摘要
随着生物化学技术的快速发展,酶作为一种高效、专一且反应条件温和的生物催化剂,被越来越多的科研工作者用于研究、治理我国日益严峻的环境污染问题。酶与环境的关系十分密切,人们可以利用生物酶降解环境中的污染物,或者通过酶催化以及仿生催化工艺减少能源消耗和污染物排放,以达到清洁化生产的目的。此外,研究环境污染物对生物体内酶的抑制机理以及生物毒理学效应,可以为制定环境标准和开展环境保护工作提供科学依据。目前实验上研究酶催化反应机理的手段多种多样,包括红外光谱法、分子散射法、X射线衍射法、核磁共振法、酶促反应动力学法、同位素标记法等,然而这些手段无法详细的描述酶的催化反应过程,限制了酶学研究的发展。近年来兴起的量子力学与分子力学联用(QM/MM)方法能够很好的描述酶的催化反应过程,对酶催化领域产生了重大影响,已成为不可或缺的强有力的研究手段之一。
本论文综合使用分子动力学(MD)方法以及QM/MM方法研究了几种与环境问题密切相关的酶体系的催化反应机理,揭示了酶催化反应过程的详细信息,验证、解释并补充了相关实验结果,促进了酶分子催化体系方法的发展及其在环境领域的应用。
一、乙酰胆碱酯酶体系
人体以及很多动物体内都存在乙酰胆碱酯酶,其主要作用是降解神经递质乙酰胆碱以终止突触传递。而有些有机磷类化合物(如化学武器制剂塔崩、杀虫剂甲胺磷)能通过抑制、老化等作用使乙酰胆碱酯酶失活,从而造成乙酰胆碱在人体内过度堆积,继而引发肌肉麻痹与呼吸困难,最后导致死亡。目前对于有机磷化合物对乙酰胆碱酯酶的抑制机理已经研究的较为深入,但是对于有机磷化合物抑制的乙酰胆碱酯酶的老化机理、药物活化机理以及自发活化机理研究的较少。
由于塔崩抑制的乙酰胆碱酯酶不能自发活化,因而本论文以塔崩为例,使用MD方法以及QM/MM方法研究了有机磷化合物抑制的乙酰胆碱酯酶的老化机理及肟类化合物的药物活化机理,发现塔崩的老化过程是通过C-O键断裂而不是通过P-N键断裂完成的,并且通过研究CH2NO、HLO-7两种肟类解毒剂对塔崩抑制的乙酰胆碱酯酶的活化机理,建立了判定药物分子是否有药效的两条基本判据,对新型药物的设计有指导意义。
由于杀虫剂甲胺磷抑制的乙酰胆碱酶的自发活化速率远高于其老化速率,因而,它是一个很好的研究有机磷类化合物抑制的乙酰胆碱酶自发活化反应机理的模型。QM/MM计算结果显示自发活化反应过程中存在一种三角双锥性质的中间体,并发现甲胺磷的不同光学异构体的自发活化能力不同。
二、黄素腺嘌呤二核甘酸依赖性亚硝基合酶体系
由碳样小单孢菌(Micromonospora carbonacea)中的基因oof36编译的黄素腺嘌呤二核甘酸依赖性亚硝基合酶(ORF36)能够催化复杂化合物中亚硝基基团的合成,在制药、食品及精细化工等工业领域有巨大的应用价值。本论文以药物前体物胸苷二磷酸-L-型万古胺为例,使用QM/MM方法深入研究了酶ORF36催化生成亚硝基基团的反应机理,以期为后续的仿生催化、清洁生产提供理论指导。计算结果显示：(1)第二次氧化反应分为三个基元反应步骤且第一步羟基转移反应为速控步。(2)产物亚硝基基团中的氧原子来源于第二次氧化而不是第一次氧化过程中的氧分子。(3)通过研究活性中心附近十八种氨基酸对羟基转移反应的静电影响发现,Ser162对速控步反应的抑制作用最为明显,而氨基酸Leu134和Gln376对速控步反应的促进能力最明显。
三、联苯间位产物水解酶体系
间位产物水解酶属于α/β-水解酶家族,能够催化芳香族化合物的C-C键水解,对全球碳循环以及人体健康有着重要影响。其中,间位产物水解酶BphD在联苯、多氯联苯(环境中的残留量大于28万吨)等环境污染物的降解过程中的地位非常重要。本论文以联苯为模型化合物,使用QM/MM方法探索了酶BphD催化降解联苯、多氯联苯类污染物的反应机理。研究结果发现：(1)Ser112-Glu237-His265催化三元体参与到了野生型酶BphD的催化酰化反应过程。(2)只有Ser112参与到了酶H265A变体的催化酰化过程,因而野生型酶与H265A变体的催化反应机理不同。(3)在酰化反应完成之后,产物HPD在BphD活性中心占有的空间由三个水分子填补,且其中一个水分子直接参与到接下来的脱酰化反应过程。(4)通过分析活性中心部位氨基酸对速控步反应的静电影响,验证并解释了突变Phe175、Arg190、Trp266将降低催化反应速率这一实验结果。(5)本论文同样发现了G1y42、Met113、Leu156、Phe239对速控步反应速率的影响,并认为针对Phe239进行饱和突变或许能发现提高酶BphD催化降解速率的变体酶。
四、谷胱甘肽转移酶体系
全世界每年约有140万人因感染疟疾这一蚊虫传播疾病而死亡,人们通常通过喷洒DDT的办法来消灭蚊虫以达到控制疟疾传播的目的。可是近年来发现某些蚊虫体内的谷胱甘肽转移酶能够将高毒性的DDT转化为低毒性的DDE,从而产生了DDT抗性。因而,为了保护人类健康,亟需研发一种能够替代DDT的杀虫剂。本论文首先使用QM/MM方法分别研究了谷胱甘肽转移酶agGSTe2催化DDT降解为DDE的两种可能的机理：质子转移机理和GS-DDT共聚物机理。结合实验数据,计算结果确定了agGSTe2解毒DDT的机理为质子转移机理。构建了一系列DDT类似物,并发现其中一个类似物,(BrC6H4)2CHCC13,抵抗agGSTe2催化解毒反应的能力最佳。本论文的研究结果为设计新型杀虫剂以控制疟疾传播提供了理论模型以及理论指导。
五、氟乙酸盐脱卤素酶体系
含氟化合物的大量生产和使用给环境带来了巨大的压力,然而目前发现的能够降解含氟化合物的酶十分稀少。研究发现氟乙酸盐脱卤素酶能够催化降解氟乙酸类化合物(该化合物在国内外被广泛用于消灭鼠害)。本论文使用QM/MM方法从分子水平上研究了氟乙酸盐脱卤素酶催化C-F键断裂的催化反应机理,探索了活性中心部位His155不同结构(Hsd或Hse)对酶催化反应的影响,发现氟乙酸盐脱卤素酶分子更倾向于通过Hse结构催化C-F键的断裂。该研究成果将有助于建立其它含氟化合物降解的理论模型。
Due to the rapid development of biochemical technology, enzymes which enjoy high efficiency, specificity, and mild reaction condition properties are more and more widely used in investigating and managing the increasingly serious environmental pollution of China. Enzymes are closely related to the environmental issues. They can be either applied in degrading the environmental pollutants or used in biomimetic catalysis for clean production purpose. In addition, studying the inhibition mechanism and toxicological effects of environmental pollutants toward the functional enzymes can provide scientific basis for environmental protection. Many experimental methods have been established to investigate the enzyme catalysis, such as infrared spectroscopy, molecular scattering method, nuclear magnetic resonance method, enzyme kinetics, and isotope labelling method. However, these methods cannot describe the detailed catalytic itinerary of enzymes which limits the development of enzymology. The quantum mechanics/molecular mechanics (QM/MM) approach is by now established as a valuable and irreplaceable tool in modelling the catalytic system of enzymes.
