TISSUE KALLIKREIN INHIBITORS IN MAMMALS

We have discovered, purified and cloned a new kallikrein-binding prote in (KBP or kallistatin) from humans and rodents. Kallistatins are memb ers of the serine proteinase inhibitor (serpin) superfamily. They are acidic glycoproteins with molecular masses of 58-62 kDa and pi values of 4.6-5.2. Kallistatin forms a SDS-stable complex with tissue kallikr ein and inhibits kallikrein's activities. Human kallistatin has a uniq ue cleavage site with Phe-Phe-Ser at the P2-P1-P1' positions. The prot ein sequence of mature human kallistatin shares 44-46% identity with o ther serpins such as human alpha(1)-antitrypsin, protein C inhibitor a nd rat kallikrein-binding protein. The kallistatin genes display the t ypical five exon-four intron serpin gene structure. The human kallista tin gene is localized on chromosome 14q31-32.1 and the RKBP gene is on chromosome 6. Kallistatin is evolutionarily diverse but functionally conserved in mammalian species. This overview summarizes the biochemis try, molecular biology and potential physiology and/or pathophysiology of this new tissue kallikrein inhibitor.