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首页> 外文期刊>Journal of Molecular Biology >Structures of substrate- and inhibitor-bound adenosine deaminase from a human malaria parasite show a dramatic conformational change and shed light on drug selectivity.
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Structures of substrate- and inhibitor-bound adenosine deaminase from a human malaria parasite show a dramatic conformational change and shed light on drug selectivity.

机译：来自人疟疾寄生虫的底物结合和抑制剂结合的腺苷脱氨酶的结构显示出显着的构象变化，并阐明了药物选择性。

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摘要

Plasmodium and other apicomplexan parasites are deficient in purine biosynthesis, relying instead on the salvage of purines from their host environment. Therefore, interference with the purine salvage pathway is an attractive therapeutic target. The plasmodial enzyme adenosine deaminase (ADA) plays a central role in purine salvage and, unlike mammalian ADA homologs, has a further secondary role in methylthiopurine recycling. For this reason, plasmodial ADA accepts a wider range of substrates, as it is responsible for deamination of both adenosine and 5'-methylthioadenosine. The latter substrate is not accepted by mammalian ADA homologs. The structural basis for this natural difference in specificity between plasmodial and mammalian ADA has not been well understood. We now report crystal structures of Plasmodium vivax ADA in complex with adenosine, guanosine, and the picomolar inhibitor 2'-deoxycoformycin. These structures highlight a drastic conformational change in plasmodial ADA upon substrate binding that has not been observed for mammalian ADA enzymes. Further, these complexes illuminate the structural basis for the differential substrate specificity and potential drug selectivity between mammalian and parasite enzymes.
机译：疟原虫和其他apicomplexan寄生虫缺乏嘌呤生物合成，而是依靠从宿主环境中拯救嘌呤。因此，干扰嘌呤挽救途径是有吸引力的治疗目标。血浆酶腺苷脱氨酶（ADA）在嘌呤的抢救中起着核心作用，并且与哺乳动物ADA的同系物不同，它在甲基硫代嘌呤的回收中具有进一步的辅助作用。由于这个原因，疟原虫ADA接受更广泛的底物，因为它负责腺苷和5'-甲硫基腺苷的去氨。哺乳动物ADA同系物不接受后一种底物。疟原虫和哺乳动物ADA之间这种天然的特异性差异的结构基础尚未广为人知。现在，我们报道了与腺苷，鸟苷和皮摩尔抑制剂2'-deoxycoformycin复杂的间日疟原虫ADA的晶体结构。这些结构突出了在底物结合后，血浆ADA中的急剧构象变化，这对于哺乳动物ADA酶还没有观察到。此外，这些复合物阐明了哺乳动物和寄生虫酶之间底物特异性差异和潜在药物选择性的结构基础。

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