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首页> 外文期刊>Biochemistry >Solvent Reorganization Plays a Temperature-Dependent Role in Antibiotic Selection by a Thermostable Aminoglycoside Nucleotidyltransferase-4′
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Solvent Reorganization Plays a Temperature-Dependent Role in Antibiotic Selection by a Thermostable Aminoglycoside Nucleotidyltransferase-4′

机译：溶剂重组通过热稳定的氨基糖苷核苷基转移酶-4'在抗生素选择中发挥温度依赖性作用

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摘要

The aminoglycoside nucleotidyltransferase-4′ (ANT) is an enzyme that causes resistance to a large number of aminoglycoside antibiotics by nucleotidylation of the 4′-site on these antibiotics. The effect of solvent reorganization on enzymeligand interactions was investigated using a thermophilic variant of the enzyme resulting from a single-site mutation (T130K). Data showed that the binding of aminoglycosides to ANT causes exposure of polar groups to solvent. However, solvent reorganization becomes the major contributor to the enthalpy of the formation of enzyme? aminoglycoside complexes only above 20 °C. The change in heat capacity (ΔC_p) shows an aminoglycoside-dependent pattern such that it correlates with the affinity of the ligand for the enzyme. Differences in ΔC_p values determined in H_2O and D_2O also correlated with the ligand affinity. The temperature-dependent increase in the offset temperature (T_(off)), the temperature difference required to observe equal enthalpies in both solvents, is also dependent on the binding affinity of the ligand, and the steepest increase was observed with the tightest binding aminoglycoside, neomycin. Overall, these data, together with earlier observations with a different enzyme, the aminoglycoside N3-acetyltransferase-IIIb [Norris, A. L., and Serpersu, E. H. (2011) Biochemistry 50, 9309], show that solvent reorganization or changes in soft vibrational modes of the protein are interchangeable with respect to the role of being the major contributor to complex formation depending on temperature. These data suggest that such effects may more generally apply to enzyme?ligand interactions, and studies at a single temperature may provide only a part of the whole picture of thermodynamics of enzyme?ligand interactions.
机译：氨基糖苷核苷酸转移酶-4'（ANT）是一种通过对这些抗生素上的4'位进行核苷酸化作用而引起对大量氨基糖苷抗生素产生抗药性的酶。使用单位点突变（T130K）产生的酶的嗜热变体研究了溶剂重组对酶配体相互作用的影响。数据表明，氨基糖苷与ANT的结合导致极性基团暴露于溶剂。但是，溶剂重组成为形成酶焓的主要因素。氨基糖苷复合物仅在20°C以上。热容的变化（ΔC_p）显示出氨基糖苷依赖性的模式，从而与配体对酶的亲和力相关。在H_2O和D_2O中确定的ΔC_p值的差异也与配体亲和力相关。补偿温度的温度依赖性增加（T_（off）），在两种溶剂中观察到相等的焓所需的温差也取决于配体的结合亲和力，并且结合最紧密的氨基糖苷观察到最急剧的增加，新霉素。总体而言，这些数据以及使用不同酶（氨基糖苷N3-乙酰基转移酶-IIIb）的早期观察结果[Norris，AL和Serpersu，EH（2011）Biochemistry 50，9309]显示，溶剂重组或软振动模式的改变就根据温度而成为复合物形成的主要贡献者的作用而言，蛋白质是可互换的。这些数据表明，这种作用可能更普遍地适用于酶-配体相互作用，而在单一温度下进行的研究可能仅提供酶-配体相互作用热力学整体情况的一部分。

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