The molecular dynamics (MD) and QM/MM approaches are used in this dissertation to study the catalytic mechanism of several environmental related enzymatic systems. The results revealed the catalytic itinerary of the studied enzymes. The calculated results also verified, explained, or supplemented the experimental ones. Thus, this dissertation may promote the use of QM/MM method in enzymatic systems and the application of QM/MM method in the environmental related field.
1. Catalytic system of acetylcholinesterase
Acetylcholinesterase (AChE) in human or animals hydrolyzes the neurotransmitter acetylcholine (ACh) to terminate synaptic transmission. However, many organophosphorus compounds can hinder its hydrolysis function towards Ach, such as chemical warfare agent tabun and insecticide methamidophos. Successive accumulation of Ach will paralyze neurotransmission and eventually lead to muscle fasciculation and respiratory failure. Without injecting proper antidote immediately, people may die soon after the poisoning. So far, the inhibition mechanism of organophosphorus compounds toward AChE has been extensively studied. However, the studies on the aging mechanism, antidote induced reactivation mechanism and spontaneous reactivation mechanism of organophosphorus compounds toward AChE are limited.
Since tabun inhibited AChE cannot be spontaneously reactivated, we only focused on studying its aging mechanism and antidote induced reactivation mechanism. The calculated results revealed that the aging mechanism is accomplished through the C-O bond scission rather than P-N bond scission. In addition, we established two criteria for forecasting the reactivate efficacy of newly designed antidote on the basis of the CH2NO-and HLO-7induced reactivation processes.
The system of methamidophos inhibited AChE serves as a perfect model for studying the spontaneous reactivation mechanism of organophosphorus compounds inhibited AChE. The QM/MM results show that there is an intermediate with a trigonal bipyramid characteristic. In addition, different optical isomers of methamidophos show different spontaneous reactivation abilities.
2. Catalytic system of a FAD-dependent nitrososynthase
A FAD-dependent nitrososynthase (ORF36) encoded by gene orf36from Micromonospora carbonacea mediates the synthesis of nitroso group of macromolecular compounds, and shows great potential in the application of pharmaceutical, finechemical and food industries. In this dissertation, we used QM/MM approaches to investigate the catalytic mechanism of ORF36toward a drug candidate (TDP)-L-epi-vancosamine. The results serve as excellent model for the future biomimetic synthesis of (TDP)-L-epi-vancosamine or other nitroso group containing macromolecular compounds. The QM/MM results reveal that (1) The catalytic mechanism of the second oxidation step of ORF36consists of three elementary steps and the first step is rate-determining.(2) Oxygen atom which comes from the second oxidation step is found in the product.(3) By studying the electrostatic influence of18amino acids, Ser162was found to suppress the hydroxylation reaction most, while Leu134and Gln376was found to contribute equally in facilitating it.
3. Catalytic system of meta-cleavage product hydrolases
The meta-cleavage product (MCP) hydrolases are members of α/β-hydrolase superfamily, which catalyze C-C bond hydrolysis of aromatic compounds and are implicated in processes like global carbon cycle and human health. For instance, a MCP hydrolase BphD from biphenyl degradation pathway is crucial in the mineralization of polychlorinated biphenyls (PCBs). There is about2.8×108kg PCBs in mobile environment reservoirs, causing a severe environmental concern. In this dissertation, QM/MM calculations on investigating the catalytic mechanism of BphD toward biphenyl (model compound) were carried out. The following results are obtained:(1)Ser112-His265-Asp237is involved in wild BphD acylation process.(2) Only Ser112is involved in H265A mutant acylation process.(3) Three water molecules are found in the active pocket after HPD release, and one of which is involved in the deacylation process.(4) Previously reported roles of residue Phe175, Arg190, and Trp266in the rate-determining step of wild BphD are further elucidated by our computational results.(5) The electrostatic analysis reveal the significant roles of some unnoticed residues, such as Gly42, Metll3, Leu156, and Phe239, the results thus highlight new promising experimental targets in improving the catalytic efficiency of wild BphD.
4. Catalytic system of glutathione transferases
Malaria is a most severe insect transmitted disease with at least1.4million deaths per year. Organochlorine insecticide DDT plays a prominent role in controlling the population of malaria vector mosquitoes since1950s. However, resistance to DDT has developed in some mosquito species (e.g. Anopheles Gambiae), raising the threat of malaria to humans. A mechanistic understanding of the detoxifying of GSTs towards DDT is critically warranted to understand the impact of DDT resistance and to develop more effective novel insecticides. We investigated the detoxification reaction of agGSTe2towards DDT by using QM/MM method. The results reveal that the proton transfer mechanism is more feasible than the GS-DDT conjugation mechanism. On the basis of the structure of DDT, structure2,(BrC6H4)CHCCl3, is the best candidate among all the tested structures in resisting the detoxification of enzyme agGSTe2. Our work serves as a theoretical model for designing new insecticides in controlling insect transmitted disease malaria.
5. Catalytic system of fluoroacetate dehalogenase
The production and use of fluorochemicals brought great pressure to the environment, however, few enzymes are found to be able to degrade those fluorochemicals. An enzyme named fluoroacetate dehalogenase (FAcD) is capable of degrading fluoroacetate (FAc), which is wildly used as rodenticide in many countries. We investigated the catalytic mechanism of FAcD toward FAc by using QM/MM method to establish a pioneer model for studying the degradation mechanism of other fluorochemicals. The results also indicate that structural differences of His155(Hsd or Hse) influence the reaction barrier of C-F bond cleavage process and FAcD prefers Hse155when catalyzing FAc.
引文
[1]Smith, A. D.; Datta, S. P.; Smith, G. H.; Campbell, P. N.; Bentley, R.; McKenzie, H. A. Oxford dictionary of biochemistry and molecular biology. Oxford University Press.1977.
[2]吴梧桐等.生物化学.人民卫生出版社.2007.
[3]Bairoch, A. The ENZYME database in 2000. Nucleic. Acids. Res.2000,28 (1),304-305.
[4]Anfinsen, C. B. Principles that govern the folding of protein chains. Science 1973,181 (4096), 223-230.
[5]Fersht, A. Structure and Mechanism in protein science:A guide to enzyme catalysis and protein folding. Freeman:New York,1999.
[6]Kamerlin, S. C.; Warshel, A. At the dawn of the 21st century:Is dynamics the missing link for understanding enzyme catalysis? Proteins 2010,78 (6),1339-1375.
[7]Pu, J.; Gao, J.; Truhlar, D. G. Multidimensional tunneling, recrossing, and the transmission coefficient for enzymatic reactions. Chem. Rev.2006,106 (8),3140-3169.
