非血红素铁酶中动态配位变化对C-H键选择性胺化反应的调控机制  

Coordination dynamics of iron enables the selective C-N coupling but bypasses unwanted C-H hydroxylation in Fe(II)/a-ketoglutaratedependent non-heme enzymes

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作  者:张璇 刘佳[1] 廖浪星 王子宽 王斌举 Xuan Zhang;Jia Liu;Langxing Liao;Zikuan Wang;Binju Wang(State Key Laboratory of Physical Chemistry of Solid Surfaces and Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry,College of Chemistry and Chemical Engineering,Xiamen University,Xiamen 361005,Fujian,China;Institute of Drug Discovery Technology,Ningbo University,Ningbo 315211,Zhejiang,China;Max-Planck-Institut für Kohlenforschung,Kaiser-Wilhelm-Platz 1,Mülheim an der Ruhr 45470,Germany)

机构地区:[1]厦门大学化学化工学院,固体表面物理化学国家重点实验室,福建省理论与计算化学重点实验室,福建厦门361005 [2]宁波大学新药技术研究院,浙江宁波315211 [3]马克斯-普朗克煤炭研究所,德国

出  处:《Chinese Journal of Catalysis》2024年第7期131-144,共14页催化学报(英文)

基  金:国家自然科学基金(22122305,21907082,22073077,22303043);中国博士后科学基金(2023M742917);宁波市甬江人才工程项目.

摘  要:氮杂环丙烷结构广泛存在于天然生物碱中,具有杀菌、抗癌等作用.然而,目前关于生物体系在合成氮杂环丙烷结构过程中如何克服氮杂环丙烷高环张力带来的热力学不利因素,以及如何避免形成热力学更稳定的羟基化副产物的报道较少.TqaL_(NC)酶是目前非血红素酶家族中唯一一种能够依赖α-酮戊二酸活化C-H键,进而生成氮杂环丙烷结构的酶.深入探究TqaL_(NC)酶选择性生成氮杂环丙烷结构并避免羟基化副产物的机制,有助于深入理解非血红素铁酶家族在C-H键活化及官能化过程中的选择性调控机理.本文以TqaL_(NC)酶的晶体结构为基础,采用分子动力学(MD)模拟以及量子力学-分子力学(QM/MM)等多尺度模拟方法对TqaL_(NC)酶与L-缬氨酸(L-Val)、TqaL_(NC)酶与L-异亮氨酸(L-Ile)和F345A-TqaL_(NC)酶与L-异亮氨酸(L-Ile)三个反应过程进行了详细的机理研究.结果表明,TqaL_(NC)酶在反应过程中生成的直立式构象的Fe(Ⅳ)=O物种会通过构象异构化获得赤道面式构象,为底物(L-Val、L-Ile、L-homoalaine)上NH_(3)^(+)与Fe的配位提供结构基础.在水和关键酸性残基的介导下,底物NH_(3)^(+)两次脱去质子与Fe(Ⅳ)=O物种配位,生成HN-Fe(Ⅳ)=O结构.随后,Fe(Ⅳ)=O物种攫取底物H原子,生成HN-Fe(Ⅲ)-OH中间体.此时NH回弹反应比传统的OH回弹反应在动力学上更有优势,因此选择性地生成了氮杂环丙烷产物.在反应过程中,底物侧链与周围氨基酸的位阻效应是影响NH回弹反应能垒的重要因素.通过改变底物侧链大小(L-Val→L-Ile)以及附近氨基酸的突变(F345A)实验,证实了该结论.本文还通过理论计算预测了TqaL_(NC)酶与L-高丙氨酸的反应产物为羟基化产物,并通过新的实验证据进一步支持了理论预测的机理.此外,在HN-Fe(Ⅲ)-OH结构中,通过前线轨道理论分析发现,dπ*Fe-N,dπ*Fe-OH轨道的能量差是影响NH/OH回弹反应能垒的另一重要因素.当底物NH与FNon-heme Fe(II)/α-ketoglutarate(αKG)-dependent enzymes catalyze numerous C-H activation and functionalization reactions.However,howαKG-dependent non-heme enzymes catalyzed C-H functionalization beyond the hydroxylation is largely unknown.Here,we addressed this issue in Fe(II)/αKG-dependent oxygenase TqaL_(Nc),which catalyzes the selective C-H amination but bypasses the thermodynamically favored C-H hydroxylation.Here,the extensive computational studies have shown that the aziridine formation involves the conformational change of the Fe(IV)=O species from the axial configuration to the equatorial one,the substrate deprotonation of NH_(3)^(+)group to form the NH-ligated intermediate,the C-H activation by the equatorial Fe(IV)=O species.Such mechanistic scenario has been cross-validated by oxidation of various substrates by TqaL_(Nc)and its variants,including the available experiments and our new experiments.While the presence of steric hindrance between the substrate and the second-sphere residues would inhibit the aziridination process,the intrinsic reactivity of aziridination vs.hydroxylation is dictated by the energy splitting between two key redox-active dπ*frontier molecular orbitals:dπ*Fe-N and dπ*_(Fe-OH).The present findings highlight the key roles of the coordination change and dynamics of iron cofactor in dictating the catalysis of non-heme enzymes and have far-reaching implications for the other non-heme Fe(II)/αKG-dependent enzymes catalyzed C-H functionalization beyond the hydroxylation.

关 键 词:联合量子力学-分子力学方法 C-H键活化 非血红素酶 胺化反应 羟基化反应 

分 类 号:O621.25[理学—有机化学]

 

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