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首页> 外文期刊>Biochemistry >The 2.0 A structure of malarial purine phosphoribosyltransferase in complex with a transition-state analogue inhibitor.
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The 2.0 A structure of malarial purine phosphoribosyltransferase in complex with a transition-state analogue inhibitor.

机译：与过渡态类似物抑制剂复合的疟疾嘌呤磷酸核糖基转移酶的2.0 A结构。

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摘要

Malaria is a leading cause of worldwide mortality from infectious disease. Plasmodium falciparum proliferation in human erythrocytes requires purine salvage by hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRTase). The enzyme is a target for the development of novel antimalarials. Design and synthesis of transition-state analogue inhibitors permitted cocrystallization with the malarial enzyme and refinement of the complex to 2.0 A resolution. Catalytic site contacts in the malarial enzyme are similar to those of human hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) despite distinct substrate specificity. The crystal structure of malarial HGXPRTase with bound inhibitor, pyrophosphate, and two Mg(2+) ions reveals features unique to the transition-state analogue complex. Substrate-assisted catalysis occurs by ribooxocarbenium stabilization from the O5' lone pair and a pyrophosphate oxygen. A dissociative reaction coordinate path is implicated in which the primary reaction coordinate motion is the ribosyl C1' in motion between relatively immobile purine base and (Mg)(2)-pyrophosphate. Several short hydrogen bonds form in the complex of the enzyme and inhibitor. The proton NMR spectrum of the transition-state analogue complex of malarial HGXPRTase contains two downfield signals at 14.3 and 15.3 ppm. Despite the structural similarity to the human enzyme, the NMR spectra of the complexes reveal differences in hydrogen bonding between the transition-state analogue complexes of the human and malarial HG(X)PRTases. The X-ray crystal structures and NMR spectra reveal chemical and structural features that suggest a strategy for the design of malaria-specific transition-state inhibitors.
机译：疟疾是导致世界范围内传染病致死的主要原因。人红细胞中恶性疟原虫的增殖需要通过次黄嘌呤-鸟嘌呤-黄嘌呤磷酸核糖基转移酶（HGXPRTase）挽救嘌呤。该酶是新型抗疟疾药物开发的目标。过渡态类似物抑制剂的设计与合成可与疟疾酶共结晶，并将复合物精制至2.0 A的分辨率。尽管底物特异性不同，但疟疾酶中的催化位点接触与人次黄嘌呤-鸟嘌呤磷酸核糖基转移酶（HGPRTase）相似。具有结合的抑制剂，焦磷酸盐和两个Mg（2+）离子的疟疾HGXPRTase的晶体结构揭示了过渡态类似物复合物特有的特征。底物辅助的催化作用是通过O5'孤对和焦磷酸盐氧的核糖氧碳鎓稳定作用进行的。牵涉解离反应坐标路径，其中主要反应坐标运动是相对固定的嘌呤碱和（Mg）（2）-焦磷酸盐之间运动的核糖基C1'。在酶和抑制剂的复合物中形成几个短的氢键。疟疾HGXPRTase的过渡态类似物复合物的质子NMR光谱包含两个在14.3和15.3 ppm的低场信号。尽管在结构上与人类酶相似，但该复合物的NMR谱揭示了人类和疟疾HG（X）PRTase过渡态类似物复合物之间氢键的差异。 X射线晶体结构和NMR光谱揭示了化学和结构特征，提示了设计疟疾特异性过渡态抑制剂的策略。

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