[8]Garcia-Viloca, M.; Gao, J.; Karplus, M.; Truhlar, D. G. How enzymes work:analysis by modern rate theory and computer simulations. Science 2004,303 (5655),186-195.
[9]Pauling, L. Molecular architecture and biological reactions. Chem. Eng. News 1946,24 (10), 1375-1377.
[10]Schowen, R. L. In transition states of Biochemical processes, Plenum Press.1978.
[11]Benkovic, S. J.; Hammes-Schiffer, S. A Perspective on Enzyme Catalysis. Science 2003,301 (5637),1196-1202.
[12]Henzler-Wildman, K. A.; Thai, V.; Lei, M.; Ott, M.; Wolf-Watz, M.; Fenn, T.; Pozharski, E.; Wilson, M. A.; Petsko, G. A.; Karplus, M.; Hiibner, C. G.; Kern, D. Intrinsic motions along an enzymatic reaction trajectory. Nature 2007,450 (7171),838-844.
[13]Masgrau, L.; Roujeinikova, A.; Johannissen, L. O.; Hothi, P.; Basran, J.; Ranaghan, K. E.; Mulholland, A. J.; Sutcliffe, M. J.; Scrutton, N. S.; Leys, D. Atomic description of an enzyme reaction dominated by proton tunneling. Science 2006,312 (5771),237-241.
[14]Marti, S.; Roca, M.; Andres, J.; Moliner, V.; Silla, E.; Tunon, I.; Bertran, J. Theoretical insights in enzyme catalysis. Chem. Soc. Rev.2004,33 (2),98-107.
[15]Antoniou, D.; Basner, J.; Nunez, S.; Schwartz, S. D. Computational and theoretical methods to explore the relation between enzyme dynamics and catalysis. Chem. Rev.2006,106 (8), 3170-3187.
[16]Warshel, A.; Sharma, P. K.; Kato, M.; Xiang, Y; Liu, H.; Olsson, M. H. Electrostatic basis for enzyme catalysis. Chem. Rev.2006,706 (8),3210-3235.
[17]Lee, J. K.; Houk, K. N. A proficient enzyme revisited:the predicted mechanism for orotidine monophosphate decarboxylase. Science 1997,276 (5314),942-945.
[18]Wolfenden, R.; Snider, M. J. The depth of chemical time and the power of enzymes as catalysts. Acc. Chem. Res.2001,34 (12),938-45.
[19]Temerowski, M.; van der Staay, F. J. Absence of long-term behavioral effects after sub-chronic administration of low doses of methamidophos in male and female rats. Neurotoxicol. Teratol.2005,27 (2),279-297.
[20]Wang, Li.; Wen, Y.; Guo, X.; Wang, G.; Li, S.; Jiang, J. Degradation of methamidophos by Hyphomicrobium species MAP-1 and the biochemical degradation pathway. Biodegradation 2010, 21,513-523.
[21]Zheng, Y. L.; Liu, D. L.; Gao, Q.; Wang, W.; Shi, X. S. Isolation and characterization of a bacterium HS-A32 capable of degrading methamidophos. Chin. J. Appl. Environ. Biol.2006,12 (3),399-403.
[22]刘佳,殷立峰,代云容,江帆,牛军峰.电化学酶传感器在环境污染监测中的应用.化学进展 2012,24(1),131-143.
[23]韩莉,陶菡,张义明,石瑞丽.酶传感器的应用.传感器世界.2012,4,9-11.
[24]Jegannathan, K. R.; Nielsen, P. H. Environmental assessment of enzyme use in industrial production-a literature review. J. Clean. Prod.2013,42,228-240.
[25]Marchetti, L.; Levine, M. Biomimetic catalysis. ACS Catal.2011,1(9),1090-1118.
[26]Warshel, A.; Levitt, M.; Theoretical studies of enzymic reactions:dielectric, electrostatic and steric stabilization of the carbonium ion in the reaction of lysozyme. J. Mol. Biol.1976,103 (2), 227-249.
[27]Szinicz L. History of chemical and biological warfare agents. Toxicology.2005,214 (3), 167-181.
[28]Delfino, R. T.; Ribeiro, T. S.; Figueroa-Villar, J. D. Organophosphorus compounds as chemical warfare agents:a review. J. Braz. Chem. Soc.2009,20 (3),407-428.
[29]Newmark, J. The birth of nerve agent warfare; Lessons from Syed Abbas Foroutan. Neurology.2004,62 (9),1590-1596.
[30]Eubanks, L. M.; Dickerson, T. J.; Janda, K. D. Technological advancements for the detection of and protection against biological and chemical warfare agents. Chem. Soc. Rev.2007,36 (3), 458-470.
[31]Costa, L. G. Current issues in organophosphate toxicology. Clinica. Chim. Acta 2006,366 (1-2),1-13.
[32]Marrs, T. C. Organophosphate poisoning. Pharmacol. Therapeut.1993,58 (1),51-56.
[33]Marrs, T. C. Clinical and experimental toxicology of organophosphates and carbamates. Butterworth & Heinemann Oxford,1992.
(34)Sussman, J. L.; Harel, M.; Frolow, F.; Oefner, C.; Goldman, A.; Toker, L.; Silman, I. Atomic structure of acetylcholinesterase from Torpedo californica:a prototypic acetylcholine-binding protein. Science 1991,253 (5022),872-879.
[35]Kovarik, Z.; Radic, Z.; Berman, H. A.; Simeon-Rudolf, V.; Reiner, E.; Taylor, P. Acetylcholinesterase active centre and gorge conformations analysed by combinatorial mutations and enantiomeric phosphonates. Biochem. J.2003,373 (Pt 1),33-40.
[36]Gilson, M. K.; Straatsma, T. P.; McCammon, J. A.; Ripoll, D. R.; Faerman, C. H.; Axelsen, P. H.; Silman, I.; Sussman, J. L. Open "back door" in a molecular dynamics simulation of acetylcholinesterase. Science 1994,263 (5151),1276-1278.
[37]Liu, J.; Zhang, Y.; Zhan, C. G. Reaction pathway and free-energy barrier for reactivation of dimethylphosphoryl-inhibited human acetylcholinesterase. J. Phys. Chem. B 2009,113 (50), 16226-16236.
[38]Barak, D.; Ordentlich, A.; Kaplan, D.; Barak, R.; Mizrahi, D.; Kronman, C.; Segall, Y.; Velan, B.; Shafferman, A. Evidence for P-N Bond Scission in Phosphoroamidate Nerve Agent Adducts of Human Acetylcholinesterase. Biochemistry 2000,39(5),1156-1161.
[39]Carletti, E.; Li, H.; Li, B.; Ekstrom, F.; Nicolet, Y.; Loiodice, M.; Gillon, E.; Froment, M. T.; Lockridge, O.; Schopfer, L. M.; Masson, P.; Nachon, F. Aging of cholinesterases phosphylated by tabun proceeds through O-dealkylation. J. Am. Chem. Soc.2008,130 (47),16011-16020.
[40]鞠家本.农药残留监测案例.新农业,2010,7,41.
[41]张海燕,孙卓然,蒙成华,赖超.2010年-2012年呼和浩特市售蔬菜农药残留情况调查分析.中国卫生检验杂志,2013,23(9),2169-2172.
