几类重要的酶催化反应的机理研究

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英文题名：Theoretical Studies on the Mechanisms of Several Important Enzymatic Reactions 作者：侯倩倩 论文级别：博士 学科专业名称：化学 中文关键词：酶催化反应 ; 反应机理 ; 密度泛函方法 ; 分子动力学方法 ; QM/MM方法 英文关键词：Enzymatic reaction ; Reaction mechanism ; Density functional theory ; Molecular dynamic methods ; QM/MM methods 学位年度：2013 导师：刘永军 学科代码：0703 学位授予单位：山东大学 论文提交日期：2013-04-06

摘要

酶是具有催化功能的特殊蛋白质,有生物催化剂之称。根据专一性的不同,可以分为六大类：氧化还原酶类、转移酶类、水解酶类、裂合酶类、异构酶类和连接酶类。随着生物化学技术的发展,酶催化反应越来越多地被科学家们应用到我们生活的各个方面。虽然目前已有实验方法可以得到酶的晶体结构、催化活性、激活剂和抑制剂等信息,但是整个反应过程的详细信息仍然无法确定。近年来,随着量子化学理论及方法的不断完善,计算机运行速度的提高,计算化学对酶催化领域产生了重大影响,成为化学工作者必不可少的强有力的理论工具。
     本论文以几种重要的酶催化反应为研究对象,综合运用量子化学、分子力学以及两者相结合的方法对其催化机理进行系统的理论研究,获得了其反应过程的详细信息,揭示了其催化反应的本质,解释了有关实验现象并补充了相关实验结果,促进了生命大分子体系计算方法的发展和应用研究。
     本论文主要工作描述如下：(1)异构酶——苯丙氨酸氨基变位酶的催化机理研究
     苯丙氨酸氨基变位酶(TcPAM)催化(2S)-α-苯丙氨酸异构化生成(3R)-β-苯丙氨酸,是著名的抗癌药紫杉醇的13位侧链合成的第一步反应,该酶是在植物中首次发现的氨基变位酶,并且是目前在生物体内所发现的唯一的苯丙氨酸氨基变位酶。在TcPAM活性口袋中,存在特殊的亲电试剂4-亚甲基-1H-咪唑-5(4H)酮(MIO), MIO结构是Ala-Ser-Gly通过自身催化而形成的。目前针对MIO-依赖氨基变位酶提出的反应机理有两种：米切尔加成反应和傅氏反应。我们应用密度泛函理论B3LYP方法研究了苯丙氨酸氨基变位酶的催化机理。计算结果表明：此反应经历了米切尔加成反应机理,而不是傅氏反应机理。在米切尔加成反应机理中,Cp脱氢过程为整个过程的决速步,Cp脱氢和氨解离过程经历了E1cB机理：中间体肉桂酸发生了分子内Cl-Cα的旋转,导致了产物的立体结构与SgTAM催化产物不同；活性中心关键残基对底物的结合和催化起到十分重要的作用。我们得到的计算结果与实验结果一致,描述了整个催化反应的细节,解释了立体化学效应,有助于生物合成前体的制备及抗癌药物的设计和研发。
     (2)水解酶——多聚腺苷二磷酸核糖水解酶和柠檬烯-1,2-环氧化物水解酶的催化机理研究
     聚腺苷二磷酸核糖化(PAR化)是一种短暂的、动态的、可逆的对核蛋白翻译后的修饰过程,参与了多方而的生理过程：DNA损伤后修复和基因组整体性的维系,对转录的调控,对蛋白质降解的调节,以及细胞凋亡和坏死细胞的死亡等。在这个过程中,聚(腺苷二磷酸核糖)聚合酶(PARP)和聚(腺苷二磷酸核糖)水解酶(PARG)具有重要的调节作用。PARG是唯一的降解腺苷二磷酸核糖聚合物的酶。PARG通过催化α[(1”-2’)和(1’”-2”)核糖基-核糖水解PAR得到构型翻转的ADP-核糖。我们通过利用密度泛函B3LYP方法研究了聚(腺苷磷酸核糖)水解酶(PARG)催化聚(腺苷二磷酸核糖)(PAR)的降解机理。基于最新得到的晶体结构,我们构建了三个不同大小的活性口袋模型,以期得到PARG的催化水解机理,以及关键残基的作用。计算结果证明,PARG催化PAR的水解反应经历了SN2的机理而不是实验猜测的SN1机理。通过不同模型的计算,我们得到了关键残基的作用。文中得到的核糖-核糖之间糖苷键的水解机理,可以为后续突变实验、抑制剂实验研究提供理论基础。
