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Insights into specificity and catalytic mechanism of amphotericin B/nystatin thioesterase
Proteins: Structure, Function, and Bioinformatics ( IF 3.2 ) Pub Date : 2021-01-02 , DOI: 10.1002/prot.26041
Rufan Wang 1 , Wentao Tao 1 , Lei Liu 1 , Chen Li 1 , Linquan Bai 1 , Yi-Lei Zhao 1 , Ting Shi 1
Affiliation  

Polyene polyketides amphotericin B (AMB) and nystatin (NYS) are important antifungal drugs. Thioesterases (TEs), located at the last module of PKS, control the release of polyketides by cyclization or hydrolysis. Intrigued by the tiny structural difference between AMB and NYS, as well as the high sequence identity between AMB TE and NYS TE, we constructed four systems to study the structural characteristics, catalytic mechanism, and product release of AMB TE and NYS TE with combined MD simulations and quantum mechanics/molecular mechanics calculations. The results indicated that compared with AMB TE, NYS TE shows higher specificity on its natural substrate and R26 as well as D186 were proposed to a key role in substrate recognition. The energy barrier of macrocyclization in AMB‐TE‐Amb and AMB‐TE‐Nys systems were calculated to be 14.0 and 22.7 kcal/mol, while in NYS‐TE‐Nys and NYS‐TE‐Amb systems, their energy barriers were 17.5 and 25.7 kcal/mol, suggesting the cyclization with their natural substrates were more favorable than that with exchanged substrates. At last, the binding free energy obtained with the MM‐PBSA.py program suggested that it was easier for natural products to leave TE enzymes after cyclization. And key residues to the departure of polyketide product from the active site were highlighted. We provided a catalytic overview of AMB TE and NYS TE including substrate recognition, catalytic mechanism and product release. These will improve the comprehension of polyene polyketide TEs and benefit for broadening the substrate flexibility of polyketide TEs.

中文翻译:

两性霉素B/制霉菌素硫酯酶的特异性和催化机制的洞察

多烯聚酮化合物两性霉素 B (AMB) 和制霉菌素 (NYS) 是重要的抗真菌药物。硫酯酶 (TE) 位于 PKS 的最后一个模块,通过环化或水解控制聚酮化合物的释放。由于AMB和NYS之间微小的结构差异以及AMB TE和NYS TE之间的高序列同一性,我们构建了四个系统来研究AMB TE和NYS TE结合MD的结构特征、催化机理和产物释放模拟和量子力学/分子力学计算。结果表明,与 AMB TE 相比,NYS TE 对其天然底物显示出更高的特异性,R26 和 D186 被认为在底物识别中起关键作用。AMB-TE-Amb 和 AMB-TE-Nys 系统中大环化的能垒计算为 14.0 和 22。7 kcal/mol,而在 NYS-TE-Nys 和 NYS-TE-Amb 系统中,它们的能垒分别为 17.5 和 25.7 kcal/mol,表明与天然底物的环化比交换底物更有利。最后,MM-PBSA.py 程序获得的结合自由能表明,天然产物在环化后更容易离开 TE 酶。突出显示了聚酮化合物产品离开活性位点的关键残留物。我们提供了 AMB TE 和 NYS TE 的催化概述,包括底物识别、催化机制和产品释放。这些将提高对多烯聚酮化合物 TE 的理解,并有利于拓宽聚酮化合物 TE 的基材柔韧性。表明与天然底物的环化比与交换底物的环化更有利。最后,MM-PBSA.py 程序获得的结合自由能表明,天然产物在环化后更容易离开 TE 酶。突出显示了聚酮化合物产品离开活性位点的关键残留物。我们提供了 AMB TE 和 NYS TE 的催化概述,包括底物识别、催化机制和产品释放。这些将提高对多烯聚酮化合物 TE 的理解,并有利于拓宽聚酮化合物 TE 的基材柔韧性。表明与天然底物的环化比与交换底物的环化更有利。最后,MM-PBSA.py 程序获得的结合自由能表明,天然产物在环化后更容易离开 TE 酶。突出显示了聚酮化合物产品离开活性位点的关键残留物。我们提供了 AMB TE 和 NYS TE 的催化概述,包括底物识别、催化机制和产品释放。这些将提高对多烯聚酮化合物 TE 的理解,并有利于拓宽聚酮化合物 TE 的基材柔韧性。py 程序表明,天然产物在环化后更容易离开 TE 酶。突出显示了聚酮化合物产品离开活性位点的关键残留物。我们提供了 AMB TE 和 NYS TE 的催化概述,包括底物识别、催化机制和产品释放。这些将提高对多烯聚酮化合物 TE 的理解,并有利于拓宽聚酮化合物 TE 的基材柔韧性。py 程序表明天然产物在环化后更容易离开 TE 酶。突出显示了聚酮化合物产品离开活性位点的关键残留物。我们提供了 AMB TE 和 NYS TE 的催化概述,包括底物识别、催化机制和产品释放。这些将提高对多烯聚酮化合物 TE 的理解,并有利于拓宽聚酮化合物 TE 的基材柔韧性。
更新日期:2021-01-02
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