J. Biol. Chem., Vol. 262, Issue 21, 10048-10052, 07, 1987

The collagen substrate specificity of human neutrophil collagenase

KA Hasty, JJ Jeffrey, MS Hibbs and HG Welgus

The substrate specificity of human neutrophil collagenase was examined using both monomeric and fibrillar collagens. The neutrophil enzyme cleaved types I, II, and III collagens, but failed to attack types IV or V. Against monomeric collagen substrates at 25 degrees C, the neutrophil enzyme displayed values for the Michaelis constant (Km) of 0.6-1.8 X 10(-6) M, essentially indistinguishable from the substrate affinities that characterize human fibroblast collagenase. Catalytic rates, however, varied considerably; type I collagen was cleaved with a specificity (kappa cat/Km) some 20-fold greater than type III. Type II collagen was degraded with intermediate selectivity, approximately equal to 25% of the type I rate, but 450% that of type III. This specificity contrasted markedly with that of human fibroblast collagenase, which cleaved human type III collagen 15-fold faster than type I and greater than 500-fold more rapidly than type II. Interestingly, the 20-fold selectivity for type I over type III exhibited by neutrophil collagenase against monomeric collagens was largely abolished following the reconstitution of these substrates into insoluble fibrils, falling to a value of just 1.5-fold. The distinctive and opposite preference by the human fibroblast enzyme for monomeric type III collagen over type I (15-fold) was similarly reduced to less than 2-fold upon substrate aggregation. The transition from native soluble collagen monomers into insoluble fibrils appeared to be handled by both the human neutrophil and fibroblast collagenases with similar facility on type I substrates. By comparison, however, the neutrophil enzyme degraded type III collagen fibrils faster than would have been predicted from solution rates, while the fibroblast enzyme cleaved such fibrils much slower than expected from solution values. In exploring this phenomenon further, solvent deuterium isotope effects were measured. The deuterium studies suggest that neutrophil collagenase, acting on type III fibrils (kappa H2O/kappa D2O = 5.0), is less sensitive to factors which govern the availability of water at the relatively hydrophobic site of peptide bond hydrolysis in the collagen molecule than is fibroblast collagenase (kappa H2O/kappa D2O = 15.0).
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