The soluble epoxide hydrolase encoded by EPXH2 is a bifunctional enzyme with novel lipid phosphate phosphatase activity

John W. Newman, Christophe Morisseau, Todd R. Harris, Bruce D. Hammock

Research output: Contribution to journalArticle

149 Citations (Scopus)

Abstract

The gene EPXH2 encodes for the soluble epoxide hydrolase (sEH), an enzyme involved in the regulation of cardiovascular and renal physiology containing two distinct domains connected via a proline-rich linker. The C-terminal domain containing the EH catalytic activity has been well studied. In contrast, a function for the N-terminal domain, which has high homology to the haloacid dehalogenase family of phosphatases, has not been definitively reported. In this study we describe the N-terminal domain as a functional phosphatase unaffected by a number of classic phosphatase inhibitors. Assuming a functional association between these catalytic activities, dihydroxy lipid phosphates were rationalized as potential endogenous substrates. A series of phosphorylated hydroxy lipids were therefore synthesized and found to be excellent substrates for the human sEH. The best substrate tested was the monophosphate of dihydroxy stearic acid (threo-9/ 10-phosphonoxy-hydroxy-octadecanoic acid) with Km = 21 ± 0.3 μM, VMax = 338 ± 12 nmol·min-1·mg-1, and kcat = 0.35 ± 0.01 s-1. Therefore dihydroxy lipid phosphates are possible candidates for the endogenous substrates of the sEH N-terminal domain, which would represent a novel branch of fatty acid metabolism with potential signaling functions.

Original languageEnglish (US)
Pages (from-to)1558-1563
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number4
DOIs
StatePublished - Feb 18 2003

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Epoxide Hydrolases
Phosphoric Monoester Hydrolases
Lipids
Enzymes
Phosphates
Cardiovascular Physiological Phenomena
Proline
Fatty Acids
Kidney
Genes
lipid phosphate phosphatase
stearic acid

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

The soluble epoxide hydrolase encoded by EPXH2 is a bifunctional enzyme with novel lipid phosphate phosphatase activity. / Newman, John W.; Morisseau, Christophe; Harris, Todd R.; Hammock, Bruce D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 4, 18.02.2003, p. 1558-1563.

Research output: Contribution to journalArticle

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