[42]黄智文,方双勇,李荣发,成珍.2012年曲靖市蔬菜中农药残留情况.职业与健康,2013,29(6),714-715.
[43]庞宏宇,王震,郭晓关,李俊.贵州省蔬菜中农药残留现状分析.耕作与裁培,2013,7,35-38.
[44]温雅君,闫建茹.蔬菜农药残留的危害性及超标原因分析.中国园艺文摘.2011,11, 153-154.
[45]洪文英,吴燕君,王道泽,谢国雄,周航,洪奎贤.乙酰甲胺磷及其高毒代谢物甲胺磷在白菜中的残留动态.农业环境科学学报,2011,30(5),860-866.
[46]Worek, F.; Thiermann, H.; Szinicz, L.; Eyer, P. Kinetic analysis of interactions between human acetylcholinesterase, structurally different organophosphorus compounds and oximes, Biochem. Pharmacol.2004,68 (11),2237-2248.
[47]Lin, K.; Zhou, S.; Xu, C.; Liu, W. Enantiomeric resolution and biotoxicity of methamidophos, J. Agric. Food Chem.2006,54 (21),8134-8138.
[48]Hornberg, A. Tunemalm, A. Ekstrom, F. Crystal structures of acetylcholinesterase in complex with organophosphorus compounds suggest that the acyl pocket modulates the aging reaction by precluding the formation of the trigonal bipyramidal transition state. Biochemistry 2007,46 (16), 4815-4825.
[49]Winkler, R.; Hertweck, C. Biosynthesis of nitro compounds. ChemBioChem.2007,8 (9), 973-977.
[50]Ju, K. S.; Parales, R. E. Nitroaromatic compounds, from synthesis to biodegradation. Microbio. Mol. Bio. Rev.2010,74 (2),250-272.
[51]van Berkel, W. J. H.; Kamerbeek, N. M.; Fraaije, M. W. Flavoprotein monooxygenases, a diverse class of oxidative biocatalysts. J. Biotechno.2006,124 (4) 670-689.
[52]Joosten, V.; van Berkel, W. J. H. Flavoenzymes, Curr. Opin. Chem. Biol.2007,11 (2), 195-202.
[53]Vey, J. L.; Mestarihi, A. A.; Hu, Y.; Funk, M. A.; Bachmann, B. O.; Iverson, T. M. Structure and mechanism of ORF36, an amino sugar oxidizing enzyme in everninomicin biosynthesis. Biochemistry 2010,49 (43),9306-9317.
[54]Seah, S. Y.; Ke, J.; Denis, G.; Horsman, G. P.; Fortin, P. D.; Whiting, C. J.; Eltis, L. D. Characterization of a C-C bond hydrolase from Sphingomonas wittichii RW1 with novel specificities towards polychlorinated biphenyl metabolites. J. Bacteriol.2007,189 (11), 4038-4045.
[55]Faroon, O. M.; Keith, L. S.; Smith-Simon, C.; De Rose, C. T. Polychlorinated Biphenyls: Human Health Aspects, World Health Organization, Geneva.2003.
[56]Agency for Toxic Substances and Disease Registry. Toxicological Profile for Polychlorinated Biphenyls (PCBs), U.S. Departmentof Human Health and Human Services, Atlanta, GA.2000.
[57]Horsman, G. P.; Ke, J.; Dai, S.; Seah, S. Y. K.; Bolin, J. T.; Eltis. L. D. Kinetic and structural insight into the mechanism of BphD, a C-C bond hydrolase from the biphenyl degradation pathway. Biochemistry 2006,45 (37),11071-11086
[58]Ruzzini, A. C.; Ghosh, S.; Horsman, G. P.; Foster, L. J.; Bolin, J. T.; Eltis. L. D. Identification of an acyl-enzyme intermediate in a meta-cleavage product hydrolase reveals the versatility of the catalytic triad. J. Am. Chem. Soc.2012,134 (10),4615-4624.
[59]Horsman, G. P. Bhowmik, S.; Seah, S. Y. K.; Kumar, P.; Bolin, J. T.; Eltis. L. D. The tautomeric half-reaction of BphD, a C-C bond hydrolase. J. Biol. Chem.2007,282 (27) 19894-19904.
[60]Ruzzini, A. C.; Bhowmik, S.; Ghosh, S.; Yam, K. C.; Bolin, J. T.; Eltis, L. D. A substrate-assisted mechanism of nucleophile activation in a Ser-His-Asp containing C-C bond hydrolase. Biochemistry.2013,52 (42),7428-7438.
[61]Ranson, H.; Prapanthadara, L.; Hemingway, J. Cloning and characterization of two glutathione S-transferases from a DDT-resistant strain of Anopheles gambiae. Biochem. J.1997, 324 (1),97-102.
[62]Ranson, H.; Rossiter, L.; Ortelli, F.; Jensen, B.; Wang, X.; Roth, C. W.; Collins, F. H.; Hemingway, J. Identification of a novel class of insect glutathione S-transferases involved in resistance to DDT in the malaria vector Anopheles gambiae. Biochem. J.2001,359 (2),295-304.
[62]Breman, J. G.; Alilio, M. S.; Mills, A. Conquering the intolerable burden of malaria:what's New, what's needed:a summary. Am. J. Trop. Med. Hyg.2004,71 (Suppl 2),1-15.
[63]Read, A. F.; Lynch, P. A.; Thomas, M. B. How to make evolution-proof insecticides for malaria control. PLoSBio.2009,7(4),1-10.
[64]Yadouleton, A. W.; Padonou, G.; Asidi, A.; Moiroux, N.; Bio-Banganna, S.; Corbel, V.; N'guessan, R.; Gbenou, D.; Yacoubou, I.; Gazard, K.; Akogbeto, M. C. Insecticide resistance status in Anopheles gambiae in southern Benin. Mala. J.2010,9 (83),1-6.
[65]David, J. P.; Strode, C.; Vontas, J.; Nikou, D.; Vaughan, A.; Pignatelli, P. M.; Louis, C.; Hemingway, J.; Ranson, H.; Beaty, B. J. The Anopheles gambiae detoxification chip:a highly specific microarray to study metabolic-based insecticide resistance in malaria vectors. Proc. Natl. Acad. Sci. USA 2005,102 (11),4080-4084.
[66]Ndiath, M. O.; Sougoufara, S.; Gaye, A.; Mazenot, C.; Konate, L.; Faye, O.; Sokhna, C.; Trape, J. F. Resistance to DDT and pyrethroids and increased kdr mutation frequency in An. gambiae after the implementation of permethrin-treated nets in senegal. PLoS ONE.2012,7 (2), 1-6.
[67]Hemingway, J.; Field, L.; Vontas, J. An overview of insecticide resistance. Science 2002,298 (5591),96-97.
[68]Prapanthadara, L. A.; Hemingway, J.; Ketterman, A. J. Partial purification and characterization of glutathione S-transferases involved in DDT resistance from the mosquito Anopheles gambiae. Pestic. Biochem. Physiol.1993,47(2),119-133.
[69]Boyland, E.; Chasseaud, L. F. The role of glutathione and glutathione S-transferases in mercapturic acid biosynthesis. Adv. Enzymol. Relat. Areas. Mol. Biol.1969,32,173-219.
