Cysteine synthase: multiple structures of a key enzyme in cysteine synthesis and a potential drug target for Chagas disease and leishmaniasis.
Cysteine synthase: multiple structures of a key enzyme in cysteine synthesis and a potential drug target for Chagas disease and leishmaniasis.
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DOI：
10.1107/s2059798323003613
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发表时间：
2023-06-01
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影响因子：
--
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对克氏锥虫、泰氏锥虫和婴儿利什曼原虫的半胱氨酸合成酶进行了生化和结构分析。这种酶是治疗查加斯病和利什曼病等被忽视的热带疾病的潜在药物靶点。恰加斯病是由克氏锥虫引起的一种被忽视的热带疾病(NTD)，而利什曼病是由20多种利什曼原虫引起的，是地球热带和亚热带地区大多数国家特有的一组NTDS。在流行国家和全球，这些疾病仍然是一个严重的健康问题。这些寄生虫和其他锥虫，包括牛的病原体泰勒氏锥虫，依靠半胱氨酸的生物合成来产生对寄生虫在宿主中的生存至关重要的色氨硫酮。半胱氨酸生物合成的从头途径需要O-乙酰-L-丝氨酸转化为L-半胱氨酸，半胱氨酸合成酶(CS)催化该反应。这些酶具有抗毛滴虫、利什曼原虫的药物开发潜力。和T.theileri。为了使这些可能性成为可能，我们对来自克氏锥虫(TCCs)、拉氏锥虫(LICs)和马尾藻(TthCS)的CS进行了生化和结晶学研究。三种酶的晶体结构分别以TCCS的1.80 ？、LICS的1.75 ？和TTHCS的2.75 ？的分辨率测定。这三个同源二聚体结构显示出相同的整体折叠，并表明活性中心的几何构型是保守的，支持共同的反应机理。详细的结构分析揭示了从头开始途径的反应中间产物，从LICS的apo结构和TCCs和TthCS的全息结构到TCCs的底物结合结构。这些结构将允许探索活性部位，以设计新的抑制剂。此外，在二聚体界面上发现的意想不到的结合位点代表了开发蛋白质-蛋白质抑制剂的新潜力。
Biochemical and structural analyses of cysteine synthase, the key enzyme in cysteine biosynthesis, from the protozoan pathogens Trypanosoma cruzi, T. theileri and Leishmania infantum are presented. This enzyme is a potential drug target for neglected tropical diseases such as Chagas disease and leishmaniasis. Chagas disease is a neglected tropical disease (NTD) caused by Trypanosoma cruzi, whilst leishmaniasis, which is caused by over 20 species of Leishmania, represents a group of NTDs endemic to most countries in the tropical and subtropical belt of the planet. These diseases remain a significant health problem both in endemic countries and globally. These parasites and other trypanosomatids, including T. theileri, a bovine pathogen, rely on cysteine biosynthesis for the production of trypanothione, which is essential for parasite survival in hosts. The de novo pathway of cysteine biosynthesis requires the conversion of O-acetyl-l-serine into l-cysteine, which is catalysed by cysteine synthase (CS). These enzymes present potential for drug development against T. cruzi, Leishmania spp. and T. theileri. To enable these possibilities, biochemical and crystallographic studies of CS from T. cruzi (TcCS), L. infantum (LiCS) and T. theileri (TthCS) were conducted. Crystal structures of the three enzymes were determined at resolutions of 1.80 Å for TcCS, 1.75 Å for LiCS and 2.75 Å for TthCS. These three homodimeric structures show the same overall fold and demonstrate that the active-site geometry is conserved, supporting a common reaction mechanism. Detailed structural analysis revealed reaction intermediates of the de novo pathway ranging from an apo structure of LiCS and holo structures of both TcCS and TthCS to the substrate-bound structure of TcCS. These structures will allow exploration of the active site for the design of novel inhibitors. Additionally, unexpected binding sites discovered at the dimer interface represent new potential for the development of protein–protein inhibitors.
影响因子：
4.8
作者：
Cornish, Katy A. S.;Lange, Joanna;Aevarsson, Arnthor;Pohl, Ehmke
通讯作者：
Pohl, Ehmke