Inhibition of matrix metalloproteinases by long chain trans-unsaturated fatty acids

Long chain trans-unsaturated fatty acids markedly inhibit gelatinase A, while their corresponding saturated forms have no effect. Inhibition of enzyme activity is dependent on the ''trans'' conformation of fatty acids whereas inhibition of neutrophil elastase activity depends on their ''cis'' conformation. Gelatinase A inhibition is observed whatever the substrate used: natural e.g. denatured type I collagen or synthetic, (7-methoxycoumarin-4-yl)acetyl-Pro-Leu-Gly-Leu-(3-[2,4-dinitrophenyl]-L-2,3-diaminopropionyl)-Ala-Arg-NH2). The most potent unsaturated acid is elaidic acid (t9-18:1) which inhibits gelatinase A in a competitive way (K-i = 0.87 mu M). Modification of the carboxylic end group of elaidic acid to alcohol, chloride or acetate derivatives partially suppresses the gelatinase A inhibitory potential of the fatty acid. Long chain trans-but not cis-unsaturated fatty acids also inhibit interstitial collagenase and stromelysin-1. Here again, the best inhibitor is elaidic acid which inhibits interstitial collagenase and stromelysin-1 with K-i(app) equal to 2.7 and 1.8 mu M respectively.