Leishmania donovani adenylosuccinate synthetase requires IMP for dimerization and organization of the active site.

IF 3.5 4区 生物学 Q1 Biochemistry, Genetics and Molecular Biology FEBS Letters Pub Date : 2024-10-27 DOI:10.1002/1873-3468.15040
Jigneshkumar A Mochi, Jaykumar Jani, Smit Shah, Anju Pappachan
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Abstract

Adenylosuccinate synthetase (AdSS), which catalyses the GTP-dependent conversion of inosine monophosphate (IMP) and aspartic acid to succinyl-AMP, plays a major role in purine biosynthesis. In some bacterial AdSS, it is implicated that IMP binding is important to organize the active site, but in certain plant AdSS, GTP performs this role. Here, we report that in Leishmania donovani AdSS, IMP binding favoured dimerization, induced greater conformational change and improved the protein stability more than GTP binding. IMP binding, which resulted in a network of hydrogen bonds, stabilized the conformation of active site loops and brought the switch loop to a closed conformation, which then facilitated GTP binding. Our results provide a basis for designing better inhibitors of leishmanial AdSS.

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唐氏利什曼原虫腺苷琥珀酸合成酶的二聚化和活性位点的组织需要 IMP。
腺苷琥珀酸合成酶(AdSS)能催化依赖于 GTP 的单磷酸肌苷(IMP)和天冬氨酸向琥珀酰-AMP 的转化,在嘌呤生物合成中发挥着重要作用。在某些细菌的 AdSS 中,IMP 的结合对于组织活性位点非常重要,但在某些植物的 AdSS 中,GTP 发挥着这一作用。在这里,我们报告了在利什曼原虫 AdSS 中,IMP 结合比 GTP 结合更有利于二聚化,诱导更大的构象变化,并提高蛋白质的稳定性。IMP 结合形成氢键网络,稳定了活性位点环的构象,并使开关环形成闭合构象,从而促进了 GTP 结合。我们的研究结果为设计更好的利什曼病 AdSS 抑制剂提供了依据。
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来源期刊
FEBS Letters
FEBS Letters 生物-生化与分子生物学
CiteScore
7.00
自引率
2.90%
发文量
303
审稿时长
1.0 months
期刊介绍: FEBS Letters is one of the world''s leading journals in molecular biology and is renowned both for its quality of content and speed of production. Bringing together the most important developments in the molecular biosciences, FEBS Letters provides an international forum for Minireviews, Research Letters and Hypotheses that merit urgent publication.
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