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首页> 外文期刊>Journal of Molecular Biology >Substrate specificity and oligomerization of human GMP synthetase
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Substrate specificity and oligomerization of human GMP synthetase

机译：人类GMP合成酶的底物特异性和寡聚

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摘要

Guanine monophosphate (GMP) synthetase is a bifunctional two-domain enzyme. The N-terminal glutaminase domain generates ammonia from glutamine and the C-terminal synthetase domain aminates xanthine monophosphate (XMP) to form GMP. Mammalian GMP synthetases (GMPSs) contain a 130-residue-long insert in the synthetase domain in comparison to bacterial proteins. We report here the structure of a eukaryotic GMPS. Substrate XMP was bound in the crystal structure of the human GMPS enzyme. XMP is bound to the synthetase domain and covered by a LID motif. The enzyme forms a dimer in the crystal structure with subunit orientations entirely different from the bacterial counterparts. The inserted sub-domain is shown to be involved in substrate binding and dimerization. Furthermore, the structural basis for XMP recognition is revealed as well as a potential allosteric site. Enzymes in the nucleotide metabolism typically display an increased activity in proliferating cells due to the increased need for nucleotides. Many drugs used as immunosuppressants and for treatment of cancer and viral diseases are indeed nucleobase- and nucleoside-based compounds, which are acting on or are activated by enzymes in this pathway. The information obtained from the crystal structure of human GMPS might therefore aid in understanding interactions of nucleoside-based drugs with GMPS and in structure-based design of GMPS-specific inhibitors.
机译：鸟嘌呤单磷酸酯（GMP）合成酶是一种双功能的双结构域酶。 N端谷氨酰胺酶结构域从谷氨酰胺中产生氨，C端合成酶结构域将黄嘌呤单磷酸酯（XMP）胺化以形成GMP。与细菌蛋白相比，哺乳动物GMP合成酶（GMPS）在合成酶结构域中包含130个残基长的插入片段。我们在这里报告了真核GMPS的结构。底物XMP结合在人GMPS酶的晶体结构中。 XMP与合成酶结构域结合并被LID基序覆盖。该酶在晶体结构中形成具有与细菌对应物完全不同的亚基方向的二聚体。显示插入的亚结构域参与底物结合和二聚化。此外，揭示了XMP识别的结构基础以及潜在的变构位点。由于对核苷酸的需求增加，核苷酸代谢中的酶通常在增殖细胞中显示出增加的活性。实际上，许多用作免疫抑制剂以及用于治疗癌症和病毒性疾病的药物都是基于核碱基和核苷的化合物，它们通过该途径的酶起作用或被酶激活。因此，从人GMPS的晶体结构获得的信息可能有助于理解基于核苷的药物与GMPS的相互作用，并有助于基于结构的GMPS特异性抑制剂的设计。

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