L-histidine inhibits production of lysophosphatidic acid by the tumor-associated cytokine, autotaxin

被引：35

作者：

Clair T. ^{[1
]}

Koh E. ^{[1
]}

Ptaszynska M. ^{[1
]}

Bandle R.W. ^{[1
]}

Liotta L.A. ^{[1
]}

Schiffmann E. ^{[1
]}

Stracke M.L. ^{[1
]}

机构：

[1] Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda

来源：

Lipids in Health and Disease | / 4卷 / 1期

关键词：

Histidine; A2058 Cell; Metal Cation; Motility Assay; Histidinol;

D O I：

10.1186/1476-511X-4-5

中图分类号：

学科分类号：

摘要：

Background: Autotaxin (ATX, NPP-2), originally purified as a potent tumor cell motility factor, is now known to be the long-sought plasma lysophospholipase D (LPLD). The integrity of the enzymatic active site, including three crucial histidine moieties, is required for motility stimulation, as well as LPLD and 5′nucleotide phosphodiesterase (PDE) activities. Except for relatively non-specific chelation agents, there are no known inhibitors of the ATX LPLD activity. Results: We show that millimolar concentrations of L-histidine inhibit ATX-stimulated but not LPA-stimulated motility in two tumor cell lines, as well as inhibiting enzymatic activities. Inhibition is reversed by 20-fold lower concentrations of zinc salt. L-histidine has no significant effect on the Km of LPLD, but reduces the Vmax by greater than 50%, acting as a non-competitive inhibitor. Several histidine analogs also inhibit the LPLD activity of ATX; however, none has greater potency than L-histidine and all decrease cell viability or adhesion. Conclusion: L-histidine inhibition of LPLD is not a simple stoichiometric chelation of metal ions but is more likely a complex interaction with a variety of moieties, including the metal cation, at or near the active site. The inhibitory effect of L-histidine requires all three major functional groups of histidine: the alpha amino group, the alpha carboxyl group, and the metal-binding imidazole side chain. Because of LPA's involvement in pathological processes, regulation of its formation by ATX may give insight into possible novel therapeutic approaches. © 2005 Clair et al; licensee BioMed Central Ltd.

引用

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