     环氧化合物水解酶(EHs),是一组催化环氧化合物水解为相应邻二醇的酶类。EHs含有高度相似的氨基酸序列,属于α/β折叠型水解酶系。但是柠檬烯-1,2-环氧化物水解酶(LEH)不具备α/β折叠结构,有着不同于一般水解酶的结构以及催化机理。最新的实验报道通过突变特定残基可以改变底物的选择性,这些突变体可以应用到生物有机合成中。我们通过量子力学和分子力学相结合的方法(QM/MM方法)研究了LEH催化环氧化物的水解反应机理。结果表明,柠檬烯环氧化物水解酶具有不同于一般水解酶的结构以及催化机理,是酸催化的单步协同反应机理,其活性中心为Asp101-Arg99-Asp132形成的三位一体结构,其催化机制为：Asp101为环氧化物的提供质子：Asp132吸引水分子中的质子,辅助羟基亲核进攻取代基多的环氧碳,导致环氧化物开环。残基Tyr53、Asn55、Asp132与水分子形成氢键,使其处于最有利于亲核进攻的位置；残基Arg99虽然没有直接参与催化反应,但是起到定位两个天冬氨酸的羧基,稳定电荷的重要作用。
     (3)氧化还原酶——丙酮酸脱羧酶的催化机理研究
     丙酮酸脱羧酶(PDC)是一种最简单的ThDP依赖脱羧酶,催化α-酮基羧酸脱羧,进而与醛类发生缩合反应,生成α-羟基酮类化合物。PDC参与生物体内的多种合成与分解代谢过程,是许多药物的作用靶点,在有机合成、药物中间体合成、手型催化等方面具有潜在的应用价值。例如,维生素E、抗真菌药Sch42427、麻黄碱等化合物的合成都是以α-羟基酮类化合物为中间体。虽然实验和理论上对PDC催化过程都有大量的研究,但是到目前为止,对于其催化细节尚没有比较一致的结论。我们采用QM/MM方法研究了丙酮酸脱羧酶(PDC)催化丙酮酸生成乙醛的反应。通过设计关键残基的不同质子化状态,我们构建了三个计算模型,得到了不同反应路径的结构和能量信息等。计算结果表明,只有当Asp27' His113'、His114'都处于质子化的状态时,该催化反应最容易进行,脱羧过程是整个反应的决速步。我们的计算结果不仅解释了实验事实,而且为设计新型PDC抑制剂提供了理论依据。
     (4)转移酶——O6-甲基鸟嘌呤-DNA甲基转移酶和苯乙胺-N-甲基转移酶的催化机理研究
     O6-甲基鸟嘌呤-DNA甲基转移酶(AGT/MGMT)是承担DNA损伤直接修复的最重要的酶,可同时发挥转移酶和甲基受体的作用,保护细胞免受烷化剂损害,防止细胞癌变和死亡。它将甲基从06-mG转移到自身的自身的半胱氨酸残基(Cys145)上,使DNA链上的鸟嘌呤复原,同时自身不可逆的失活。本章采用QM/MM方法研究了人类修复酶O6-氧-甲基嘌呤-DNA甲基转移酶(AGT)的催化反应机理。通过计算,我们得到了该反应的反应路径,反应势垒,并且得出结论：该反应中甲基转移过程是甲基正离子的转移,其决速步是甲基正离子的生成过程。残基Glu172, Ser159和Tyr114起到稳定过渡态降低能垒的作用。值得注意的是,本章采用的QM/MM方法更能体现蛋白质环境对反应机理有重要的影响,弥补了之前QM方法计算的不足。
     肾上腺素(EPI)是在人体在应激状态下由肾上腺髓质分泌的一种几茶酚胺激素。它可以通过作用于α、β型肾上腺能受体,在体内产生变化,使心脏收缩力上升、兴奋性增高、收缩或舒张血管、调节血压、扩张气管、提高机体代谢等等。肾上腺素是酪氨酸在不同种类的酶催化下经历不同的中间体而生成的。在最后一步反应中,苯乙胺-N-甲基转移酶(PNMT)在辅酶甲硫氨酸(AdoMet)的作用下催化去肾上腺素(NE)生成肾上腺素(EPI)。研究表明,这是合成肾上腺素唯一的反应路径。因此研究PNMT催化机理对PNMT的基础研究以及新型肾上腺素抑制剂的研究都是非常有意义的。本章通过QM/MM方法研究了PNMT催化反应的反应机理。整个反应过程包括三个基元反应,其中甲基转移反应是决速步,经历了SN2反应机理,能垒为16.4kcal/mol。(?)(?)性口袋中的残基Glu219、 Glu185、Tyr35,以及两个水分子对催化反应都有非常重要的作用。尤其是Glu219和Glu185都参与反应,但是发挥了不同的作用：Glu185在第一步质子转移反应中作为质子受体接收一个质子：Glu219,在最后一步反应中,从质子化的EPI上得到一个质子,从而生成最终产物。所以,这两个残基都可以作为改变PNMT催化速率的目标残基。
