Structure and function of the transketolase from Mycobacterium tuberculosis and comparison with the human enzyme.
Structure and function of the transketolase from Mycobacterium tuberculosis and comparison with the human enzyme.
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DOI：
10.1098/rsob.110026
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发表时间：
2012-01
期刊：
影响因子：
5.8
通讯作者：
Cole ST
中科院分区：
文献类型：
--
作者：
Fullam E;Pojer F;Bergfors T;Jones TA;Cole ST
结核分枝杆菌中的转酮醇酶（TKT）代表了结核病治疗的新药物靶标，并且与人的正链酶具有低同源性。在这里，我们报告的结构和动力学特性的转酮醇酶从M。结核分枝杆菌（TBTKT），其单体各自包含700个氨基酸的同源二聚体。我们表明，TBTKT催化供体糖木酮糖-5-磷酸和果糖-6-磷酸的氧化以及受体糖核糖-5-磷酸的还原。硫胺素辅因子结合所需的TKT共有序列的不变残基在TBTKT中发生突变;但其催化活性不受影响，全长TBTKT的2.5 kDa分辨率结构对此提供了解释。揭示了人类和分枝杆菌TKT酶之间影响底物和辅因子识别和结合的关键结构差异。这些变化解释了TBTKT和其人类对应物之间的动力学差异，以及它们被小分子抑制的差异。详细的TBTKT结构模型的可用性将使人类和M之间的差异成为可能。结核病TKT结构被用来设计具有潜在抗结核活性的选择性抑制剂。
The transketolase (TKT) enzyme in Mycobacterium tuberculosis represents a novel drug target for tuberculosis treatment and has low homology with the orthologous human enzyme. Here, we report on the structural and kinetic characterization of the transketolase from M. tuberculosis (TBTKT), a homodimer whose monomers each comprise 700 amino acids. We show that TBTKT catalyses the oxidation of donor sugars xylulose-5-phosphate and fructose-6-phosphate as well as the reduction of the acceptor sugar ribose-5-phosphate. An invariant residue of the TKT consensus sequence required for thiamine cofactor binding is mutated in TBTKT; yet its catalytic activities are unaffected, and the 2.5 Å resolution structure of full-length TBTKT provides an explanation for this. Key structural differences between the human and mycobacterial TKT enzymes that impact both substrate and cofactor recognition and binding were uncovered. These changes explain the kinetic differences between TBTKT and its human counterpart, and their differential inhibition by small molecules. The availability of a detailed structural model of TBTKT will enable differences between human and M. tuberculosis TKT structures to be exploited to design selective inhibitors with potential antitubercular activity.
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