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

Authors
 Timothy Clair  ;  Eunjin Koh  ;  Mary L Stracke  ;  Elliott Schiffmann  ;  Lance A Liotta  ;  Russell W Bandle  ;  Malgorzata Ptaszynska 
Citation
 LIPIDS IN HEALTH AND DISEASE, Vol.4(5) : 1-15, 2005 
Journal Title
 LIPIDS IN HEALTH AND DISEASE 
Issue Date
2005
MeSH
Cations, Divalent/chemistry ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Chelating Agents/pharmacology ; Cytokines/pharmacology* ; Enzyme Activation/drug effects ; Histidine/analogs & derivatives ; Histidine/pharmacology* ; Humans ; Lysophospholipids/biosynthesis* ; Molecular Structure ; Multienzyme Complexes/pharmacology* ; Neoplasms/metabolism* ; Neoplasms/pathology ; Phosphodiesterase I/pharmacology* ; Phosphoric Diester Hydrolases/metabolism ; Pyrophosphatases/pharmacology* ; Substrate Specificity ; Zinc/chemistry ; Zinc/pharmacology
Keywords
15737239
Abstract
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.
Files in This Item:
T200505082.pdf Download
DOI
10.1186/1476-511X-4-5
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Koh, Eun Jin(고은진) ORCID logo https://orcid.org/0000-0001-8967-6266
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/114985
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