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首页> 外文期刊>The FEBS journal >Structures of type B ribose 5-phosphate isomerase from Trypanosoma cruzi shed light on the determinants of sugar specificity in the structural family
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Structures of type B ribose 5-phosphate isomerase from Trypanosoma cruzi shed light on the determinants of sugar specificity in the structural family

机译：克氏锥虫B型核糖5-磷酸异构酶的结构阐明了结构家族中糖特异性的决定因素

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摘要

Ribose-5-phosphate isomerase (Rpi; EC 5.3.1.6) is a key activity of the pentose phosphate pathway. Two unrelated types of sequence/structure possess this activity: type A Rpi (present in most organisms) and type B Rpi (RpiB) (in some bacteria and parasitic protozoa). In the present study, we report enzyme kinetics and crystallographic studies of the RpiB from the human pathogen, Trypanosoma cruzi. Structures of the wild-type and a Cys69Ala mutant enzyme, alone or bound to phosphate, D-ribose 5-phosphate, or the inhibitors 4-phospho-D-erythronohydroxamic acid and D-allose 6-phosphate, highlight features of the active site, and show that small conformational changes are linked to binding. Kinetic studies confirm that, similar to the RpiB from Mycobacterium tuberculosis, the T. cruzi enzyme can isomerize D-ribose 5-phosphate effectively, but not the 6-carbon sugar D-allose 6-phosphate; instead, this sugar acts as an inhibitor of both enzymes. The behaviour is distinct from that of the more closely related (to T. cruzi RpiB) Escherichia coli enzyme, which can isomerize both types of sugars. The hypothesis that differences in a phosphate-binding loop near the active site were linked to the differences in specificity was tested by construction of a mutant T. cruzi enzyme with a sequence in this loop more similar to that of E. coli RpiB; this mutant enzyme gained the ability to act on the 6-carbon sugar. The combined information allows us to distinguish the two types of specificity patterns in other available sequences. The results obtained in the present study provide insights into the action of RpiB enzymes generally, and also comprise a firm basis for future work in drug design.
机译：5-磷酸核糖异构酶（Rpi; EC 5.3.1.6）是磷酸戊糖途径的关键活性。两种不相关的序列/结构类型具有此活性：A Rpi型（存在于大多数生物中）和B Rpi型（RpiB）（在某些细菌和寄生虫中）。在本研究中，我们报告了来自人类病原体克氏锥虫的RpiB的酶动力学和晶体学研究。单独或与磷酸盐，D-核糖5-磷酸盐或抑制剂4-磷酸-D-赤藓基异羟肟酸和D-阿洛糖6-磷酸盐结合的野生型和Cys69Ala突变酶的结构突出了活性位点的特征，并表明构象的微小变化与结合有关。动力学研究证实，与结核分枝杆菌中的RpiB相似，克鲁维酵母可以有效地使D-核糖5-磷酸异构化，但不能使6碳糖D-阿洛糖6-磷酸异构化。相反，这种糖可作为两种酶的抑制剂。该行为不同于与之紧密相关的（与克鲁维酵母RpiB）大肠杆菌酶的行为，后者可以使两种类型的糖异构化。通过构建突变的克鲁斯氏螺旋体酶来验证活性位点附近磷酸结合环的差异与特异性差异有关的假说，该突变体的克鲁斯酶在该环中的序列与大肠杆菌RpiB的序列更相似。这种突变酶具有作用于6碳糖的能力。组合的信息使我们能够区分其他可用序列中的两种类型的特异性模式。在本研究中获得的结果提供了对RpiB酶一般作用的见解，也为药物设计的未来工作奠定了坚实的基础。

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