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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Heme-thiolate sulfenylation of human cytochrome P450 4A11 functions as a redox switch for catalytic inhibition.

Authors: Albertolle, Matthew E; Kim, Donghak; Nagy, Leslie D; Yun, Chul-Ho; Pozzi, Ambra; Savas, Üzen; Johnson, Eric F; Guengerich, F Peter

Published In J Biol Chem, (2017 07 07)

Abstract: Cytochrome P450 (P450, CYP) 4A11 is a human fatty acid ω-hydroxylase that catalyzes the oxidation of arachidonic acid to the eicosanoid 20-hydroxyeicosatetraenoic acid (20-HETE), which plays important roles in regulating blood pressure regulation. Variants of P450 4A11 have been associated with high blood pressure and resistance to anti-hypertensive drugs, and 20-HETE has both pro- and antihypertensive properties relating to increased vasoconstriction and natriuresis, respectively. These physiological activities are likely influenced by the redox environment, but the mechanisms are unclear. Here, we found that reducing agents (e.g. dithiothreitol and tris(2-carboxyethyl)phosphine) strongly enhanced the catalytic activity of P450 4A11, but not of 10 other human P450s tested. Conversely, added H2O2 attenuated P450 4A11 catalytic activity. Catalytic roles of five of the potentially eight implicated Cys residues of P450 4A11 were eliminated by site-directed mutagenesis. Using an isotope-coded dimedone/iododimedone-labeling strategy and mass spectrometry of peptides, we demonstrated that the heme-thiolate cysteine (Cys-457) is selectively sulfenylated in an H2O2 concentration-dependent manner. This sulfenylation could be reversed by reducing agents, including dithiothreitol and dithionite. Of note, we observed heme ligand cysteine sulfenylation of P450 4A11 ex vivo in kidneys and livers derived from CYP4A11 transgenic mice. We also detected sulfenylation of murine P450 4a12 and 4b1 heme peptides in kidneys. To our knowledge, reversible oxidation of the heme thiolate has not previously been observed in P450s and may have relevance for 20-HETE-mediated functions.

PubMed ID: 28533430 Exiting the NIEHS site

MeSH Terms: Animals; Catalysis; Cytochrome P-450 CYP4A/chemistry*; Cytochrome P-450 CYP4A/genetics; Cytochrome P-450 CYP4A/metabolism; Dithiothreitol/chemistry*; Dithiothreitol/metabolism; Heme/chemistry*; Heme/genetics; Heme/metabolism; Humans; Hydrogen Peroxide/chemistry*; Hydrogen Peroxide/metabolism; Hydroxyeicosatetraenoic Acids/biosynthesis; Hydroxyeicosatetraenoic Acids/chemistry; Hydroxyeicosatetraenoic Acids/genetics; Kidney/enzymology; Liver/enzymology; Mice; Mice, Transgenic; Oxidation-Reduction; Rats

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