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Interactive Regulation between Aliphatic Hydroxylation and Aromatic Hydroxylation of Thaxtomin D in TxtC: A Theoretical Investigation
Inorganic Chemistry ( IF 4.3 ) Pub Date : 2021-04-16 , DOI: 10.1021/acs.inorgchem.1c00154
Chang Yuan 1 , Qingwen Ouyang 1 , Xixi Wang 1 , Xichen Li 1 , Hongwei Tan 1 , Guangju Chen 1
Inorganic Chemistry ( IF 4.3 ) Pub Date : 2021-04-16 , DOI: 10.1021/acs.inorgchem.1c00154
Chang Yuan 1 , Qingwen Ouyang 1 , Xixi Wang 1 , Xichen Li 1 , Hongwei Tan 1 , Guangju Chen 1
Affiliation
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TxtC is an unusual bifunctional cytochrome P450 that is able to perform sequential aliphatic and aromatic hydroxylation of the diketopiperazine substrate thaxtomin D in two distinct sites to produce thaxtomin A. Though the X-ray structure of TxtC complexed with thaxtomin D revealed a binding mode for its aromatic hydroxylation, the preferential hydroxylation site is aliphatic C14. It is thus intriguing to unravel how TxtC accomplishes such two-step catalytic hydroxylation on distinct aliphatic and aromatic carbons and why the aliphatic site is preferred in the hydroxylation step. In this work, by employing molecular docking and molecular dynamics (MD) simulation, we revealed that thaxtomin D could adopt two different conformations in the TxtC active site, which were equal in energy with either the aromatic C20–H or aliphatic C14–H pointing toward the active Cpd I oxyferryl moiety. Further ONIOM calculations indicated that the energy barrier for the rate-limiting hydroxylation step on the aliphatic C14 site was 9.6 kcal/mol more favorable than that on the aromatic C20 site. The hydroxyl group on the monohydroxylated intermediate thaxtomin B C14 site formed hydrogen bonds with Ser280 and Thr385, which induced the l-Phe moiety to rotate around the Cβ–Cγ bond of the 4-nitrotryptophan moiety. Thus, it adopted an energetically favorable conformation with aromatic C20 adjacent to the oxyferryl moiety. In addition, the hydroxyl group induced solvent water molecules to enter the active site, which propelled thaxtomin B toward the heme plane and resulted in heme distortion. Based on this geometrical layout, the rate-limiting aromatic hydroxylation energy barrier decreased to 15.4 kcal/mol, which was comparable to that of the thaxtomin D aliphatic hydroxylation process. Our calculations indicated that heme distortion lowered the energy level of the lowest Cpd I α-vacant orbital, which promoted electron transfer in the rate-limiting thaxtomin B aromatic hydroxylation step in TxtC.
中文翻译:
TxtC中Thaxtomin D脂肪族羟基化与芳香族羟基化的相互作用调控:理论研究
TxtC 是一种不寻常的双功能细胞色素 P450,能够在两个不同的位点对二酮哌嗪底物 thaxtomin D 进行连续的脂肪族和芳香族羟基化,以产生 thaxtomin A。尽管与 thaxtomin D 复合的 TxtC 的 X 射线结构揭示了其结合模式芳香族羟基化,优先羟基化位点是脂肪族C 14。因此,解开 TxtC 如何在不同的脂肪族和芳香族碳上完成这种两步催化羟基化以及为什么在羟基化步骤中优选脂肪族位点是很有趣的。在这项工作中,通过分子对接和分子动力学 (MD) 模拟,我们发现 thaxtomin D 可以在 TxtC 活性位点采用两种不同的构象,它们的能量与芳香 C20 -H 或脂肪族 C 14 -H 指向活性 Cpd I oxyferryl 部分。进一步的 ONIOM 计算表明,脂肪族 C 14位点上的限速羟基化步骤的能垒比芳香族 C 20位点上的能垒高9.6 kcal/mol 。单羟基化中间体 thaxtomin BC 14位点上的羟基与 Ser280 和 Thr385 形成氢键,诱导l -Phe 部分围绕4-硝基色氨酸部分的 C β -C γ键旋转。因此,它采用了具有芳香族 C 20的能量有利构象与氧铁基部分相邻。此外,羟基诱导溶剂水分子进入活性位点,将thaxtomin B推向血红素平面并导致血红素变形。基于这种几何布局,限速芳香羟基化能垒降低到15.4 kcal/mol,与thaxtomin D脂肪羟基化过程相当。我们的计算表明,血红素畸变降低了最低 Cpd I α-空轨道的能级,这促进了 TxtC 中限速 thaxtomin B 芳香羟基化步骤中的电子转移。
更新日期:2021-05-03
中文翻译:
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TxtC中Thaxtomin D脂肪族羟基化与芳香族羟基化的相互作用调控:理论研究
TxtC 是一种不寻常的双功能细胞色素 P450,能够在两个不同的位点对二酮哌嗪底物 thaxtomin D 进行连续的脂肪族和芳香族羟基化,以产生 thaxtomin A。尽管与 thaxtomin D 复合的 TxtC 的 X 射线结构揭示了其结合模式芳香族羟基化,优先羟基化位点是脂肪族C 14。因此,解开 TxtC 如何在不同的脂肪族和芳香族碳上完成这种两步催化羟基化以及为什么在羟基化步骤中优选脂肪族位点是很有趣的。在这项工作中,通过分子对接和分子动力学 (MD) 模拟,我们发现 thaxtomin D 可以在 TxtC 活性位点采用两种不同的构象,它们的能量与芳香 C20 -H 或脂肪族 C 14 -H 指向活性 Cpd I oxyferryl 部分。进一步的 ONIOM 计算表明,脂肪族 C 14位点上的限速羟基化步骤的能垒比芳香族 C 20位点上的能垒高9.6 kcal/mol 。单羟基化中间体 thaxtomin BC 14位点上的羟基与 Ser280 和 Thr385 形成氢键,诱导l -Phe 部分围绕4-硝基色氨酸部分的 C β -C γ键旋转。因此,它采用了具有芳香族 C 20的能量有利构象与氧铁基部分相邻。此外,羟基诱导溶剂水分子进入活性位点,将thaxtomin B推向血红素平面并导致血红素变形。基于这种几何布局,限速芳香羟基化能垒降低到15.4 kcal/mol,与thaxtomin D脂肪羟基化过程相当。我们的计算表明,血红素畸变降低了最低 Cpd I α-空轨道的能级,这促进了 TxtC 中限速 thaxtomin B 芳香羟基化步骤中的电子转移。