Lipid sulfates and sulfonates are allosteric competitive inhibitors of the N-terminal phosphatase activity of the mammalian soluble epoxide hydrolase

Katherine L. Tran, Pavel A. Aronov, Hiromasa Tanaka, John W. Newman, Bruce D. Hammock, Christophe Morisseau

Research output: Contribution to journalArticle

52 Citations (Scopus)

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 KI 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.

Original languageEnglish (US)
Pages (from-to)12179-12187
Number of pages9
JournalBiochemistry
Volume44
Issue number36
DOIs
StatePublished - Sep 13 2005

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Epoxide Hydrolases
Phosphoric Monoester Hydrolases
Sulfates
Lipids
Epoxy Compounds
Polyisoprenyl Phosphates
Pressure regulation
Inflammation
Organophosphonates
Blood pressure
Cell growth
Sterols
Arachidonic Acid
Metabolism
Hydrolysis
Genes
Monomers
Binding Sites
Blood Pressure
Substrates

ASJC Scopus subject areas

  • Biochemistry

Cite this

Lipid sulfates and sulfonates are allosteric competitive inhibitors of the N-terminal phosphatase activity of the mammalian soluble epoxide hydrolase. / Tran, Katherine L.; Aronov, Pavel A.; Tanaka, Hiromasa; Newman, John W.; Hammock, Bruce D.; Morisseau, Christophe.

In: Biochemistry, Vol. 44, No. 36, 13.09.2005, p. 12179-12187.

Research output: Contribution to journalArticle

Tran, Katherine L. ; Aronov, Pavel A. ; Tanaka, Hiromasa ; Newman, John W. ; Hammock, Bruce D. ; Morisseau, Christophe. / Lipid sulfates and sulfonates are allosteric competitive inhibitors of the N-terminal phosphatase activity of the mammalian soluble epoxide hydrolase. In: Biochemistry. 2005 ; Vol. 44, No. 36. pp. 12179-12187.
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