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


CONCLUSIONS
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.
Clair
Timothy
T
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. timclair@helix.nih.gov
Koh
Eunjin
E
Ptaszynska
Malgorzata
M
Bandle
Russell W
RW
Liotta
Lance A
LA
Schiffmann
Elliott
E
Stracke
Mary L
ML
D002413:Cations, Divalent / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006639:Histidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D008246:Lysophospholipids / Q000096:biosynthesis*; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000494:pharmacology*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D043264:Phosphodiesterase I / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011755:Pyrophosphatases / Q000494:pharmacology*; D013379:Substrate Specificity; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology; D000099189:Lysophospholipase D
D002413:Cations, Divalent; D002614:Chelating Agents; D016207:Cytokines; D006639:Histidine; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D015032:Zinc; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid
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