title: Interaction of Bothrops jararaca venom metalloproteinases with protein inhibitors.
abstract: Snake venom metalloproteinases (SVMPs) play important roles in the local and systemic hemorrhage observed upon envenomation. In a previous study on the structural elements important for the activities of HF3 (highly hemorrhagic, P-III-SVMP), bothropasin (hemorrhagic, P-III-SVMP) and BJ-PI (non-hemorrhagic, P-I-SVMP), from Bothrops jararaca, it was demonstrated that they differ in their proteolysis profile of plasma and extracellular matrix proteins. In this study, we evaluated the ability of proteins DM43 and α2-macroglobulin to interfere with the proteolytic activity of these SVMPs on fibrinogen and collagen VI and with their ability to induce hemorrhage. DM43 inhibited the proteolytic activity of bothropasin and BJ-PI but not that of HF3, and was not cleaved the three proteinases. On the other hand, α2-macroglobulin did not inhibit any of the proteinases and was rather cleaved by them. In agreement with these findings, binding analysis showed interaction of bothropasin and BJ-PI but not HF3 to DM43 while none of the proteinases bound to α2-macroglobulin. Moreover, DM43 promoted partial inhibition of the hemorrhagic activity of bothropasin but not that of HF3. Our results demonstrate that metalloproteinases of B. jararaca venom showing different domain composition, glycosylation level and hemorrhagic potency show variable susceptibilities to protein inhibitors.
authors.affiliation: Laboratório Especial de Toxinologia Aplicada-CeTICS, Instituto Butantan, Av. Vital Brasil 1500, 05503-000 São Paulo, Brazil. Electronic address: amanda.asega@butantan.gov.br.
authors.forename: Amanda F
authors.initials: AF
authors.lastname: Asega
authors.affiliation: Laboratório Especial de Toxinologia Aplicada-CeTICS, Instituto Butantan, Av. Vital Brasil 1500, 05503-000 São Paulo, Brazil. Electronic address: ana.karina@butantan.gov.br.
authors.forename: Ana K
authors.initials: AK
authors.lastname: Oliveira
authors.affiliation: Laboratório Especial de Toxinologia Aplicada-CeTICS, Instituto Butantan, Av. Vital Brasil 1500, 05503-000 São Paulo, Brazil. Electronic address: milene.santos@butantan.gov.br.
authors.forename: Milene C
authors.initials: MC
authors.lastname: Menezes
authors.affiliation: Laboratório de Toxinologia, Instituto Oswaldo Cruz, Fiocruz, Brazil. Electronic address: anag@ioc.fiocruz.br.
authors.forename: Ana Gisele C
authors.initials: AG
authors.lastname: Neves-Ferreira
authors.affiliation: Laboratório Especial de Toxinologia Aplicada-CeTICS, Instituto Butantan, Av. Vital Brasil 1500, 05503-000 São Paulo, Brazil. Electronic address: solange.serrano@butantan.gov.br.
authors.forename: Solange M T
authors.initials: SM
authors.lastname: Serrano
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D017837:Bothrops; D003094:Collagen / Q000378:metabolism; D003435:Crotalid Venoms / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006031:Glycosylation; D006470:Hemorrhage / Q000473:pathology; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011480:Protease Inhibitors / Q000378:metabolism*; D011487:Protein Conformation; D059748:Proteolysis; D000511:alpha-Macroglobulins / Q000378:metabolism*
chemical_list: D001798:Blood Proteins; D003435:Crotalid Venoms; C454462:DM43 protein, Didelphis marsupialis; D011480:Protease Inhibitors; D000511:alpha-Macroglobulins; D005340:Fibrinogen; D003094:Collagen; C576279:BJ-PI2 non-hemorrhagic metalloproteinase, Bothrops jararaca; D045726:Metalloproteases; C543527:HF3 protein, Bothrops jararaca; D008666:Metalloendopeptidases; C472493:bothropasin, Bothrops jararaca
keywords: Hemorrhage; Inhibition; Metalloproteinase; Proteolysis; Snake venom