Hand Christine E, Auzanneau France-Isabelle, Honek John F
Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, Canada N2L 3G1.
Carbohydr Res. 2006 Jul 3;341(9):1164-73. doi: 10.1016/j.carres.2006.03.020. Epub 2006 Apr 21.
Intracellular thiols are essential biomolecules, which play several critical roles in living organisms including controlling intracellular redox potential and acting as cofactors for several vital detoxification enzymes including S-transferases and formaldehyde dehydrogenases. The tripeptide gamma-L-glutamyl-L-cysteinylglycine, more commonly known as glutathione, is well known as the major intracellular thiol in eukaryotes and in some bacteria. However, glutathione is absent in the Actinomycetales bacteria such as Mycobacteria and Streptomyces and is believed to be replaced by 1-D-myo-inosityl-2-(N-acetyl-L-cysteinyl)amido-2-deoxy-alpha-D-glucopyranoside, mycothiol, in these organisms. Although much is known about the chemistry and biochemistry of glutathione, currently much less is known concerning mycothiol and its properties. The structure of mycothiol is composed of a glycoside linkage between myo-inositol and D-glucosamine with an N-acetyl-L-cysteine linked to the 2'-amino group of the d-glucosamine moiety. Mycothiol is currently of intense interest due to its essential role in the cellular physiology of Mycobacteria, such as Mycobacterium tuberculosis, and its possible role in antimycobacterial drug resistance. A detailed investigation of its chemistry is therefore essential in ameliorating our knowledge of this key glycothiol, and in shedding additional light on its biochemical role in these pathogenic organisms. This report presents a detailed conformational analysis of mycothiol utilizing a variety of force fields and stochastic search protocols. Cluster analyses of energetically low lying conformations have indicated the presence of several key conformations that are populated in the gas phase and with implicit water solvation. These conformations are compared to recent NMR studies on a derivative of mycothiol. This information should be an important contribution to our basic understanding of the chemistry of this glycothiol and critical in the design of novel inhibitors of pathogen enzymes that require it.
细胞内硫醇是重要的生物分子，在生物体中发挥着多种关键作用，包括控制细胞内氧化还原电位以及作为几种重要解毒酶（如S -转移酶和甲醛脱氢酶）的辅助因子。三肽γ-L-谷氨酰-L-半胱氨酰甘氨酸，更常见的名称是谷胱甘肽，是真核生物和一些细菌中主要的细胞内硫醇。然而，在放线菌目细菌如分枝杆菌和链霉菌中不存在谷胱甘肽，据信在这些生物体中它被1-D-肌醇-2-(N-乙酰-L-半胱氨酰)氨基-2-脱氧-α-D-吡喃葡萄糖苷，即肌醇硫醇所取代。尽管对谷胱甘肽的化学和生物化学了解很多，但目前关于肌醇硫醇及其性质的了解要少得多。肌醇硫醇的结构由肌醇和D-葡萄糖胺之间的糖苷键组成，其中N-乙酰-L-半胱氨酸连接到D-葡萄糖胺部分的2'-氨基上。由于肌醇硫醇在结核分枝杆菌等分枝杆菌的细胞生理学中的重要作用及其在抗分枝杆菌耐药性中的可能作用，目前它备受关注。因此，对其化学性质进行详细研究对于增进我们对这种关键糖硫醇的了解以及进一步阐明其在这些致病生物体中的生化作用至关重要。本报告利用多种力场和随机搜索协议对肌醇硫醇进行了详细的构象分析。对能量较低构象的聚类分析表明，存在几种在气相和隐式水溶剂化条件下占主导的关键构象。将这些构象与最近对肌醇硫醇衍生物的核磁共振研究进行了比较。这些信息应有助于我们对这种糖硫醇的化学性质有基本的了解，并且对于设计需要它的病原体酶的新型抑制剂至关重要。
