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首页> 外文期刊>Biochemistry >Structural comparison of MTA phosphorylase and MTA/AdoHcy nucleosidase explains substrate preferences and identifies regions exploitable for inhibitor design.
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Structural comparison of MTA phosphorylase and MTA/AdoHcy nucleosidase explains substrate preferences and identifies regions exploitable for inhibitor design.

机译：MTA磷酸化酶和MTA / AdoHcy核苷酶的结构比较解释了底物的偏好，并确定了可用于抑制剂设计的区域。

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摘要

The development of new and effective antiprotozoal drugs has been a difficult challenge because of the close similarity of the metabolic pathways between microbial and mammalian systems. 5'-Methylthioadenosine/S-adenosylhomocysteine (MTA/AdoHcy) nucleosidase is thought to be an ideal target for therapeutic drug design as the enzyme is present in many microbes but not in mammals. MTA/AdoHcy nucleosidase (MTAN) irreversibly depurinates MTA or AdoHcy to form adenine and the corresponding thioribose. The inhibition of MTAN leads to a buildup of toxic byproducts that affect various microbial pathways such as quorum sensing, biological methylation, polyamine biosynthesis, and methionine recycling. The design of nucleosidase-specific inhibitors is complicated by its structural similarity to the human MTA phosphorylase (MTAP). The crystal structures of human MTAP complexed with formycin A and 5'-methylthiotubercidin have been solved to 2.0 and 2.1 A resolution, respectively. Comparisons of the MTAP and MTAN inhibitor complexes reveal size and electrostatic potential differences in the purine, ribose, and 5'-alkylthio binding sites, which account for the substrate specificity and reactions catalyzed. In addition, the differences between the two enzymes have allowed the identification of exploitable regions that can be targeted for the development of high-affinity nucleosidase-specific inhibitors. Sequence alignments of Escherichia coli MTAN, human MTAP, and plant MTA nucleosidases also reveal potential structural changes to the 5'-alkylthio binding site that account for the substrate preference of plant MTA nucleosidases.
机译：由于微生物和哺乳动物系统之间代谢途径的紧密相似性，因此开发新的有效的抗原生动物药物一直是一项艰巨的挑战。 5'-甲基硫代腺苷/ S-腺苷同型半胱氨酸（MTA / AdoHcy）核苷酶被认为是治疗药物设计的理想靶标，因为该酶存在于许多微生物中，而不存在于哺乳动物中。 MTA / AdoHcy核苷酶（MTAN）不可逆地将MTA或AdoHcy脱嘌呤化，形成腺嘌呤和相应的硫代核糖。 MTAN的抑制导致有毒副产物的积累，这些副产物会影响各种微生物途径，例如群体感应，生物甲基化，多胺生物合成和蛋氨酸再循环。核苷酶特异性抑制剂的设计因其与人MTA磷酸化酶（MTAP）的结构相似而变得复杂。已将人MTAP与福霉菌素A和5'-甲基硫代小球蛋白复合的晶体结构分别解析为2.0和2.1 A的分辨率。 MTAP和MTAN抑制剂复合物的比较显示了嘌呤，核糖和5'-烷硫基结合位点的大小和静电势差，这说明了底物特异性和催化的反应。另外，两种酶之间的差异使得可以鉴定可用于开发高亲和力的核苷酸酶特异性抑制剂的可利用区域。大肠杆菌MTAN，人MTAP和植物MTA核苷酶的序列比对还揭示了5'-烷硫基结合位点的潜在结构变化，这说明了植物MTA核苷酶的底物偏爱。

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