[70]Lipke, H.; Chalkley, J.; The conversion of DDT to DDE by some anophelines. Bull. World Health Organ.1964,30,57-64.
[71]Hemingway, J.; Hawkes, N. J.; McCarroll, L.; Ranson, H. The molecular basis of insecticide resistance in mosquitoes. Insect Biochem. Mol. Biol.2004,34 (7),653-665.
[72]Wang, Y.; Qiu, L.; Ranson, H.; Lumjuan, N.; Hemingway, J.; Setzer, W. N.; Meehan, E. J.; Chen, L. Structure of an insect epsilon class glutathione S-transferase from the malaria vector Anopheles gambiae provides an explanation for the high DDT-detoxifying activity. J. Struct. Bio. 2008,164 (2),228-235.
[73]Muller, K.; Faeh, C.; Diederich, F. Fluorine in pharmaceuticals:looking beyond intuition. Science 2007,317 (5846),1881-1886.
[74]Douvris, C.; Ozerov, O. V. Hydrodefluorination of perfluoroalkyl groups using silylium-carborane catalysts. Science 2008,321 (5893),1188-1190.
[75]Houde, M.; Martin, J. W.; Letcher, R. J.; Solomon, K. R.; Muir, D. C. Biological monitoring of polyfluoroalkyl substances:a review. Environ. Sci. Technol.2006,40 (11),3463-3473.
[76]Kurihara, T.; Esaki, N. Bacterial hydrolytic dehalogenases and related enzymes:Occurrences, reaction mechanisms, and applications. Chem. Rec.2008,8 (2),67-74.
[77]Liu, J. Q.; Kurihara, T.; Ichiyama, S.; Miyagi, M.; Tsunasawa, S.; Kawasaki, H.; Soda, K.; Esaki, N. Reaction mechanism of fluoroacetate dehalogenase from Moraxella sp. B. J. Biol. Chem. 1998,273 (47),30897-30902.
[78]Proudfoot, A. T.; Bradberry, S. M.; Vale, J. A. Sodium fluoroacetate poisoning. Toxicol. Rev. 2006,25 (4),213-219.
[79]Chan, P. W. Y.; Yakunin, A. F.; Edwards, E. A.; Pai, E. F. Mapping the reaction coordinates of enzymatic defluorination. J. Am. Chem. Soc.2011,133 (19),7461-7468.
[80]Henzler-Wildman, K.; Kern, D. Dynamic personalities of proteins. Nature,2007,450 (7172), 964-972.
[81]Lonsdale, R.; Harvey, J. N.; Mulholland, A. J. A practical guide to modelling enzyme-catalysed reactions. Chem. Soc. Rev.2012,41 (8),3025-3038.
[82]van der Kamp, M. W.; Mulholland, A. J. Combined quantum mechanics/molecular mechanics (QM/MM) methods in computational enzymology. Biochemistry 2013,52 (16),2708-2728.
[83]Jorgensen, W. L. Foundations of biomolecular modeling. Cell 2013,155 (6),1199-1202.
[84]Adamczyk, A. J.; Cao, J.; Kamerlin, S. C. L.; Warshel, A. Catalysis by dihydrofolate reductase and other enzymes arises from electrostatic preorganization, not conformational motions. Proc. Natl. Acad. Sci. USA.2011,108 (34),14115-14120.
[85]Pisliakova, A. V.; Cao, J.; Kamerlin, S. C. L.; Warshel. A. Enzyme millisecond conformational dynamics do not catalyze the chemical step. Proc. Natl. Acad. Sci. USA 2009,106 (41),17359-17364.
[86]Rosta, E.; Klalhn, M.; Warshel. A. Towards accurate ab initio QM/MM calculations of free-energy profiles of enzymatic Reactions. J. Phys. Chem. B 2006,110 (6),2934-2941.
[87]Hohenberg, P.; Kohn, W. Inhomogeneous electron gas. Phys. Rev.1964,136, B864-B871.
[88]Kohn, W.; Sham, L. J. Self-consistent equations including exchange and correlation effects. Phys. Rev.1965,140, (4A) A1133-A1138.
[89]Parr, R. G; Yang, W. Density-functional theory of atoms and molecules. Oxford:Oxford University Press.1994.
[90]Perdew, J. P.; Yue, W. Accurate and simple density function for the electronic exchange energy:generalized gradient approximation. Phys. Res. B 1986,33,8800-8802.
[91]Becke, A. D. Density functional calculations of molecular bond energies, J. Chem. Phys, 1986,84,4524-4529.
[92]Becke, A. D. Density-functional thermochemistry. Ⅲ. The role of exact exchange. J. Chem. Phys.1993,98,5648-5652.
[93]MacKerell, A. D.; Bashford, D.; Bellott, M.; Dunbrack, R. L.; Evanseck, J. D.; Field, M. J.; Fischer, S.; Gao, J.; Guo, H.; Ha, S.; Joseph-McCarthy, D.; Kuchnir, L.; Kuczera, K.; Lau, F. T. K.; Mattos, C.; Michnick, S.; Ngo, T.; Nguyen, D. T.; Prodhom, B.; Reiher, W. E.; Roux, B.; Schlenkrich, M.; Smith, J. C.; Stote, R.; Straub, J.; Watanabe, M.; Wiorkiewicz-Kuczera, J.; Yin, D.; Karplus, M. All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins. J. Phys. Chem. B 1998,102 (18),3586-3616.
[94]Cornell, W. D.; Cieplak, P.; Bayly, C. I.; Gould, I. R.; Merz, Jr. K. M.; Ferguson, D. M.; Spellmeyer, D. C.; Fox, T. Caldwell, J. W.; Kollman, P. A. A second generation force field for the simulation of proteins, nucleic acids, and organic molecules. J. Am. Chem. Soc.1995,117 (19), 5179-5197.
[95]Jorgensen, W. L.; Tirado-Rives, J. The OPLS force field for proteins. Energy minimizations for crystals of cyclic peptides and crambin. J. Am. Chem. Soc.1988,110 (6),1657-1666.
[96]Car, R.; Parrinello, M. Unified approach for molecular dynamics and density-functional theory. Phys. Rev. Lett.1985,55,2471-2474.
[97]Warshel, A.; Karplus, M. Calculation of ground and excited state potential surfaces of conjugated molecules. I. Formulation and parametrization. J. Am. Chem. Soc.1972,94 (16), 5612-5625.
[98]Warshel, A.; Levitt, M. Theoretical studies of enzymic reactions:dielectric, electrostatic and steric stabilization of the carbonium ion in the reaction of lysozyme. J. Mol. Biol.1976,103 (2), 227-249.
[99]Senn, H. M.; Thiel. W. QM/MM methods for biological systems. Top. Curr. Chem.2007,268, 173-290.
[100]Das, D.; Eurenius, K. P.; Billings, E. M.; Sherwood, P.; Chatfield, D. C.; Hodoscek, M.; Brooks, B. R. Optimization of quantum mechanical molecular mechanical partitioning schemes: Gaussian delocalization of molecular mechanical charges and the double link atom method. J. Chem. Phys.2002,117(23),10534.
