L-histidine inhibits production of lysophosphatidic acid by the tumor-associated cytokine, autotaxin.
Lipids Health Dis
; 4: 5, 2005 Feb 28.
Article
in En
| MEDLINE
| ID: mdl-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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrophosphatases
/
Lysophospholipids
/
Cytokines
/
Phosphodiesterase I
/
Histidine
/
Multienzyme Complexes
/
Neoplasms
Type of study:
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
Lipids Health Dis
Journal subject:
BIOQUIMICA
/
METABOLISMO
Year:
2005
Type:
Article
Affiliation country:
United States