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首页> 外文期刊>Biochemistry >Consequences of Binding an S-Adenosylmethionine Analogue on the Structure and Dynamics of the Thiopurine Methyltransferase Protein Backbone
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Consequences of Binding an S-Adenosylmethionine Analogue on the Structure and Dynamics of the Thiopurine Methyltransferase Protein Backbone

机译：结合S-腺苷甲硫氨酸类似物对硫嘌呤甲基转移酶蛋白骨架的结构和动力学的影响

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In humans,the enzyme thiopurine methyltransferase (TPMT) metabolizes 6-thiopurine (6-TP) medications,commonly used for immune suppression and for the treatment of hematopoietic malignancies.Genetic polymorphisms in the TPMT protein sequence accelerate intracellular degradation of the enzyme through an ubiquitylation and proteasomal-dependent pathway.Research has led to the hypothesis that these polymorphisms destabilize the native structure of TPMT,resulting in the formation of misfolded or partially unfolded states,which are subsequently recognized for intracellular degradation.Addition of the cosubstrate,5-adenosylmethionine (SAM),prevents degradation of the TPMT polymorphs in experimental assays,presumably by stabilizing the native structure.Using a bacterial orthologue of TPMT from Pseudomonas syringae,we have used NMR spectroscopy to describe the consequences of binding sinefungin,a SAM analogue,on the structure and dynamics of the TPMT protein backbone.NMR chemical shift mapping experiments localize sinefungin to a highly conserved site in classical methyltransferases.Distal chemical shift changes involving the presumed active site cover imply indirect conformational changes induced by sinefungin,which may play a role in substrate recognition or the catalytic mechanism.Analysis of protein backbone dynamics based on NMR relaxation reveals a combination of complementary effects.Whereas the peripheral,inserted structural elements of the TPMT topology are conformationally stabilized by the presence of sinefungin,a consistent increase in backbone mobility is observed for the central,conserved structural elements.The potential implications for the structural and dynamic effects of binding sinefungin for the catalytic mechanism of the enzyme and the stabilization of the degradation-susceptible TPMT polymorphs are discussed.
机译：在人类中，硫代嘌呤甲基转移酶（TPMT）代谢6-硫嘌呤（6-TP）药物，通常用于免疫抑制和治疗造血系统恶性肿瘤。TPMT蛋白序列中的基因多态性通过泛素化作用加速了酶的细胞内降解。研究导致了这样的假说，即这些多态性破坏了TPMT的天然结构的稳定性，导致形成错误折叠或部分展开的状态，这些状态随后被认为可用于细胞内降解。 SAM），通过稳定天然结构来防止实验分析中TPMT多晶型的降解。使用来自丁香假单胞菌（Pseudomonas syringae）的TPMT细菌直向同源物，我们使用NMR光谱描述了SAM类似物西非芬净结合结构的后果。 TPMT蛋白骨架的结构和动力学实验将西芬芬净定位于经典甲基转移酶中一个高度保守的位点。涉及假定的活性位点覆盖的远距离化学位移变化暗示西芬芬净诱导的间接构象变化，这可能在底物识别或催化机制中起作用。基于蛋白质的骨架动力学分析NMR弛豫揭示了互补效应的组合。尽管TPMT拓扑结构的外围，插入结构元素通过西芬芬净的存在在构象上得以稳定，但中心，保守结构元素的主链迁移率却不断提高。讨论了西奈芬净结合对酶催化机理的结构和动力学影响以及对降解敏感的TPMT多晶型物的稳定作用。

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