[101]Sherwood, P.; Vries A. H. D.; Guest, M. F.; Schreckenbach, G.; Catlow, C. R. A.; French, S. A.; Sokol, A. A.; Bromley, S. T.; Thiel, W., Turner; A. J.; Billeter, S.; Terstegen, F.; Thiel, S.; Kendrick, J.; Rogers, S. C.; Casci, J.; Watson, M.; King, F.; Karlsen, E.; Sjovollf, M.; Fahmi, A.; Schafer, A.; Lennartz, C. QUASI:A general purpose implementation of the QM/MM approach and its application to problems in catalysis. J. Mol. Struc-Theochem.2003,632 (1-3),1-28.
[102]Ahlrichs, R.; Bar, M.; Haser, M.; Horn, H.; Kolmel, C. Electronic structure calculations on workstation computers:the program system turbomole. Chem. Phys. Lett.1989,162 (3),165-169.
[103]Smith, W.; Forester, T. R.; DL-POLY-2.0:A general-purpose parallel molecular dynamics simulation package. J. Mol.Graph.1996,14(3),136-141.
[104]Munro, N. Toxicity of the Organophosphate Chemical Warfare Agents GA, GB, and VX: Implications for Public Protection. Environ. Health. Perspect.1994,102 (1),18-37.
[105]Worek, F.; Aurbek, N.; Koller, M.; Becker, C.; Eyer, P.; Thiermann, H. Kinetic analysis of reactivation and aging of human acetylcholinesterase inhibited by different phosphoramidates. Biochem. Pharmacol.2007,73 (11),1807-1817.
[106]Masson, P; Nachon, F.; Lockridge, O. Structural approach to the aging of phosphylated cholinesterases. Chem. Biol. Interact.2010,187(1-3),157-162.
[107]Marti-Renom, M. A.; Stuart, A. C.; Fiser, A.; Sanchez, R.; Melo, F.; Sali, A. Comparative protein structure modeling of genes and genomes. Annu. Rev. Biophys. Biomol. Struct.2000,29 (1):291-325.
[108]Brooks, B. R.; Bruccoleri, R. E.; Olafson, B. D.; States, D. J.; Swaminathan, S.; Karplus, M. CHLARMM:A program for macromolecular energy, minimization, and dynamics calculations. J. Comput. Chem.1983,4 (2),187-217.
[109]Morris, G. M.; Goodsell, D. S.; Halliday, R. S.; Huey, R.; Hart, W. E.; Belew, R. K.; Olson, A. J. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J. Comput. Chem.1998,19(14),1539-1562.
[110]Ewing, T. J.; Makino, S.; Skillman, A. G.; Kuntz, I. D. DOCK 4.0:search strategies for automated molecular docking of flexible molecule databases. J. Comput. Aided. Mol.Des.2001, 15 (5),411-428.
[111]Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, M. L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys.1983,79 (2),926-935.
[112]Berkowitz, M.; McCammon, J. A. Molecular dynamics with stochastic boundary conditions. Chem. Phys. Lett.1982,90 (3),215-217.
[113]Brooks, C. L.; Karplus, M. Deformable stochastic boundaries in molecular dynamics. J. Chem. Phys.1983,79(12),6312-6325.
[114]de Vries, A. H.; Sherwood, P.; Collins, S. J.; Rigby, A. M.; Rigutto, M.; Kramer, G. J. Zeolite structure and reactivity by combined quantum-chemical-classical calculations. J. Phys. Chem. B 1999,103 (29),6133-6141.
[115]Tian, B.; Strid, A.; Eriksson, L. A. Catalytic roles of active-site residues in 2-methyl-3-hydroxypyridine-5-carboxylic acid oxygenase:an ONIOM/DFT study. J Phys Chem B 2011,775(8),1918-1926.
[116]Wang, J.; Gu, J.; Leszczynski, J. Theoretical modeling study for the phosphonylation mechanisms of the catalytic triad of acetylcholinesterase by sarin. J Phys Chem B 2008,112 (11), 3485-3494.
[117]Li, H.; Robertson, A. D.; Jensen, J. H. Very fast empirical prediction and rationalization of protein pKa values. Proteins 2005,61 (4),704-721.
[118]Zhang, Y.; Zhan, C. Reaction pathway and free-energy barrier for reactivation of dimethylphosphoryl-inhibited human acetylcholinesterase, J. Phys. Chem. B 2009,113 (50), 16226-16236.
[119]Jones, R. N.; Hare, R. S.; Sabatelli, F. J. In vitro Grampositive antimicrobial activity of evernimicin (SCH 27899), a novel oligosaccharide, compared with other antimicrobials:A multicentre international trial. J. Antimicrob. Chemother.2001,47(1),15-25.
[120]Terakubo, S.; Takemura, H.; Yamamoto, H.; Ikejima, H.; Kunishima, H.; Kanemitsu, K.; Kaku, M.; Shimada, J. Antimicrobial activity of everninomicin against clinical isolates of Enterococcus spp., Staphylococcus spp., and Streptococcus spp. tested by Etest. J. Infect. Chemother.2001,7 (4),263-266.
[121]Jorge, R.; Josep, A.; Antoni, V.; Jordi, R. New developments in therapeutic agents for Legionnaires'disease. Anti-Infective Agents in Medic.2007,6 (4),228-242.
[122]Poulet, F. M.; Veneziale, R.; Vancutsem, P. M.; Losco, P.; Treinen, K.; Morrissey, R. E. Ziracin-induced congenital urogenital malformations in female rats, Toxicol. Pathol.2005,33 (3), 320-328.
[123]Nakashio, S.; Iwasawa, H.; Dun, F.Y.; Kanemitsu, K.; Shimada, J. Everninomicin, a new oligosaccharide antibiotic:its antimicrobial activity, post-antibiotic effect and synergistic bactericidal activity. Drugs. Exp. Clin. Res.1995,21 (1),7-16.
[124]Ganguly, A. K.; Girijavallabhan, V. M.; Miller, G. H.; Sarre, O. Z. Chemical modification of everninomicins. J. Antibiot.1982,35 (5),561-570.
[125]Dodson, G.; Wlodawer, A. Catalytic triads and their relatives. Trends. Biochem. Sci.1998, 23 (9),347-52.
[126]Hedstrom, L. Serine protease mechanism and specificity. Chem. Rev.2002,102 (12), 4501-4523.
[127]Brooks, B. R.; Bruccoleri, R. E.; Olafson, B. D.; States, D. J.; Swaminathan, S.; Karplus, M. CHARMM:A program for macromolecular energy, minimization, and dynamics calculations, J. Comput. Chem.1983,4 (2),187-217.
[128]Brooks, B. R.; Brooks Ⅲ, C. L.; Mackerell, A. D.; Nilsson, L.; Petrella, R. J.; Roux, B.; Won, Y.; Archontis, G.; Bartels, C.; Boresch, S.; Caflisch, A.; Caves, L.; Cui, Q.; Dinner, A. R.; Feig, M.; Fischer, S.; Gao, J.; Hodoscek, M.; Im, W.; Kuczera, K.; Lazaridis, T.; Ma, J.; Ovchinnikov, V.; Paci, E.; Pastor, R. W.; Post, C. B.; Pu, J. Z.; Schaefer, M.; Tidor, B.; Venable, R. M.; Woodcock, H. L.; Wu, X.; Yang, W.; York, D. M.; Karplus, M. CHARMM:The Biomolecular simulation Program. J. Comp. Chem.2009,30(10),1545-1615.
