THE 84-KDA FORM OF HUMAN MATRIX METALLOPROTEINASE-9 DEGRADES SUBSTANCE-P AND GELATIN

Matrix metalloproteinase-9 (MMP-9) is secreted from cells and, once ac tivated, is thought to degrade collagen in the extracellular matrix. B ecause collagen is not readily localized where neurons have been shown to produce MMP-9 in the human brain, the ability of this enzyme to de grade bioactive peptides was investigated with representative tachykin in peptides [substance P (SP), neurokinin A, neurokinin B, and kassini n]. Latent MMP-9 (94 kDa) was purified from the human cell line HL-60 and converted to an intermediary active form (84 kDa) with p-aminophen ylmercuric acetate. This active form of MMP-9 degraded SP with a k(cat )/K-m of 170 mM(-1) min(-1), which is 30-fold greater than the previou sly reported value for a representative collagen-derived peptide. The major digestion products were identified as SP1-6 and SP7-11, which we re derived from cleavage of the Gln(6)-Phe(7) bond. Minor products wer e also generated from cleavage of the Gly(9)-Leu(10) bond. The other r epresentative tachykinin peptides were cleaved at rates >10-fold slowe r than that of SP. The 84-kDa peptidase was also active as a gelatinas e. Longer treatment of MMP-9 with p-aminophenylmercuric acetate caused the conversion of the 84-kDa enzyme to the established 68-kDa active form; however, the rate of SP degradation did not increase. Because MM P-9 is produced by neurons of the CNS, these results suggest a possibl e regulatory role for the enzyme in intercellular communication by alt ering the availability of bioactive peptides.