Electrostatic Perturbations in the Substrate-Binding Pocket of Taurine/α-Ketoglutarate Dioxygenase Determine its Selectivity.
Electrostatic Perturbations in the Substrate-Binding Pocket of Taurine/α-Ketoglutarate Dioxygenase Determine its Selectivity.
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DOI：
10.1002/chem.202104167
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发表时间：
2022-02-16
影响因子：
4.3
通讯作者：
de Visser, Sam P.
中科院分区：
文献类型：
--
作者：
Ali, Hafiz Saqib;de Visser, Sam P.
关键词：
牛磺酸/α‐酮戊二酸双加氧酶是一种重要的酶，参与人体半胱氨酸分解代谢过程，并选择性地在C1‐位置羟基化牛磺酸。最近的计算研究表明，在气相中牛磺酸的C2−H键明显弱于C1−H键，但没有证据表明存在2 -羟基牛磺酸产物。为此，对TauD中的选择性模式进行了详细的计算研究。计算表明，第二配位球和残基的质子化态在引导酶达到正确的选择性方面起着重要作用。具体来说，活性位点组氨酸残基上的单个质子可以通过其在活性位点的静电扰动改变反应的区域选择性，有效地改变牛磺酸的C1−H和C2−H键强度。TauD中蛋白质笼与底物和氧化剂之间的许多极性和氢键相互作用进一步强调了这一点，这些相互作用削弱了亲R的C1−H键并触发了化学选择反应过程。大簇模型较好地再现了实验激活自由能。对牛磺酸/α‐酮戊二酸双加氧酶大活性位点模型的密度泛函理论计算表明，极性和带电荷氨基酸残基的第二配位球效应对于正确描述该酶对牛磺酸活化的区域选择性至关重要。特别是，带电荷的组氨酸残基会引起局部电场效应，从而引导C1‐羟基化的反应性。
Taurine/α‐ketoglutarate dioxygenase is an important enzyme that takes part in the cysteine catabolism process in the human body and selectively hydroxylates taurine at the C1‐position. Recent computational studies showed that in the gas‐phase the C2−H bond of taurine is substantially weaker than the C1−H bond, yet no evidence exists of 2‐hydroxytaurine products. To this end, a detailed computational study on the selectivity patterns in TauD was performed. The calculations show that the second‐coordination sphere and the protonation states of residues play a major role in guiding the enzyme to the right selectivity. Specifically, a single proton on an active site histidine residue can change the regioselectivity of the reaction through its electrostatic perturbations in the active site and effectively changes the C1−H and C2−H bond strengths of taurine. This is further emphasized by many polar and hydrogen bonding interactions of the protein cage in TauD with the substrate and the oxidant that weaken the pro‐R C1−H bond and triggers a chemoselective reaction process. The large cluster models reproduce the experimental free energy of activation excellently. Density functional theory calculations on large active site models of taurine/α‐ketoglutarate dioxygenase show that second‐coordination sphere effects of polar and charged amino acid residues are essential for the correct description of the regioselectivity of taurine activation by this enzyme. In particular, a charged histidine residue incurs a local electric field effect that guides the reactivity to C1‐hydroxylation.
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影响因子：
15
作者：
Aluri, Swathi;de Visser, Sam P.
通讯作者：
de Visser, Sam P.
影响因子：
4.4
作者：
BECKE, AD
通讯作者：
BECKE, AD
影响因子：
2.9
作者：
Ali, Hafiz Saqib;Henchman, Richard H.;de Visser, Sam P.
通讯作者：
de Visser, Sam P.
影响因子：
4.5
作者：
Ali, Hafiz Saqib;Henchman, Richard H.;de Visser, Sam P.
通讯作者：
de Visser, Sam P.
影响因子：
4.3
作者：
Ali, Hafiz Saqib;Henchman, Richard H.;de Visser, Sam P.
通讯作者：
de Visser, Sam P.