Effect of Cu2+ and Zn2+ on the inhibition of human leucocyte elastase by 6-alkyl-3-(omega-carboxyalkyl)-2-pyrone, oleic acid and sulindac sulfide.

Inhibition of human leucocyte elastase by oleic acid and the structurally related 3-(1'-oxo-7'-carboxyheptyl)-4-hydroxy-6-octyl-2-pyrone is considerably enhanced by the addition of Cu2+, Zn2+ and, to a lesser extent, Co2+ and Ca2+. Sulindac sulfide and diflunisal also respond to changes in copper concentration, while Boc-Ala-Pro-Val-NH[CH2]10CO2H does not. Binding of the -CO2H group in the vicinity of the S5 subsite is proposed for all but the last compound to account for this effect. Incubation experiments indicate that Cu2+ binds more rapidly to the enzyme than does the inhibitor. Local changes in conformation result in improved binding of the inhibitor, but do not affect the substrate (Km unchanged). Chelation by EDTA is time-dependent, indicating that the Cu2+ is shielded by the inhibitor. The results may partially explain the well-known anti-arthritic and anti-inflammatory properties of copper and zinc and their organic salts.