期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 100, 期 4, 页码 1558-1563出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0437724100
关键词
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资金
- NIEHS NIH HHS [P01 ES011269, P30 ES005705, R37 ES02710, P01 ES11269, R37 ES002710, P42 ES04699, P42 ES004699, P30 ES05705] Funding Source: Medline
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 K-m = 21 +/- 0.3 muM, V-Max = 338 +/- 12 nmol.min(-1).mg(-1), and k(cat) = 0.35 +/- 0.01 s(-1). Therefore clihydroxy 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.
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