     (5)新型双功能酶——1,6-二磷酸果糖醛缩酶/磷酸酶的催化机理研究
     古细菌1,6-二磷酸果糖醛缩酶/磷酸酶(FBPA/P),是一种新型双功能酶,这种酶只包含一个活性中心,但是催化两种不同的糖异生反应,包括二羟基丙酮磷酸(DHAP)和3-磷酸甘油醛(GA3P)可逆的羟醛缩合反应,生成1,6-二磷酸果糖(FBP),以及二磷酸果糖不可逆的脱磷酸反应,生成6-磷酸果糖(F6P)。直到最近,人们才发现了其醛缩酶的功能,并得到了其在这种功能状态下的晶体结构,而在这之前,FBPA/P被归类为V型果糖双磷酸酶。对于FBPA/P新发现的醛缩酶功能,尚没有详细的理论研究。本章采用QM/MM方法,基于最新得到的晶体结构,研究了双功能酶FBPA/P的醛缩合反应机理。计算结果与实验致,在反应过程中经历了希夫碱的中间体。整个反应的决速步是FBP的C3-C4成键的过程,其自由能垒为24.7kcal/mol。Lys232和Tyr229直接参与催化反应；Lys232与DHAP(?)结合后形成希夫碱中间体：Tyr229在整个反应过程中既可以作为质子供体,也可以作为质子受体,发挥了传递质子的作用。在原子水平上对FBPA/P醛缩合反应的研究,有助于理解其在糖异生过程中发挥的作用。关于FBPA/P由构象变化引起的两种功能之间转换正在研究中。
Enzymes are biological catalysts. Most enzymes are proteins, although some catalytic RNA molecules have been identified. Due to their different specificity, they could be classified to several categories, including oxidoreductases, transferases, hydrolases, lyases, isomerases, ligases. Enzymes are responsible for the thousands of chemical reactions that sustain life. With the development of science and technology, more and more enzymes are applied in our daily life. Although some information such as the crystal structures, the catalytic activity, activating agent, inhibitors, could be obtained through the experimental methods, the details of their catalytic mechanisms are not sure. Computer simulations are able to give the detailed information of the enzymatic reactions on the atomic level.
     In this dissertation, we use quantum mechanics (QM), molecular mechanics (MM), and combined quantum mechanics and molecular mechanics (QM/MM) methods to study several important enzymatic reactions.
     The main contents as follow:
     (1) The mechanism of isomerase—phenylalanine aminomutase.