[129]MacKerell, Jr, A. D.; Brooks, B.; Brooks, Ⅲ, C.L.; Nilsson, L.; Roux, B.; Won, Y; Karplus, M. CHARMM:The energy function and its parameterization with an overview of the program, Encyclopedia of Computational Chemistry 1998,1,271-277.
[130]Bakowies, D.; Thiel, W. J. Hybrid models for combined quantum mechanical and molecular mechanical approaches. Phys. Chem.1996,100 (25),10580-10594.
[131]Roca, M.; Messer, B.; Hilvert, D.; Warshel, A. On the relationship between folding and chemical landscapes in enzyme catalysis. Proc. Natl. Acad. Sci. USA 2008,105 (37), 13877-13882.
[132]Li, J.; Li, C.; Blindauer, C. A.; Bugg. T. D. H. Evidence for a gem-diol reaction intermediate in bacterial C-C hydrolase enzymes BphD and MhpC from 13C NMR Spectroscopy. Biochemistry 2006,45(41),12461-12469.
[133]Armstrong, R. N. Glutathione S-Transferases:reaction mechanism, structure, and function. Chem. Res. Toxicol.1991,4 (2),131-140.
[134]Ali-Osman, F.; Akande, O.; Antoun, G.; Mao, J.; Buolamwini, J. Molecular cloning, characterization, and expression in Escherichia coli of full-length cDNAs of three human glutathione S-transferase Pi gene variants. Evidence for differential catalytic activity of the encoded proteins. J. Biol. Chem.1997,272 (15),10004-10012.
[135]Batist, G.; Tulpule, A.; Sinha, B. K.; Katki, A. G.; Myers, C. E.; Cowan, K. H. Overexpression of a novel anionic glutathione transferase in multidrug-resistant human breast cancer cells. J. Biol. Chem.1986,261 (33),15544-15549.
[136]Meyer, D. J.; Coles, B.; Pemble, S. E.; Gilmore, K. S.; Fraser, G. M.; Ketterer, B. Theta, a new class of glutathione transferases purified from rat and man. Biochem. J.1991,274 (2), 409-414.
[137]Sinning, I.; Kleywegt, G. J.; Cowan, S. W.; Reinemer, P.; Dirr, H. W.; Huber, R.; Gilliland, G. L.; Armstrong, R. N.; Ji, X.; Board, P. G. Structure determination and refinement of human alpha class glutathione transferase A1-1, and a comparison with the Mu and Pi class enzymes. J. Mol. Biol.1993,232(1),192-212.
[138]Edwards, R.; Dixon, D. P.; Walbot, V. Plant glutathione S-transferases:enzymes with multiple functions in sickness and in health. Trends Plant Sci.2000,5 (5),193-198.
[139]Dourado, D.F., Fernandes, P. A., Ramos, M. J. Mammalian cytosolic glutathione transferases. Curr. Protein Pept. Sci.2008,9 (4),325-337.
[140]Satoh, K.; Kitahara, A.; Soma, Y.; Inaba, Y.; Hatayama, I.; Sato,K. Purification, induction, and distribution of placental glutathione transferase:a new marker enzyme for preneoplastic cells in the rat chemical hepatocarcinogenesis. Proc. Natl. Acad. Sci. U.S.A.1985,82 (12),3964-3968.
[141]Dirr, H.; Reinemer, P.; Huber, R. X-ray crystal structures of cytosolic glutathione S-transferases. Implications for protein architecture, substrate recognition and catalytic function. Eur. J. Biochem.1994,220 (3),645-61.
[142]Mannervik, B.; Alin, P.; Guthenberg, C.; Jensson, H.; Tahir, M. K.; Warholm, M.; Jornvall, H. Identification of three classes of cytosolic glutathione transferase common to several mammalian species:correlation between structural data and enzymatic properties. Proc. Natl. Acad. Sci. U.S.A.1985,82 (21),7202-7206.
[143]Widersten, M.; Bjornestedt, R.; Mannervik, B. Involvement of the carboxyl groups of glutathione in the catalytic mechanism of human glutathione transferase A1-1. Biochemistry 1996, 35 (24),7731-7742.
[144]Adler V.; Yin, Z.; Fuchs, S. Y; Benezra, M.; Rosario, L.; Tew, K. D.; Pincus, M. R.; Sardana, M.; Henderson, C. J.; Wolf, C. R.; Davis, R. J.; Ronai, Z. Regulation of JNK signaling by GSTp. EMBO J.1999,18 (5),1321-1334.
[145]Koonin, E. V.; Mushegian, A. R.; Tatusov, R. L.; Altschul, S. F.; Bryant, S. H.; Bork, P.; Valencia, A. Eukaryotic translation elongation factor 1 gamma contains a glutathione transferase domain-study of a diverse, ancient protein superfamily using motif search and structural modeling. Protein Sci.1994,3 (11),2045-2054.
[146]Danielson, U. H.; Esterbauer, H.; Mannervik, B. Structure-activity relationships of 4-hydroxyalkenals in the conjugation catalysed by mammalian glutathione transferases. Biochem. J.1981,247 (3),707-713.
[147]Robertson, I. G.; Guthenberg, C.; Mannervik, B.; Jernstrom, B. Differences in stereoselectivity and catalytic efficiency of three human glutathione transferases in the conjugation of glutathione with 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene. Cancer. Res.1986,46(5),2220-2224.
[148]Booth, J.; Boyland, E.; Sims, P. An enzyme from rat liver catalyzing conjugations with glutathione. Biochem. J.1961,19 (3),516-524.
[149]Habig, W. H.; Pabst, M. J.; Jakoby, W. B.; Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. J. Biol. Chem.1974,249 (22),7130-7139.
[150]Aniya, Y.; Naito, A. Oxidative stress-induced activation of microsomal glutathione S-transferase in isolated rat liver. Biochem. Pharmacol.1993,45 (1),37-42.
[151]Hayes, J. D.; Pulford, D. J. The glutathione S-transferase supergene family:regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit. Rev. Biochem. Mol. Biol.1995,30 (6),445-600.
[152]Raza, H.; Robin, M. A.; Fang, J. K.; Avadhani, N. G. Multiple isoforms of mitochondrial glutathione S-transferases and their differential induction under oxidative stress. Biochem. J.2002, 366(1),45-55.
[153]Boyland,E.；Chasseaud,L.F. The role of glutathione and glutathione S-transferases in mercapturic acid biosynthesis.Adv.Enzymo.Relat.Areas.Mol.Biol.1969,32,173-219.
[154]Johansson,A.S.；Mannervik,B.Human glutathione transferase A3-3,a highly efficient catalyst of double-bond isomerization in the biosynthetic pathway of steroid hormones.J.Biol. Chem.2001,276(35),33061-33065.
[155]Huang,H.S.；Hu,N.T.；Yao,Y.E.；Wu,C.Y；Chiang,S.W.；Sun,C.N.；c expression of a glutathione S-transferase involved in insecticide resistance from the diamondback moth Plutella xylostella.Insect Biochem.Mol.Biol.1998,28(9),651-658.
