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J. Biol. Chem., Vol. 276, Issue 23, 20458-20465, June 8, 2001
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From the The matrix metalloproteinases
gelatinase A (MMP-2) and gelatinase B (MMP-9) are implicated in the
physiological and pathological breakdown of several extracellular
matrix proteins. In the present study, we show that long-chain fatty
acids (e.g. oleic acid, elaidic acid, and cis-
and trans-parinaric acids) inhibit gelatinase A as well as
gelatinase B with Ki values in the micromolar range
but had only weak inhibitory effect on collagenase-1 (MMP-1), as
assessed using synthetic or natural substrates. The inhibition of
gelatinases depended on fatty acid chain length (with C18 > C16,
C14, and C10), and the presence of unsaturations increased their
inhibitory capacity on both types of gelatinase. Ex vivo experiments on human skin tissue sections have shown that micromolar concentrations of a long-chain unsaturated fatty acid (elaidic acid)
protect collagen and elastin fibers against degradation by gelatinases
A and B, respectively. In order to understand why gelatinases are more
susceptible than collagenase-1 to inhibition by long-chain fatty acids,
the possible role of the fibronectin-like domain (a domain unique to
gelatinases) in binding inhibitory fatty acids was investigated.
Affinity and kinetic studies with a recombinant fibronectin-like domain
of gelatinase A and with a recombinant mutant of gelatinase A from
which this domain had been deleted pointed to an interaction of
long-chain fatty acids with the fibronectin-like domain of the
protease. Surface plasmon resonance studies on the interaction of
long-chain fatty acids with the three individual type II modules of the
fibronectin-like domain of gelatinase A revealed that the first type II
module is primarily responsible for binding these compounds.
Involvement of Fibronectin Type II Repeats in the Efficient
Inhibition of Gelatinases A and B by Long-chain Unsaturated Fatty
Acids*
§,
,,,,,, and¶¶
CNRS FRE 2260, IFR 53 Biomolecules, Faculty
of Medicine, 51 Rue Cognacq Jay, F-51100 Reims, France, the
¶ Cell Biology Unit, Institute of Cellular Pathology and
Université catholique de Louvain, B-1200
Brussels, Belgium, the ** Institute of Enzymology, Biological Research
Center, Hungarian Academy of Sciences, H-1518 Budapest, Hungary, and
the §§ Laboratory of Biochemistry, Faculty of
Odontology, Paris V, F-92120 Montrouge, France
*
This work was supported in part by a CNRS grant, France, and
grants from the Fondation pour la Recherche Médicale, ARERS, Ligue Régionale des Ardennes Contre le Cancer, Région
Champagne-Ardennes, the Belgian Fonds de la Recherche Scientifique
Médicale, Interuniversity Attraction Poles and Concerted Research
Actions of the Université catholique de Louvain.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Postdoctoral fellow of the Christian de Duve Institute of
Cellular Pathology (Brussels, Belgium) and of the Association de la
Recherche Contre le Cancer, France.
Supported by International Center for Genetic
Engineering and Biotechnology Grant CRP/HUN98-03 and Hungarian
National Research Fund Grant T0022949.
¶¶
To whom correspondence should be addressed: CNRS FRE
2260, Faculté de Médecine, 51 rue Cognacq Jay, 51095 Reims
Cedex, France. Tel.: 33-326-91-80-56; Fax: 33-326-91-80-55; E-mail:
herve.emonard@univ-reims.fr.
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