Stepwise Strategy to Identify Thrombin as a Hydrolytic Substrate for Nattokinase,Journal of Chemical Information and Modeling

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Stepwise Strategy to Identify Thrombin as a Hydrolytic Substrate for Nattokinase
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2022-11-04 , DOI: 10.1021/acs.jcim.2c00978
Ying Wang ₁ , Huan Wang ₁ , Yupeng Zhang ₁ , Feng Xu ₁ , Jian Wang ₂ , Fengjiao Zhang ₁

Affiliation

Nattokinase (NK) is a serine protease with a potent thrombolytic activity that possesses multiple cardiovascular disease (CVD) preventative and treatment activities. In light of its advanced beneficial cardiovascular effects and its nature as a serine protease, characterizing its biological substrates is essential for informing and ultimately delineating the molecular mechanism of its thrombolytic and anticoagulant activities that will unlock the powerful strategic design of effective therapies for CVDs. Given the efficacy of NK to break the vicious loop between inflammation, oxidative stress, and thrombosis, and the extensive role of thrombin in the loop, a stepwise computational strategy was developed to investigate the cleavage events of NK, including both a protein–protein complex model for protein substrate recognition and a protease–peptide complex model for the cleavage site identification, whereby their contact region was sited to allow for the prediction of the corresponding cleavage site that was successfully verified by both mass spectrometry (MS)-based N-terminal sequencing and various functional assays. Collectively, thrombin was predicted and identified to be a novel biological substrate of NK, which expanded the comprehensive antithrombus mechanism of NK via breaking the vicious loop between inflammation, oxidative stress, and thrombosis. This study not only provided insight into the interaction characteristics between NK and its hydrolytic substrate for a better understanding toward its catalytic mechanism but also developed a comprehensive computational strategy to elucidate the proteolytic targets of NK for the breakthrough of feature drug development.

中文翻译：

鉴定凝血酶作为纳豆激酶水解底物的逐步策略

纳豆激酶 (NK) 是一种丝氨酸蛋白酶，具有强大的血栓溶解活性，具有多种心血管疾病 (CVD) 预防和治疗活性。鉴于其先进的有益心血管作用及其作为丝氨酸蛋白酶的性质，表征其生物底物对于告知并最终描述其溶栓和抗凝活性的分子机制至关重要，这将开启 CVD 有效疗法的强大战略设计。鉴于 NK 打破炎症、氧化应激和血栓形成之间恶性循环的功效，以及凝血酶在循环中的广泛作用，开发了一种逐步计算策略来研究 NK 的切割事件，包括用于蛋白质底物识别的蛋白质-蛋白质复合物模型和用于裂解位点识别的蛋白酶-肽复合物模型，它们的接触区域被定位以允许预测相应的裂解位点，该裂解位点已通过质谱法成功验证（基于 MS) 的 N 端测序和各种功能测定。总的来说，凝血酶被预测并确定为 NK 的一种新型生物底物，它通过打破炎症、氧化应激和血栓形成之间的恶性循环，扩展了 NK 的综合抗血栓机制。

更新日期：2022-11-04

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