THE POTENTIAL ROLE OF ALPHA(2)-MACROGLOBULIN IN THE CONTROL OF CYSTEINE PROTEINASES (GINGIPAINS) FROM PORPHYROMONAS-GINGIVALIS

Porphyromonas gingivalis is closely associated with the development of some forms of periodontitis. The major cysteine proteinases released by this bacterium hydrolyze peptide bonds only after arginyl (gingipai n R) or lysyl residues (gingipain K). No target protein inhibitors hav e been identified for either enzyme, leading us to investigate their i nhibition by human plasma alpha(2)-macroglobulin (alpha(2)M). Both 50- and 95 kDa gingipain R were efficiently inhibited by alpha(2)M, where as the catalytic activity of gingipain K could not be eliminated. All 3 enzymes were, however, inhibited by a homologous macroglobulin from rat plasma, alpha(1)-inhibitor-3 (alpha(1)I(3)). alpha-Macroglobulins must be cleaved in the so-called ''bait region'' in order to inhibit p roteinases by a mechanism involving physical entrapment of the enzyme. A comparison of the aminio acid sequences of the 2 macroglobulins ind icates that the lack of lysyl residues within the bait region of alpha (2)M protects Lys-specific proteinases from being trapped. On this bas is, other highly specific proteinases might also not be inhibited by a lpha(2)M, possibly explaining the inability of the inhibitor to contro l proteolytic activity in some bacterially induced inflammatory states , despite its abundance (2-5 mg/ml) in vascular fluids.