[156]Holt,R.A.；Subramanian,G.M.；Halpern,A.；Sutton,G.G.；Charlab,R.；Nusskern,D.R.； Wincker,P.；Clark,A.G.；Ribeiro,J.M.；Wides,R.；Salzberg,S.L.；Loftus,B.；Yandell,M.； Majoros,W.H.；Rusch,D.B.；Lai,Z.；Kraft,C.L.；Abril,J.F.Anthouard,V.；Arensburger,P.； Atkinson,P.W.；Baden,H.；de Berardinis,V.；Baldwin,D.；Benes,V；Biedler,J.；Blass,C.； Bolanos,R.；Boscus,D.；Barnstead,M.；Cai,S.；Center,A.；Chaturverdi,K.；Christophides,G.K.； Chrystal,M.A.；Clamp,M.；Cravchik,A.；Curwen,V.；Dana,A.；Delcher,A.；Dew,I.；Evans,C. A.；Flanigan,M.；Grundschober-Freimoser,A.；Friedli,L.；Gu,Z.；Guan,P.；Guigo,R.； Hillenmeyer,M.E.；Hladun,S.L.；Hogan,J.R.；Hong,Y.S.；Hoover,J.；Jaillon,O.；Ke,Z.； Kodira,C.；Kokoza,E.；Koutsos,A.；Letunic,I.；Levitsky,A.；Liang,Y；Lin,J.J.；Lobo,N.F.； Lopez,J.R.；Malek,J.A.；McIntosh,T.C.；Meister,S.；Miller,J.；Mobarry,C.；Mongin,E.； Murphy,S.D.；O'Brochta,D.A.；Pfannkoch,C.；Qi,R.；Regier,M.A.；Remington,K.；Shao,H.； Sharakhova,M.V:；Sitter,C.D.；Shetty,J.；Smith,T. J.；Strong,R.；Sun,J.；Thomasova,D.；Ton, L.Q.；Topalis,P.；Tu,Z.；Unger,M.F.；Walenz,B.；Wang,A.；Wang,J.；Wang,M.；Wang,X.； Woodford,K.J.；Wortman,J.R.；Wu,M.；Yao,A.；Zdobnov,E.M.；Zhang,H.；Zhao,Q.；Zhao,S.； Zhu,S.C.；Zhimulev,I.；Coluzzi,M,；della Torre,A.；Roth,C.W.；Louis,C.；Kalush,F.；Mural, R.J.；Myers,E.W.；Adams,M.D.；Smith,H.O.；Broder,S.；Gardner,M.J.Fraser,C.M.；Birney, E.；Bork,P.；Brey,P.T.；Venter,J.C.；Weissenbach,J.；Kafatos,F.C.；Collins,F.H.；Hoffman,S. L.The genome sequence of the malaria mosquit Anopheles gambiae.Science 2002,298(5591), 129-149.
[157]Ding,Y. C；Ortelli,F；Rossiter,L.C；Hemingway,J；Ranson,H.The Anopheles gambiae glutathione transferase supergene family:annotation,phylogeny and expression profiles.BMC Genomics 2003,4(35),1-16.
[158]Ranson,H.；Paton,M.G.；Jensen,B.；McCarroll,L.；Vaughan,A.；Hogan,J.R.；Hemingway, J.；Collins,F.H.Genetic mapping of genes conferring permethrin resistance in the malaria vector, Anophelesg.Insect Mol.Biol.2004,13(4),379-386.
[159]Ranson, H.; Prapanthadara, L.; Hemingway, J. Cloning and characterization of two glutathione S-transferases from a DDT-resistant strain of Anopheles gambiae. Biochem. J.1997, 324 (1),97-102.
[160]Ortelli, F.; Rossiter, L. C.; Vontas, J.; Ranson, H.; Hemingway, J. Heterologous expression of four glutathione transferase genes genetically linked to a major insecticide-resistance locus from the malaria vector Anopheles gambiae. Biochem. J.2003,373 (3),957-963.
[161]Adang, A. E.; Brussee, J.; van der Gen, A.; Mulder, G. J. The glutathione-binding site in glutathione S-transferases. Investigation of the cysteinyl, glycyl and gamma-glutamyl domains. Biochem. J.1990,269 (1),47-54.
[162]Dourado, D. F. A. R.; Fernandes, P. A.; Ramos, M. J. Glutathione transferase A1-1:catalytic role of water. Theor. Chem. Acc.2009,124 (1-2),71-83.
[163]Dourado, D. F. A. R.; Fernandes, P. A.; Mannervik, B.; Ramos, M. J. Glutathione transferase: new model for glutathione activation. Chem. Eur. J.2008,14 (31),9591-9598.
[164]Dourado, D. F. A. R.; Fernandes, P. A.; Mannervik, B.; Ramos, M. J. Glutathione transferase A1-1:catalytic importance of arginine 15. J. Phys. Chem. B 2010,114 (4),1690-1697.
[165]Dourado, D. F. A. R.; Fernandes, P. A.; Ramos, M. J. Glutathione transferase classes alpha, pi, and mu:GSH activation mechanism.J. Phys. Chem. B 2010,114 (40),12972-12980.
[166]Dourado, D. F. A. R.; Fernandes, P. A.; Ramos, M. J.; Mannervik, B. Mechanism of glutathione transferase P1-1-catalyzed activation of the prodrug canfosfamide (TLK286, TELCYTA). Biochemistry 2013,52 (45),8069-8078.
[167]Baker, J. An algorithm for the location of transition states. J. Comput. Chem.1986,7 (4), 385-395.
[168]Liu, D. C.; Nocedal, J. On the limited memory BFGS method for large scale optimization. Math. Program.1989,45 (3),503-528.
[169]Lonsdale, R. Harvey, J. N.; Mulholland, A. J. Compound I reactivity defines alkene oxidation selectivity in cytochrome P450cam. J. Phys. Chem. B 2010,114 (2),1156-1162.
[170]Rommel, J. B.; Kastner, J. The fragmentation-recombination mechanism of the enzyme glutamate mutase studied by QM/MM simulations. J. Am. Chem. Soc.2011,133 (26), 10195-10203.
[171]Prapanthadara, L.; Hemingway, J.; Ketterman, A. J. DDT-resistance in Anopheles gambiae (Diptera:Culicidae) from Zanzibar, Tanzania, based on increased DDT-dehydrochlorinase activity of glutathione S-transferases. B. Entomol. Res.1995,85 (2),267-274.
[172]Wongtrakul, J.; Pongjaroenkit, S.; Leelapat, P.; Nachaiwieng, W.; Prapanthadara, L. A.; Ketterman, A. J. Expression and characterization of three new glutathione transferases, an epsilon (AcGSTE2-2), omega (AcGSTOl-1), and theta (AcGSTTl-1) from Anopheles cracens (Diptera: Culicidae), a major Thai malaria vector. J. Med. Entomol.2010,47 (2),162-171.
[174]Goldman, P. The Carbon-Fluorine Bond in Compounds of Biological Interest. Science 1969, 164(3884),1123-1130.
[175]Smart, B. E. Fluorine substituent effects (on bioactivity). J. Fluor. Chem.2001,109 (1), 3-11.
[176]Ritter, S. K. Fluorochemicals go short. Chem. Eng. News 2010,88 (5),12-17.