Defining the involvement of HOCl or Cl2 as enzyme-generated intermediates in chloroperoxidase-catalyzed reactions.

Libby, R. Daniel; Shedd, A L; Phipps, A. Kathryn; Beachy, Tina M.; Gerstberger, S M

doi:10.1016/s0021-9258(18)46012-7

Cited by 47 publications

(26 citation statements)

References 12 publications

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“…Under these conditions, compounds that bind to LPO, compound I, or LPO-OI could alter the apparent binding constant for iodide ion or the maximal rate of triiodide ion formation or both. This interpretation is consistent with the findings of Libby et al, who noted that saturation kinetics and noncompetitive inhibition can result when substrate reacts exclusively with an enzyme-generated freely dissociable species (27). In this case, trimethylphenol oxidation was effected by CI2 generated by chloroperoxidase-catalyzed Cl" oxidation in competition with peroxidation of catechol.…”

Section: Discussionsupporting

confidence: 91%

Inhibition of Peroxidase-Catalyzed Reactions by Arylamines: Mechanism for the Anti-Thyroid Action of Sulfamethazine

Doerge¹,

Decker²

1994

Chem. Res. Toxicol.

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Sulfonamide antibiotics, typified by sulfamethazine (SMZ), are widely used in veterinary practice. Sulfonamide residues in milk and meat products are of regulatory concern since SMZ is a thyroid carcinogen in rodents and sulfonamide-induced hypersensitivity reactions, including hypothyroidism, have been reported in humans. SMZ and other primary arylamines inhibited iodination reactions catalyzed by thyroid peroxidase (TPO) and the closely related lactoperoxidase (LPO). Inhibition of LPO-catalyzed triiodide ion formation by SMZ and other primary arylamines was complex as both apparent Km and Vmax values were affected, but consistent with a rapid equilibrium binding mechanism. The apparent Ki for SMZ inhibition of TPO- and LPO-catalyzed iodide ion oxidation was approximately 0.42 and 0.11 mM, respectively. The corresponding Ki values for a series of para-substituted anilines correlated with the ease of one-electron N-oxidation as measured by ionization potentials determined from semiempirical molecular orbital calculations. The aniline derivatives containing electron-donating substituents (e.g., p-CH3, p-OEt, p-Cl) were converted by LPO to colored products characteristic of one-electron oxidation. However, sulfonamides were not consumed in such reactions nor were any N-oxygenated derivatives formed in the absence of ascorbate (e.g., hydroxylamino, nitroso, nitro, azoxy). These observations suggest that the primary mechanism for sulfonamide-induced hypothyroidism is reversible inhibition of TPO-mediated thyroid hormone synthesis and not the formation and covalent binding of reactive N-oxygenated metabolites. These results are consistent with a hormonal mechanism for SMZ-induced thyroid carcinogenesis mediated by thyroid-stimulating hormone (TSH).(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionsupporting

confidence: 91%

Inhibition of Peroxidase-Catalyzed Reactions by Arylamines: Mechanism for the Anti-Thyroid Action of Sulfamethazine

Doerge¹,

Decker²

1994

Chem. Res. Toxicol.

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“…The selectivity of the MPOcatalyzed oxidation of LDL is most readily attributed to the intermediacy of an enzyme-substrate complex. Marquez and Dunford (19) have reported kinetic evidence for an enzyme-bound intermediate in the MPO-catalyzed chlorination of taurine, and Libby et al (20,21) have observed similar effects in their studies of substrate oxidation by chloroperoxidase. However, large proteins, especially those ensconced in even more bulky lipoprotein particles, should have more difficulty in accessing the restrictive active site of MPO ( 22) than would the much smaller molecules studied by the other investigators.…”

Section: Discussionmentioning

confidence: 93%

Selective modification of apoB-100 in the oxidation of low density lipoproteins by myeloperoxidase in vitro