     The Taxus canadensis phenylalanine aminomutase (TcPAM) catalyzes the isomeriazation of (S)-a-phenylalanine to the (R)-β-isomer. The active site of TcPAM contains the signature5-methylene-3,5-dihydroimidazol-4-one (MIO) prosthesis, observed in the ammonia lyase class of enzymes. An enchanting place of PAM is that the product of PAM is also an obligatory biosynthetic precursor of the phenylisoserine side chain of antimitotic pharmaceutical Taxol. Up to now, there are two plausible mechanisms for these MIO-dependent enzymes, i.e., the amino-MIO adduct mechanism and the Friedel-Crafts-type reaction mechanism. In response to this mechanistic uncertainty, the phenylalanine aminomutase mechanism was investigated by using density functional methods. The main results can be summarized as follows: The reaction proceeds through an amino-MIO adduct mechanism, but not a Fricdel-Crafts-type mechanism. In the amino-MIO adduct mechanism, the deprotonation at the (3-position and ammonia elimination occur on the amino-MIO adduct through an ElcB mechanism. The stereochemistry of the TcPAM reaction can be achieved by rotation of the intermediate cinnamate round the Cl-Cα bond prior to rebinding of the amino group at the β-position on the intermediate. This would be the reason that TcPAM catalyzes the opposite stereochemistry production compared with PaPAM and SgTAM. The role of several important active-site residues are illustrated according to our calculations. The mechanism described here for TcPAM is consistent with several experimental results, and provides strong theoretical support for the stereochemistry. This is expected to shed light on the preparation of the chiral building blocks and the biosynthetic engineering toward novel therapeutics.
     (2) The catalytic mechanisms of hydrolascs—poly(ADP-ribose) glycohydrolase and limonene1,2-epoxide hydrolase.
     Poly(ADP-ribose) glycohydrolase (PARC) is the only enzyme responsible for the degradation of ADP-ribose polymers. PARC activity is critical for the prevention of poly(ADP-ribose) polymerase (PARP) dependent cell death by regulating the intracellular levels of PAR. Very recently, the first crystal structure of PARG was reported (Dea Slade, et al, Nature477(2011)616), and a possible SN1-type-like mechanism was proposed. Apart from these observations, little is known about the PAR degrading reaction. Our calculations confirm that PARG catalyzes the hydrolysis of PAR via an SN2-like mechanism. By using different active site models, the roles of key residues have been illustrated. Glu115works as a proton donor to the glycosidic oxygen as well as a proton acceptor from the activated water molecule. The other glutamic residue Glu114plays an important role in stabilizing ribose" by forming a hydrogen bond to the C2"-OH of ribose". The negative diphosphate group significantly lowers the reaction barrier by providing a strong hydrogen bond to the water molecule and influencing the sterie orientation of ribose". And Phe227provides the spacial effects to position the terminal ribose". Our mechanism picture described here is expected to present a versatile paradigm of the mechanisms of ribose-ribose O-glycosidic bond hydrolysis.
     Limonene1,2-epoxide hydrolase (LEH) is completely different from those of classic epoxide hydrolases (EHs) which catalyze the hydrolysis of epoxides to vicinal diols. A novel concerted general acid catalysis step involving the Asp101-Arg99-Asp132triad is proposed to play an important role in the mechanism. The detailed mechanism of epoxide ring-opening catalyzed by limonene1,2-epoxide hydrolase has been studied by combined QM/MM methodologies. The calculations indicate that the LEH-catalyzed hydrolysis proceeds via a novel single-step conceited general acid reaction mechanism. The reaction path is demonstrated to involve simultaneous donation of an Asp101proton to the epoxide oxygen, nucleophilic attack of water at the more substituted oxirane carbon, and abstraction of a proton from water by Asp132. Our QM/MM calculations give an energy barrier of16.9kcal/mol for the formation of limonene-1,2-diol by nucleophilic attack on the more substituted epoxide carbon. According to the QM/MM optimized structures and minimized energy profiles for mutagenesis, the proximal protein environment, especially the positions of Arg99, Tyr53and Asn55, plays an important role in the LEH-mediated catalytic reaction.
     (3) The catalytic mechanism of oxidoreductase—pyruvate decarboxylase.
