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首页> 外文期刊>The FEBS journal >Crystal structures of a bacterial 6-phosphogluconate dehydrogenase reveal aspects of specificity, mechanism and mode of inhibition by analogues of high-energy reaction intermediates
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Crystal structures of a bacterial 6-phosphogluconate dehydrogenase reveal aspects of specificity, mechanism and mode of inhibition by analogues of high-energy reaction intermediates

机译：细菌6-磷酸葡萄糖酸脱氢酶的晶体结构揭示了高能反应中间体类似物抑制的特异性，机理和抑制方式

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摘要

Crystal structures of recombinant Lactococcus lactis 6-phosphogluconate dehydrogenase (LlPDH) in complex with substrate, cofactor, product and inhibitors have been determined. LlPDH shares significant sequence identity with the enzymes from sheep liver and the protozoan parasite Trypanosoma brucei for which structures have been reported. Comparisons indicate that the key residues in the active site are highly conserved, as are the interactions with the cofactor and the product ribulose 5-phosphate. However, there are differences in the conformation of the substrate 6-phosphogluconate which may reflect distinct states relevant to catalysis. Analysis of the complex formed with the potent inhibitor 4-phospho-D-erythronohydroxamic acid, suggests that this molecule does indeed mimic the high-energy intermediate state that it was designed to. The analysis also identified, as a contaminant by-product of the inhibitor synthesis, 4-phospho-D-erythronamide, which binds in similar fashion. LlPDH can now serve as a model system for structure-based inhibitor design targeting the enzyme from Trypanosoma species.
机译：已经确定了重组乳酸乳球菌6-磷酸葡萄糖酸酯脱氢酶（LlPDH）与底物，辅因子，产物和抑制剂的复合物的晶体结构。 LlPDH与来自绵羊肝和原生动物寄生虫布鲁氏锥虫的酶具有明显的序列同一性，据报道其结构。比较表明，活性位点中的关键残基是高度保守的，与辅因子和产物核糖5-磷酸的相互作用也是如此。但是，底物6-磷酸葡萄糖酸酯的构象存在差异，这可能反映了与催化有关的不同状态。对与有效抑制剂4-磷酸-D-赤藓基异羟肟酸形成的配合物的分析表明，该分子确实确实模仿了其设计所要达到的高能中间态。该分析还鉴定出4-磷酸-D-赤藓酰胺作为抑制剂合成的污染物副产物，其以相似的方式结合。 LlPDH现在可以用作针对锥虫物种酶的基于结构的抑制剂设计的模型系统。

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