Disruption of heme-peptide covalent cross-linking in mammalian peroxidases by hypochlorous acid

Husam M. Abu-Soud, Dhiman Maitra, Faten Shaeib, Sana N. Khan, Jaeman Byun, Ibrahim Abdulhamid, Zhe Yang, Ghassan M. Saed, Michael Peter Diamond, Peter R. Andreana, Subramaniam Pennathur

Research output: Contribution to journalArticle

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Abstract

Myeloperoxidase (MPO), lactoperoxidase (LPO) and eosinophil peroxidase (EPO) play a central role in oxidative damage in inflammatory disorders by utilizing hydrogen peroxide and halides/pseudo halides to generate the corresponding hypohalous acid. The catalytic sites of these enzymes contain a covalently modified heme group, which is tethered to the polypeptide chain at two ester linkages via the methyl group (MPO, EPO and LPO) and one sulfonium bond via the vinyl group (MPO only). Covalent cross-linking of the catalytic site heme to the polypeptide chain in peroxidases is thought to play a protective role, since it renders the heme moiety less susceptible to the oxidants generated by these enzymes. Mass-spectrometric analysis revealed the following possible pathways by which hypochlorous acid (HOCl) disrupts the heme-protein cross-linking: (1) the methyl-ester bond is cleaved to form an alcohol; (2) the alcohol group undergoes an oxygen elimination reaction via the formation of an aldehyde intermediate or undergoes a demethylation reaction to lose the terminal CH2group; and (3) the oxidative cleavage of the vinyl-sulfonium linkage. Once the heme moiety is released it undergoes cleavage at the carbon-methyne bridge either along the δ-β or a α-γ axis to form different pyrrole derivatives. These results indicate that covalent cross-linking is not enough to protect the enzymes from HOCl mediated heme destruction and free iron release. Thus, the interactions of mammalian peroxidases with HOCl modulates their activity and sets a stage for initiation of the Fenton reaction, further perpetuating oxidative damage at sites of inflammation.

Original languageEnglish (US)
Pages (from-to)245-254
Number of pages10
JournalJournal of Inorganic Biochemistry
Volume140
DOIs
StatePublished - Jun 8 2014

Fingerprint

Hypochlorous Acid
Peroxidases
Heme
Peptides
Eosinophil Peroxidase
Peroxidase
Lactoperoxidase
Catalytic Domain
Esters
Enzymes
Alcohols
Hemeproteins
Pyrroles
Oxidants
Aldehydes
Hydrogen Peroxide
Carbon
Iron
Oxygen
Inflammation

Keywords

  • Heme destruction
  • Hypochlorous acid
  • Inflammation
  • Mammalian peroxidase
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Inorganic Chemistry

Cite this

Abu-Soud, H. M., Maitra, D., Shaeib, F., Khan, S. N., Byun, J., Abdulhamid, I., ... Pennathur, S. (2014). Disruption of heme-peptide covalent cross-linking in mammalian peroxidases by hypochlorous acid. Journal of Inorganic Biochemistry, 140, 245-254. https://doi.org/10.1016/j.jinorgbio.2014.06.018

Disruption of heme-peptide covalent cross-linking in mammalian peroxidases by hypochlorous acid. / Abu-Soud, Husam M.; Maitra, Dhiman; Shaeib, Faten; Khan, Sana N.; Byun, Jaeman; Abdulhamid, Ibrahim; Yang, Zhe; Saed, Ghassan M.; Diamond, Michael Peter; Andreana, Peter R.; Pennathur, Subramaniam.

In: Journal of Inorganic Biochemistry, Vol. 140, 08.06.2014, p. 245-254.

Research output: Contribution to journalArticle

Abu-Soud, HM, Maitra, D, Shaeib, F, Khan, SN, Byun, J, Abdulhamid, I, Yang, Z, Saed, GM, Diamond, MP, Andreana, PR & Pennathur, S 2014, 'Disruption of heme-peptide covalent cross-linking in mammalian peroxidases by hypochlorous acid', Journal of Inorganic Biochemistry, vol. 140, pp. 245-254. https://doi.org/10.1016/j.jinorgbio.2014.06.018
Abu-Soud, Husam M. ; Maitra, Dhiman ; Shaeib, Faten ; Khan, Sana N. ; Byun, Jaeman ; Abdulhamid, Ibrahim ; Yang, Zhe ; Saed, Ghassan M. ; Diamond, Michael Peter ; Andreana, Peter R. ; Pennathur, Subramaniam. / Disruption of heme-peptide covalent cross-linking in mammalian peroxidases by hypochlorous acid. In: Journal of Inorganic Biochemistry. 2014 ; Vol. 140. pp. 245-254.
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abstract = "Myeloperoxidase (MPO), lactoperoxidase (LPO) and eosinophil peroxidase (EPO) play a central role in oxidative damage in inflammatory disorders by utilizing hydrogen peroxide and halides/pseudo halides to generate the corresponding hypohalous acid. The catalytic sites of these enzymes contain a covalently modified heme group, which is tethered to the polypeptide chain at two ester linkages via the methyl group (MPO, EPO and LPO) and one sulfonium bond via the vinyl group (MPO only). Covalent cross-linking of the catalytic site heme to the polypeptide chain in peroxidases is thought to play a protective role, since it renders the heme moiety less susceptible to the oxidants generated by these enzymes. Mass-spectrometric analysis revealed the following possible pathways by which hypochlorous acid (HOCl) disrupts the heme-protein cross-linking: (1) the methyl-ester bond is cleaved to form an alcohol; (2) the alcohol group undergoes an oxygen elimination reaction via the formation of an aldehyde intermediate or undergoes a demethylation reaction to lose the terminal CH2group; and (3) the oxidative cleavage of the vinyl-sulfonium linkage. Once the heme moiety is released it undergoes cleavage at the carbon-methyne bridge either along the δ-β or a α-γ axis to form different pyrrole derivatives. These results indicate that covalent cross-linking is not enough to protect the enzymes from HOCl mediated heme destruction and free iron release. Thus, the interactions of mammalian peroxidases with HOCl modulates their activity and sets a stage for initiation of the Fenton reaction, further perpetuating oxidative damage at sites of inflammation.",
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AU - Byun, Jaeman

AU - Abdulhamid, Ibrahim

AU - Yang, Zhe

AU - Saed, Ghassan M.

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AU - Andreana, Peter R.

AU - Pennathur, Subramaniam

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