleterious effects on cells, including apoptosis and DNA damage.CC BY · PubMed Central
Figure 13 Scheme of reaction of phosphatidylcholine with HOCl.
Figure 13 Scheme of reaction of phosphatidylcholine with HOCl.CC BY · PubMed Central
Figure 14 Formation of monochloramine and dichloramine from the oxidation of dipalmitoyl phosphatidylethanolamine by hypochlorous acid.
Figure 14 Formation of monochloramine and dichloramine from the oxidation of dipalmitoyl phosphatidylethanolamine by hypochlorous acid.CC BY · PubMed Central
Figure 15 Formation of monochloramine from the oxidation of phosphatidylserine by HOCl.
Figure 15 Formation of monochloramine from the oxidation of phosphatidylserine by HOCl.CC BY · PubMed Central
Figure 16 Decomposition of dichloroamine, formation of a transient (chloro)imine.
Figure 16 Decomposition of dichloroamine, formation of a transient (chloro)imine.CC BY · PubMed Central
Figure 17 Conversion of the amino group of phosphatidylethanolamine and phosphatidylserine by reaction with HOCl.
Figure 17 Conversion of the amino group of phosphatidylethanolamine and phosphatidylserine by reaction with HOCl.CC BY · PubMed Central
Figure 18 Synthesis of mono, di, and trichloro ammonia.
Figure 18 Synthesis of mono, di, and trichloro ammonia.CC BY · PubMed Central
Figure 19 Dihaloamines obtained by the disproportionation reaction of the corresponding N-monohaloamine in an acid medium.
Figure 19 Dihaloamines obtained by the disproportionation reaction of the corresponding N-monohaloamine in an acid medium.CC BY · PubMed Central
Figure 20 Transition state of the amine chlorination reaction.
Figure 20 Transition state of the amine chlorination reaction.CC BY · PubMed Central
Figure 21 Schematic the mechanism of formation of N-chloro-α-amino acids from amino acids includes an electrophilic attack via the Cl+ of HOCl on the nitrogen atom together with a proton transfer from the nitrogen atom to HOCl to release a water molecule.
Figure 21 Schematic the mechanism of formation of N-chloro-α-amino acids from amino acids includes an electrophilic attack via the Cl+ of HOCl on the nitrogen atom together with a proton transfer from the nitrogen atom to HOCl to release a water molecule.CC BY · PubMed Central
Figure 22 Products obtained in the reaction of aromatic amino acids with HOCl.
Figure 22 Products obtained in the reaction of aromatic amino acids with HOCl.CC BY · PubMed Central
Figure 23 Reaction of P-protected tyrosine with HOCl and formation of 3-chloro- and 3,5-dichlorotyrosine derivatives.
Figure 23 Reaction of P-protected tyrosine with HOCl and formation of 3-chloro- and 3,5-dichlorotyrosine derivatives.CC BY · PubMed Central
Figure 24 Mechanism of the electrophilic substitution in tyrosine and the formation of 3-chlorotyrosine. Stage 1: electrophilic attack; Stage 2: proton loss.
Figure 24 Mechanism of the electrophilic substitution in tyrosine and the formation of 3-chlorotyrosine. Stage 1: electrophilic attack; Stage 2: proton loss.CC BY · PubMed Central
Figure 25 Formation of p-hydroxyphenylacetaldehyde [77] and 3-chloro-4-hydroxyphenylacetaldehyde.
Figure 25 Formation of p-hydroxyphenylacetaldehyde [77] and 3-chloro-4-hydroxyphenylacetaldehyde.CC BY · PubMed Central
Figure 26 Hypochlorous acid could directly attack the free amino group of the amino acid Trip, with the consequent formation of a chloramine, in an electrophilic substitution mechanism [78].
Figure 26 Hypochlorous acid could directly attack the free amino group of the amino acid Trip, with the consequent formation of a chloramine, in an electrophilic substitution mechanism [78].CC BY · PubMed Central
Figure 27 HOCl reaction with Lys and formation of monochloroamine and dichloroamine.
Figure 27 HOCl reaction with Lys and formation of monochloroamine and dichloroamine.CC BY · PubMed Central
Figure 28 Proposed structures of chlorinate L-arginine products.
Figure 28 Proposed structures of chlorinate L-arginine products.CC BY · PubMed Central
Figure 29 Summary of products of oxidation of Cys and Cystine residues by HOCl.
Figure 29 Summary of products of oxidation of Cys and Cystine residues by HOCl.CC BY · PubMed Central
Figure 30 Formation of S-chloro-L-cysteine.
Figure 30 Formation of S-chloro-L-cysteine.CC BY · PubMed Central
Figure 31 Proposed reaction pathways for S–N cross-linking and oxidation by HOCl of Cys.
Figure 31 Proposed reaction pathways for S–N cross-linking and oxidation by HOCl of Cys.CC BY · PubMed Central
Figure 32 Mechanism of Met oxidation mediated by Cl–taurine to yield methionine sulfoxide.
Figure 32 Mechanism of Met oxidation mediated by Cl–taurine to yield methionine sulfoxide.CC BY · PubMed Central
Figure 33 Proposed transition state for the N-chlorotaurin disproportionation reaction.
Figure 33 Proposed transition state for the N-chlorotaurin disproportionation reaction.CC BY · PubMed Central
