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A novel single-chain enzyme complex with chain reaction properties rapidly producing thromboxane A2 and exhibiting powerful anti-bleeding functions.

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 A2 (TXA2 ) synthase (TXAS), through a 10-amino acid residue linker. This recombinant COX-1-10aa-TXAS can effectively pass COX-1-derived intermediate prostaglandin (PG) H2 (PGH2 ) to the active site of TXAS, resulting in an effective chain reaction property to produce the haemostatic prostanoid, TXA2 , rapidly. Advantageously, COX-1-10aa-TXAS constrains the production of other pro-bleeding prostanoids, such as prostacyclin (PGI2 ) and prostaglandin E2 (PGE2 ), through reducing the common substrate, PGH2 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 TXA2 -deficient and PGI2 -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.

SUBMITTER: Li Y

PROVIDER: S-EPMC6850917 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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A novel single-chain enzyme complex with chain reaction properties rapidly producing thromboxane A2 and exhibiting powerful anti-bleeding functions.

Li Yan Y Li Qun-Ying QY Ling Qing-Lan QL So Shui-Ping SP Ruan Ke-He KH

Journal of cellular and molecular medicine 20191019 12

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 A2 (TXA2 ) synthase (TXAS), th ...[more]

PMID: 31628732

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Project description:Lipolytic enzymes that retain high levels of catalytic activity when exposed to a variety of denaturing conditions are of high importance for a number of biotechnological applications. In this study, we aimed to identify new lipolytic enzymes, which are highly resistant to prolonged exposure to elevated temperatures. To achieve this, we searched for genes encoding for such proteins in the genomes of a microbial consortium residing in a hot spring located in China. After performing functional genomic screening on a bacterium of the genus Dictyoglomus, which was isolated from this hot spring following in situ enrichment, we identified a new esterolytic enzyme, termed EstDZ3. Detailed biochemical characterization of the recombinant enzyme, revealed that it constitutes a slightly alkalophilic and highly active esterase against esters of fatty acids with short to medium chain lengths. Importantly, EstDZ3 exhibits remarkable thermostability, as it retains high levels of catalytic activity after exposure to temperatures as high as 95°C for several hours. Furthermore, it exhibits very good stability against exposure to high concentrations of a variety of organic solvents. Interestingly, EstDZ3 was found to have very little similarity to previously characterized esterolytic enzymes. Computational modeling of the three-dimensional structure of this new enzyme predicted that it exhibits a typical ?/? hydrolase fold that seems to include a "subdomain insertion", which is similar to the one present in its closest homolog of known function and structure, the cinnamoyl esterase Lj0536 from Lactobacillus johnsonii. As it was found in the case of Lj0536, this structural feature is expected to be an important determinant of the catalytic properties of EstDZ3. The high levels of esterolytic activity of EstDZ3, combined with its remarkable thermostability and good stability against a range of organic solvents and other denaturing agents, render this new enzyme a candidate biocatalyst for high-temperature biotechnological applications.

Dataset Information

A novel single-chain enzyme complex with chain reaction properties rapidly producing thromboxane A2 and exhibiting powerful anti-bleeding functions.

Publications

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

Similar Datasets

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