Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, 4111, Australia.
Department of Chemistry, Chonnam National University, Gwangju, 61186, Republic of Korea.
Sci Rep. 2017 May 17;7(1):2015. doi: 10.1038/s41598-017-02220-2.
Owing to the key role of trehalose in pathogenic organisms, there has recently been growing interest in trehalose metabolism for therapeutic purposes. Trehalose-6-phosphate phosphatase (TPP) is a pivotal enzyme in the most prominent biosynthesis pathway (OtsAB). Here, we compare the enzyme characteristics of recombinant TPPs from five important nematode and bacterial pathogens, including three novel members of this protein family. Analysis of the kinetics of trehalose-6-phosphate hydrolysis reveals that all five enzymes display a burst-like kinetic behaviour which is characterised by a decrease of the enzymatic rate after the pre-steady state. The observed super-stoichiometric burst amplitudes can be explained by multiple global conformational changes in members of this enzyme family during substrate processing. In the search for specific TPP inhibitors, the trapping of the complex conformational transitions in TPPs during the catalytic cycle may present a worthwhile strategy to explore.
由于海藻糖在病原生物中的关键作用，近年来人们对海藻糖代谢在治疗方面的应用越来越感兴趣。海藻糖-6-磷酸磷酸酶（TPP）是最主要生物合成途径（OtsAB）中的关键酶。在这里，我们比较了来自五种重要线虫和细菌病原体的重组 TPP 的酶特性，包括该蛋白家族的三个新成员。对海藻糖-6-磷酸水解动力学的分析表明，所有五种酶都表现出爆发式的动力学行为，其特征是在稳态前阶段后酶活性降低。观察到的超化学计量爆发幅度可以通过该酶家族成员在底物处理过程中发生的多个全局构象变化来解释。在寻找特定的 TPP 抑制剂时，在催化循环过程中捕获 TPP 中复杂的构象转变可能是一种值得探索的策略。