Figure 34 Formation of chloramide.
Figure 34 Formation of chloramide.CC BY · PubMed Central
Figure 35 Formation of the radical centred on the N of Lys with subsequent transformation to a C-centred radical.
Figure 35 Formation of the radical centred on the N of Lys with subsequent transformation to a C-centred radical.CC BY · PubMed Central
Figure 36 Reaction of GSH with HOCl and formation of glutathione sulphonamide.
Figure 36 Reaction of GSH with HOCl and formation of glutathione sulphonamide.CC BY · PubMed Central
Figure 37 Intramolecular cyclisation of the RSCl intermediate with the terminal amino group on oxidation by hypochlorous acid. The proposed mechanism of formation is through the condensation of the sulphonyl chloride with the amino group of the glutamyl residue of glutathione.
Figure 37 Intramolecular cyclisation of the RSCl intermediate with the terminal amino group on oxidation by hypochlorous acid. The proposed mechanism of formation is through the condensation of the sulphonyl chloride with the amino group of the glutamyl residue of glutathione.CC BY · PubMed Central
Figure 38 Cyclic amides formed in the reaction of GSH with HOCl.
Figure 38 Cyclic amides formed in the reaction of GSH with HOCl.CC BY · PubMed Central
Figure 39 Decomposition of lysine monochloramide with formation of aldehyde and nitrile from dichlorinated Lys.
Figure 39 Decomposition of lysine monochloramide with formation of aldehyde and nitrile from dichlorinated Lys.CC BY · PubMed Central
Figure 40 Degradation mechanisms of N-chloro-α-amino acid anions under neutral conditions.
Figure 40 Degradation mechanisms of N-chloro-α-amino acid anions under neutral conditions.CC BY · PubMed Central
Figure 41 (a) β-fragmentation reaction by homolytic cleavage of the C-C bond in position to an N-centred radical, giving rise to an iminic derivative and a C-radical R; and (b) β-fragmentation by homolytic cleavage with the loss of CO2 and a C-centred radical.
Figure 41 (a) β-fragmentation reaction by homolytic cleavage of the C-C bond in position to an N-centred radical, giving rise to an iminic derivative and a C-radical R; and (b) β-fragmentation by homolytic cleavage with the loss of CO2 and a C-centred radical.CC BY · PubMed Central
Figure 42 Intra- or intermolecular hydrogen abstraction reactions.
Figure 42 Intra- or intermolecular hydrogen abstraction reactions.CC BY · PubMed Central
Figure 43 Reaction of AMP/ADP/ATP with HOCl and chlorination at the primary amino group of the adenosine derivative.
Figure 43 Reaction of AMP/ADP/ATP with HOCl and chlorination at the primary amino group of the adenosine derivative.CC BY · PubMed Central
Figure 44 (a) Faster NH-chlorination of thymidine, uridine, inosine, and guanosine; and (b) slower –NH2 chlorination of adenosine, cytidine, and guanosine.
Figure 44 (a) Faster NH-chlorination of thymidine, uridine, inosine, and guanosine; and (b) slower –NH2 chlorination of adenosine, cytidine, and guanosine.CC BY · PubMed Central
Figure 45 Formation of chloroamines and the breaking of the hydrogen bond.
Figure 45 Formation of chloroamines and the breaking of the hydrogen bond.CC BY · PubMed Central
Figure 46 Formation of 8-chloro-2′-deoxyguanosine, 8-chloro-2′-deoxyadenosine, and 5-chloro-2′-deoxycytidine by the reaction of DNA with HOCl or N-chloramines.
Figure 46 Formation of 8-chloro-2′-deoxyguanosine, 8-chloro-2′-deoxyadenosine, and 5-chloro-2′-deoxycytidine by the reaction of DNA with HOCl or N-chloramines.CC BY · PubMed Central
Figure 47 Possible mechanism of formation of 8-chloro-9-methyl-9H-purin-6-amine from the N-chloro-9H-purin-6-amine derivative and formation of the N-centred radical.
Figure 47 Possible mechanism of formation of 8-chloro-9-methyl-9H-purin-6-amine from the N-chloro-9H-purin-6-amine derivative and formation of the N-centred radical.CC BY · PubMed Central
Figure 48 Scheme of N-centred amidyl-radical formation and transformation into C-centred radical with the fragmentation of the polysaccharide chain during the reaction of HOCl with the acetylamide-group of hyaluronic acid.
Figure 48 Scheme of N-centred amidyl-radical formation and transformation into C-centred radical with the fragmentation of the polysaccharide chain during the reaction of HOCl with the acetylamide-group of hyaluronic acid.CC BY · PubMed Central
Figure 49 Arrows indicate possible chlorination sites with HOCl.
Figure 49 Arrows indicate possible chlorination sites with HOCl.CC BY · PubMed Central
Figure 50 Free radical-induced damage to the cardiovascular system.
Figure 50 Free radical-induced damage to the cardiovascular system.CC BY · PubMed Central
Figure 51 Relationship of HOCl with different pathologies.
Figure 51 Relationship of HOCl with different pathologies.CC BY · PubMed Central

