Open AccessA novel single‐chain enzyme complex with chain reaction properties rapidly producing thromboxane A 2 and exhibiting powerful anti‐bleeding functions
Author(s) -
Li Yan,
Li QunYing,
Ling QingLan,
So ShuiPing,
Ruan KeHe
Publication year - 2019
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.14711
Subject(s) - cyclooxygenase , thromboxane a2 , thromboxane , thromboxane a synthase , prostaglandin h2 , prostacyclin , prostaglandin , chemistry , pharmacology , enzyme , prostanoid , thromboxane b2 , biochemistry , platelet , medicine , receptor
Abstract 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.