Porphyrin π-cation and protein radicals in peroxidase catalysis and inhibition by anti-thyroid chemicals

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Abstract
1. Thyroid peroxidase (TPO) catalyses the iodination and phenolic coupling reactions in the biosynthesis of thyroid hormones. 2. The two-electron oxidation of TPO by H2O2 produces an oxoferryl porphyrin π-cation radical compound I that isomerizes spontaneously to a form of compound I that contains an oxoferryl haem and the second oxidizing equivalent as an amino acid radical. 3. The π-cation radical compound I is the catalytic species that effects iodide ion oxidation and the protein radical compound I is most likely the catalytic species that catalyses coupling. 4. Methimazole, a therapeutic, anti-hyperthyroid drug, is a suicide substrate for TPO and effects irreversible inactivation by TPO-mediated S-oxygenation to a reactive sulphenic acid that binds covalently to the prosthetic haem. 5. Sulphamethazine and other arylamines containing electron-withdrawing substituents inhibit TPO compound I-mediated reactions by reversible, mixed-type inhibition. 6. Ethylenethiourea, a fungicide metabolite, blocks TPO-mediated iodination by reacting with the catalytic iodinating species as an alternate substrate. 7. Resorcinol and related dietary flavonoids are suicide substrates for TPO and act by covalent binding to amino acid residues, presumably those radical sites present in the compound I isomer. 8. Nitrosobenzene, a known radical-trapping agent, blocks TPO-mediated coupling but not iodination or phenolic oxidations presumably by interception of the 3,5-diiodotyrosyl radical species generated during the coupling reaction.