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Research works printed but not linked: 3

  1. Ouellette, R.J., and Rawn, J.D. (2015). Organic Chemistry Study Guide: Key Concepts, Problems, and Solutions, Elsevier.
  2. Fernández-Pérez, M.-I. (2002). Mecanismos de Oxidación y Fotooxidación de Compuestos de Relevancia Bioquímica y Medioambiental: 1. Halogenación de Aminoácidos Azufrados. 2. Fotodegradación de Biocidas Tipo S. Triazina. [Ph.D. Thesis, University of Coruña]. Available online: https://ruc.udc.es/dspace/handle/2183/11706.
  3. Biscardi, 1995, Inactivación de la lipoamida deshidrogenasa de miocardio por catecolaminas: Protección por captopril y otros tioles, Med. B. Aires, 55, 397

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Metadata

Authors
Andrés, C. M. C., Pérez de la Lastra, J. M., Juan, C. A., Plou, F. J., & Pérez-Lebeña, E.
Affiliations
  • Hospital Clínico Universitario de Valladolid (ES)
  • Institute of Natural Products and Agrobiology, IPNA-CSIC-Spanish Research Council, Avda. Astrofísico Fco. Sánchez, 38206 San Cristóbal de La Laguna, Spain
  • Cinquima Institute and Department of Organic Chemistry, Faculty of Sciences, Valladolid University, Paseo de Belén, 7, 47011 Valladolid, Spain
  • Consejo Superior de Investigaciones Científicas (ES)
  • Sistemas de Biotecnología y Recursos Naturales, 47625 Valladolid, Spain
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2022-09-14
Volume
23
Issue
18
Pages
10735
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms231810735
PMC
PMC9504810
OpenAlex
W4295977692
Cited by
166
References
224
Citations by year
2026: 55 · 2025: 48 · 2024: 41 · 2023: 19 · 2022: 3
FWCI
2.91
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Agencia Canaria de Investigación, Innovación y Sociedad de la Información (ACIISI) del Gobierno de Canarias (ProID2020010134, PID2019-105838RB-C31)
  • Spanish Ministry of Economy and Competitiveness (ProID2020010134, PID2019-105838RB-C31)
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
  • Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
Keywords
hypochlorous acid, myeloperoxidase, oxidative stress, leukocytes, lipid peroxidation, atherosclerosis, arthritis, neurological disorders, kidney disease, diabetes mellitus, obesity, infection
MeSH terms
Amines, Amino Acids, Animals, Carbohydrates, Hypochlorous Acid, Lipids, Mammals, Peroxidase, Nucleic Acids

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