TAILIEUCHUNG - Báo cáo khoa học: Tissue factor pathway inhibitor is highly susceptible to chymase-mediated proteolysis

Bacillus cereusis an opportunistic pathogenic bacterium closely related to Bacillus anthracis, the causative agent of anthrax in mammals. A significant portion of theB. cereuschromosomal genes are common to B. anthracis, including genes which in B. anthraciscode for putative virulence and sur-face proteins. | ỊFEBS Journal Tissue factor pathway inhibitor is highly susceptible to chymase-mediated proteolysis Tsutomu Hamuro1 Hiroshi Kido2 Yujiro Asada3 Kinta Hatakeyama3 Yuushi Okumura2 Youichi Kunori4 Takashi Kamimura4 Sadaaki Iwanaga1 and Shintaro Kamei1 1 Therapeutic Protein Products Research Department The Chemo-Sero-Therapeutic Research Institute Kaketsuken Japan 2 Division of Enzyme Chemistry Institute for Enzyme Research University of Tokushima Japan 3 Department of Pathology Faculty of Medicine University of Miyazaki Japan 4 Institute for BiomedicalResearch Teijin Pharma Limited Japan Keywords chymase inflammation protease inhibitor serine proteinase tissue factor pathway inhibitor TFPI Correspondence T. Hamuro Therapeutic Protein Products Research Department The Chemo-Sero-Therapeutic Research Institute Kaketsuken 1-6-1 Okubo Kumamoto 860-8568 Japan Fax 81 96 3449234 Tel 81 96 3442189 E-mail hamuro@ Received 20 December 2006 revised 12 March 2007 accepted 17 April 2007 doi Tissue factor pathway inhibitor TFPI is a multivalent Kunitz-type protease inhibitor that primarily inhibits the extrinsic pathway of blood coagulation. It is synthesized by various cells and its expression level increases in inflammatory environments. Mast cells and neutrophils accumulate at sites of inflammation and vascular disease where they release proteinases as well as chemical mediators of these conditions. In this study the interactions between TFPI and serine proteinases secreted from human mast cells and neutrophils were examined. TFPI inactivated human lung tryptase and its inhibitory activity was stronger than that of antithrombin. In contrast mast cell chymase rapidly cleaved TFPI even at an enzyme to substrate molar ratio of 1 500 resulting in markedly decreased TFPI anticoagulant and anti- factor Xa activities. N-Terminal amino-acid sequencing and MS analyses of the proteolytic fragments revealed that chymase preferentially cleaved

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