Yang

et al. 1999

Journal of Lipid Research

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Oxidative modification of LDL may be important in the initiation and/or progression of atherosclerosis, but the precise mechanisms through which low density lipoprotein (LDL) is oxidized are unknown. Recently, evidence for the existence of HOCl-oxidized LDL in human atherosclerotic lesions has been reported, and myeloperoxidase (MPO), which is thought to act through production of HOCl, has been identified in human atherosclerotic lesions. In the present report we describe the formation of 2,4-dinitrophenylhydrazine (DNPH)-reactive modifications in the apolipoprotein (apo) by exposure of LDL to myeloperoxidase in vitro. In contrast with the complex mixture of peptides from oxidation of LDL with reagent HOCl, oxidation with MPO in vitro produced a major tryptic peptide showing absorbance at 365 nm. This peptide was isolated and characterized as VELEVPQL(*C)SFILK . . . , corresponding to amino acid residues 53-66 . . . on apoB-100. Mass spectrometric analyses of two tryptic peptides from oxidation of LDL by HOCl indicated formation of the corresponding methionine sulfoxide (M O), cysteinyl azo (*C), RS-N N-DNP, derivatives of EEL(*C)T(M O)FIR and LNDLNS VLV(M O)PTFHVPFTDLQVPS(*C)K, which suggest oxidation to the corresponding sulfinic acids (RSO 2 H) by HOCl.The present results demonstrate that DNPH-reactive modifications other than aldehydes and ketones can be formed in the oxidation of proteins and illustrate how characterization of specific products of protein oxidation can be useful in assessing the relative contributions of different and unexpected mechanisms to the oxidation of LDL and other target substrates. The data also suggest a direct interaction of the LDL particle with the active site on myeloperoxidase and indicate that effects of the protein microenvironment can greatly influence product formation and stability. -Yang, C-y.,

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“…Chloroperoxidase (EC 1.11.1.10, pH optimum: 2.75) is known to generate a variety of reactive oxygen species (ROS) depending upon the chemical substrates turned over by the enzyme. Generally, CPO has been utilized to generate chlorine dioxide (ClO 2 ) from sodium chlorite (NaClO 2 ); however, in the presence of NaCl and H 2 O 2 (at acidic pH) HOCl is generated (Figure A). , Since HOCl is the desired oxidant in these studies, we have employed CPO to produce a potential oxidative response in PPS particles through the addition of NaCl and H 2 O 2 substrates. As a primary control, PPS particles were examined in the presence of varying concentrations of H 2 O 2 (a known oxidant) in the range of 500 μM to 3 mM (Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

Encapsulation and Enzyme-Mediated Release of Molecular Cargo in Polysulfide Nanoparticles

2011

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Poly(propylene sulfide) nanoparticles (<150 nm) have been synthesized by an anionic, ring-opening emulsion polymerization. Upon exposure to parts per million (ppm) levels of oxidizing agent (NaOCl), hydrophobic polysulfide particles are oxidized to hydrophilic polysulfoxides and polysulfones. Utilizing this mechanism, the encapsulation of hydrophobic molecular cargo, including Nile red and Reichardt's dye, within polysulfide nanoparticles has been characterized by a variety of microscopic and spectroscopic methods and its release demonstrated via chemical oxidation. Moreover, release of cargo has been enzymatically driven by oxidoreductase enzymes such as chloroperoxidase and myeloperoxidase in the presence of low concentrations of sodium chloride (200 mM) and hydrogen peroxide (500 μM). This oxidation-driven mechanism holds promise for controlled encapsulation and release of a variety of hydrophobic cargos.

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Defining the involvement of HOCl or Cl2 as enzyme-generated intermediates in chloroperoxidase-catalyzed reactions.

Cited by 47 publications

References 12 publications

Inhibition of Peroxidase-Catalyzed Reactions by Arylamines: Mechanism for the Anti-Thyroid Action of Sulfamethazine

Inhibition of Peroxidase-Catalyzed Reactions by Arylamines: Mechanism for the Anti-Thyroid Action of Sulfamethazine

Selective modification of apoB-100 in the oxidation of low density lipoproteins by myeloperoxidase in vitro

Encapsulation and Enzyme-Mediated Release of Molecular Cargo in Polysulfide Nanoparticles

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