     Pyruvate decarboxylase (PDC) is a typical thiamin diphosphate (ThDP)-dependent enzyme with widespread applications in industry. Though studies regarding the reaction mechanism of PDC have been reported, they are mainly focused on the formation of ThDP ylide and some elementary steps in the catalytic cycle, studies about the whole catalytic cycle of PDC are still not completed. In these previous studies, a major controversy is whether the key active residues (Glu473, Glu50', Asp27', His113', His114') are protonated or ionized during the reaction. To explore the catalytic mechanism and the role of key residues in the active site, three whole-enzyme models were considered and the combined QM/MM calculations on the nonoxidative decarboxylation of pyruvate to acetaldehyde catalyzed by PDC were performed. According to our computational results, the fundamental reaction pathways, the complete energy profiles of the whole catalytic cycle, and the specific role of key residues in the common steps were obtained. It is also found that the same residue with different protonation states will lead to different reaction pathways and energy profiles. The mechanism derived from the model in which the residues (Glu473, Glu50', Asp27', His113', Hisl14') are in their protonated states is most consistent with experimental observations. Therefore, extreme care must be taken when assigning the protonation states in the mechanism study.
     (4) The catalytic mechanisms of transferases—O6-alkylguanine-DNA alkyltransferase and phenylethanolamine N-methyltransferase.
     DNA alkylation can be caused from both endogenous and exogenous DNA-damaging agents, such as S-adenosylmethionine in the cell, methylmethane sulfonate (MMS) or N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) in the environment. Alkylation adducts frequently occur at O6-position of guanine, resulting to O6-methylguanine (O6-mG), which if not repaired leads to GC to AT transition mutations and cancer. The combined quantum-mechanical/molecular-mechanical (QM/MM) approaches have been applied to investigate the detailed reaction mechanism of human06-alkylguanine-DNA alkyltransferase (AGT). AGT is a direct DNA repair protein, which is capable of repairing the alkylated DNA by transferring the methyl group to the thiol group of cysteine residue (Cys145) in the active site in an irreversible and stoichiometric reaction. Our QM/MM calculations reveal that the methyl group transferring step is expected to occur through two steps, in which the methyl carbocation generating step is the rate-determining step with an energy barrier of14.4kcal/mol at QM/MM B3LYP/6-31G(d, p)//CHARMM22level of theory. It is different from the previous theoretical studies based on QM calculations by using cluster model that the methyl group transferring step is a one-step process with higher energy barrier.
     Epinephrine is a naturally occurring adrenomedullary hormone that transduces environmental stressors into cardiovascular actions. As the only route in the catecholamine biosynthetie pathway, Phenylethanolamine N-methyltransferase (PNMT) catalyzes the synthesis of epinephrine. To elucidate the detailed mechanism of enzymatic catalysis of PNMT, combined quantum-mechanical/molecular-mechanical (QM/MM) calculations were performed. The calculation results reveal that this catalysis contains three elementary steps:the deprotonation of protonated norepinphrine, the methyl transferring step and deprotonation of the methylated norepinphrine. The methyl transferring step was proved to be the rate-determining step undergoing a SN2mechanism with an energy barrier of16.4kcal/mol. During the whole catalysis, two glutamic acids Glu185and Glu219were proved to be loaded with different effects according to the calculations results of the mutants. These calculation results can be used to explain the experimental observations and make a good complementarity for the previous QM study.
     (5) The mechanism of biofunctional enzyme—fructose-1,6-bisphosphate aldolase/phosphatase (FBPA/P).
     Arc/weal fructose-1,6-bisphosphale (FBP) aldolase/phosphalase (FBPA/P) is a bifunctional enzyme that catalyses two chemically distinct reactions of gluconeogenesis:(a) the reversible aldol condensation of dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (GA3P) to FBP;(b) the dephosphorylation of FBP to fructose-6-phosphate (F6P). Thus, FBPA/P is fundamentally different from ordinary enzymes whose active sites are responsible for a specific reaction. There are very less studies focus on the catalytic mechanism of FBPA/P. We have investigated the mechanism of FBPA/P using QM/MM methods. Our results agree well with the experiments that the Schiff base was obtained as one intermediate during the reaction process. Formation of C3-C4bond of FBP is the rate-limiting step and undergoes a free energy barrier of24.7kcal/mol. Lys232formed a Schiff base intermediate with the substrate of DHAP. Try229could sever as the catalytic acid/base residue for all the steps. Study on the simulation of the active-site remodeling in FBPA/P is ongoing.

引文

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