title: Lipid sulfates and sulfonates are allosteric competitive inhibitors of the N-terminal phosphatase activity of the mammalian soluble epoxide hydrolase.
abstract: The EPXH2 gene encodes for the soluble epoxide hydrolase (sEH), a homodimeric enzyme with each monomer containing two domains with distinct activities. The C-terminal domain, containing the epoxide hydrolase activity (Cterm-EH), is involved in the metabolism of arachidonic acid epoxides, endogenous chemical mediators that play important roles in blood pressure regulation, cell growth, and inflammation. We recently demonstrated that the N-terminal domain contains a Mg2+-dependent lipid phosphate phosphatase activity (Nterm-phos). However, the biological role of this activity is unknown. The inability of known phosphatase inhibitors to inhibit the Nterm-phos constitutes a significant barrier to the elucidation of its function. We describe herein sulfate, sulfonate, and phosphonate lipids as novel potent inhibitors of Nterm-phos. These compounds are allosteric competitive inhibitors with K(I) in the hundred nanomolar range. These inhibitors may provide a valuable tool to investigate the biological role of the Nterm-phos. We found that polyisoprenyl phosphates are substrates of Nterm-phos, suggesting a possible role in sterol synthesis or inflammation. Furthermore, some of these compounds inhibit the C-terminal sEH activity through a noncompetitive inhibition mechanism involving a new binding site on the C-terminal domain. This novel site may play a role in the natural in vivo regulation of epoxide hydrolysis by sEH.
authors.affiliation: Department of Entomology and U. C. Davis Cancer Center, University of California, Davis, California 95616, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Tran
authors.forename: Pavel A
authors.initials: PA
authors.lastname: Aronov
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Tanaka
authors.forename: John W
authors.initials: JW
authors.lastname: Newman
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004952:Esters / Q000737:chemistry; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D008055:Lipids / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010710:Phosphates / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D013379:Substrate Specificity; D013431:Sulfates / Q000737:chemistry* / Q000494:pharmacology*; D013451:Sulfonic Acids / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D004952:Esters; D008055:Lipids; D010710:Phosphates; D013431:Sulfates; D013451:Sulfonic Acids; D010744:Phosphoric Monoester Hydrolases; D004851:Epoxide Hydrolases