A novel single-chain enzyme complex with chain reaction properties rapidly producing thromboxane A 2 and exhibiting powerful anti-bleeding functions.

Autor: Li Y; Department of Pharmacological and Pharmaceutical Sciences, Center for Experimental Therapeutics and Pharmacoinformatics, College of Pharmacy, University of Houston, Houston, TX, USA., Li QY; Department of Pharmacological and Pharmaceutical Sciences, Center for Experimental Therapeutics and Pharmacoinformatics, College of Pharmacy, University of Houston, Houston, TX, USA.; Visiting Scholar from Department of Ultrasound, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou City, China., Ling QL; Department of Pharmacological and Pharmaceutical Sciences, Center for Experimental Therapeutics and Pharmacoinformatics, College of Pharmacy, University of Houston, Houston, TX, USA., So SP; Department of Pharmacological and Pharmaceutical Sciences, Center for Experimental Therapeutics and Pharmacoinformatics, College of Pharmacy, University of Houston, Houston, TX, USA., Ruan KH; Department of Pharmacological and Pharmaceutical Sciences, Center for Experimental Therapeutics and Pharmacoinformatics, College of Pharmacy, University of Houston, Houston, TX, USA.
Jazyk: angličtina
Zdroj: Journal of cellular and molecular medicine [J Cell Mol Med] 2019 Dec; Vol. 23 (12), pp. 8343-8354. Date of Electronic Publication: 2019 Oct 19.
DOI: 10.1111/jcmm.14711
Abstrakt: Uncontrollable bleeding is still a worldwide killer. In this study, we aimed to investigate a novel approach to exhibit effective haemostatic properties, which could possibly save lives in various bleeding emergencies. According to the structure-based enzymatic design, we have engineered a novel single-chain hybrid enzyme complex (SCHEC), COX-1-10aa-TXAS. We linked the C-terminus of cyclooxygenase-1 (COX-1) to the N-terminus of the thromboxane A 2 (TXA 2 ) synthase (TXAS), through a 10-amino acid residue linker. This recombinant COX-1-10aa-TXAS can effectively pass COX-1-derived intermediate prostaglandin (PG) H 2 (PGH 2 ) to the active site of TXAS, resulting in an effective chain reaction property to produce the haemostatic prostanoid, TXA 2 , rapidly. Advantageously, COX-1-10aa-TXAS constrains the production of other pro-bleeding prostanoids, such as prostacyclin (PGI 2 ) and prostaglandin E 2 (PGE 2 ), through reducing the common substrate, PGH 2 being passed to synthases which produce aforementioned prostanoids. Therefore, based on these multiple properties, this novel COX-1-10aa-TXAS indicated a powerful anti-bleeding ability, which could be used to treat a variety of bleeding situations and could even be useful for bleeding prone situations, including nonsteroidal anti-inflammatory drugs (NSAIDs)-resulted TXA 2 -deficient and PGI 2 -mediated bleeding disorders. This novel SCHEC has a great potential to be developed into a biological haemostatic agent to treat severe haemorrhage emergencies, which will prevent the complications of blood loss and save lives.
(© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)
Databáze: MEDLINE
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