Glutathione Adduct Patterns of Michael-Acceptor Carbonyls

Christian Slawik; Christiane Rickmeyer; Martin Brehm; Alexander Böhme; Gerrit Schuiirmann

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Glutathione Adduct Patterns of Michael-Acceptor Carbonyls

机译：迈克尔受体羰基的谷胱甘肽加合物模式

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Glutathione (GSH) has so far been considered to facilitate detoxification of soft organic electrophiles through covalent binding at its cysteine (Cys) thiol group, followed by stepwise catalyzed degradation and eventual elimination along the mercapturic acid pathway. Here we show that in contrast to expectation from HSAB theory, Michael-acceptor ketones, aldehydes and esters may form also single, double and triple adducts with GSH involving β-carbon attack at the much harder N-terminus of the γ-glutamyl (Glu) unit of GSH. In particular, formation of the GSH-N single adduct contradicts the traditional view that S alkylation always forms the initial reaction of GSH with Michael-acceptor carbonyls. To this end, chemoassay analyses of the adduct formation of GSH with nine α,β-unsaturated carbonyls employing high performance liquid chromatography and tandem mass spectrometry have been performed. Besides enriching the GSH adductome and potential biomarker applications, electrophilic N-terminus functionalization is likely to impair GSH homeostasis substantially through blocking the γ-glutamyl transferase catalysis of the first breakdown step of modified GSH, and thus its timely reconstitution. The discussion includes a comparison with cyclic adducts of GSH and furan metabolites as reported in literature, and quantum chemically calculated thermodynamics of hard-hard, hard-soft, and soft-soft adducts.

机译：迄今为止，谷胱甘肽（GSH）被认为通过在其半胱氨酸（Cys）硫醇基团上共价结合，促进软有机亲电子试剂的解毒，然后逐步催化降解并最终沿着巯基酸途径消除。在这里，我们证明，与HSAB理论的预期相反，迈克尔受体酮，醛和酯也可能与GSH形成单，双和三价加合物，其中GSH在较难的γ-谷氨酰胺N端（Glu ）的GSH单位。特别是，GSH-N单一加合物的形成与传统观点相矛盾，传统观点认为S烷基化始终形成GSH与Michael受体羰基的初始反应。为此，已经使用高效液相色谱和串联质谱法对九种α，β-不饱和羰基与GSH形成加合物进行了化学分析。除了丰富GSH加合物和潜在的生物标志物应用外，亲电子N端功能化还可能通过阻止γ-谷氨酰转移酶催化修饰的GSH的第一步降解，从而实质性地破坏GSH的稳态，从而及时地重构。讨论内容包括与文献报道的GSH和呋喃代谢物的环状加合物进行比较，以及硬-硬，硬-软和软-软加合物的量子化学计算热力学。

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《Environmental Science & Technology》 |2017年第7期|4018-4026|共9页
作者
Christian Slawik; Christiane Rickmeyer; Martin Brehm; Alexander Böhme; Gerrit Schuiirmann;
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UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research, Permoserstraße 15, 04318 Leipzig, Germany,Institute for Organic Chemistry, Technical University Bergakademie Freiberg, Leipziger Straße 29, 09596 Freiberg, Germany;

UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research, Permoserstraße 15, 04318 Leipzig, Germany;

UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research, Permoserstraße 15, 04318 Leipzig, Germany;

UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research, Permoserstraße 15, 04318 Leipzig, Germany;

UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research, Permoserstraße 15, 04318 Leipzig, Germany,Institute for Organic Chemistry, Technical University Bergakademie Freiberg, Leipziger Straße 29, 09596 Freiberg, Germany;

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1. Temporal patterns of DNA adduct formation and glutathione S-transferase activity in the testes of rats fed aflatoxin B1: a comparison with patterns in the liver. [J] . Sotomayor RE, Sahu S, Washington M, Environmental and molecular mutagenesis. . 1999,第4期

机译：用黄曲霉毒素B1喂养的大鼠睾丸中DNA加合物形成和谷胱甘肽S-转移酶活性的时间变化：与肝脏中的变化比较。
2. Carbonyl cyanide phenylhydrazones as probes of the anionic activator site of the human erythrocyte glutathione adduct transport ATPase [J] . DeLuca DC, Hinds T, Winter CG Archives of Biochemistry and Biophysics . 1997,第1期

机译：羰基氰化物苯hydr类化合物作为人类红细胞谷胱甘肽加合物的阴离子活化剂位点的探针运输ATP酶
3. Reactivities of carbonyl-activated angular and vinyl chlorine substituents in chloranyl-cyclopentadiene adduct toward nucleophiles. Synthesis of new 1,4-benzoquinones containing an unusual ortho pattern of substitution. [J] . Di Vitta C., Marzorati L., Wladislaw B. Synthetic Communications . 2000,第18期

机译：呋喃基-环戊二烯加合物中的羰基活化的角和乙烯基氯取代基对亲核试剂的反应性。包含不寻常邻位取代的新1,4-苯醌的合成。
4. Development of a Higher-throughput Metabolic Soft Spot Assay with Integrated Assessment of Glutathione Adduct Formation [C] . Anthony Paiva, Wilson Shou, Cheryl Klakouski, ASMS Conference on Mass Spectrometry and Allied Topics . 2016

机译：通过含有谷胱甘肽加合物形成的综合评估，开发较高通量的代谢软点测定
5. Co-exposure of arsenite and benzo[a]pyrene: Effect of glutathione on DNA adduct levels. [D] . Vietas, Jay A. 2005

机译：砷和苯并[a]的共同暴露：谷胱甘肽对DNA加合物水平的影响。
6. The Roles of Glutathione Glutathione Peroxidase Glutathione Reductase and the Carbonyl Protein in Pulmonary and Extra Pulmonary Tuberculosis [O] . Shubhangi M. Dalvi, Vinayak W. Patil, Nagsen N. Ramraje 2012

机译：谷胱甘肽谷胱甘肽过氧化物酶谷胱甘肽还原酶和羰基蛋白在肺结核和肺外结核中的作用
7. Metabotropic glutamate receptor 3 neuroprotection A. Berent-Spillson and J. W. Russell Received June 12, 2006; revised manuscript received October 3, 2006; accepted October 5, 2006. Address correspondence and reprint requests to James W. Russell, Department of Neurology, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD 21201-1595, USA. E-mail: jruss@umich.edu Abbreviations used : APDC , 2 R ,4 R -4-aminopyrrolidine-2,4-dicarboxylate (specific metabotropic glutamate receptor 3 agonist) ; BSO , buthionine sulfoximine (GSH synthesis inhibitor) ; caspase , cysteine-requiring aspartate protease ; CysGly , cysteinylglycine (GSH degradation product) ; DAPI , 4′-6-diamidino-2-phenylindole ; DCF , dichlorodihydrofluorescein ; DCFDA , 5-(and 6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate, acetyl ester ; DHE , dihydroethidium ; DRG , dorsal root ganglion ; FCCP , carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (electron transport uncoupler) ; GCP II/III , glutamate carboxypeptidase II/III ; GSH , glutathione ; GSH-EE , glutathione ethyl ester ; GST , glutathione-s-transferase ; H 2 O 2 , hydrogen peroxide ; HBSS , Hank’s balanced salt solution ; JC-1 , 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide ; MCB , monochlorobimane ; mGluR , metabotropic glutamate receptor ; NAAG , N -acetyl-aspartyl-glutamate ; PBS , phosphate-buffered saline ; PCD , programmed cell death ; Rh123 , rhodamine123 ; ROS , reactive oxygen species ; δψ μ , inner mitochondrial membrane potential . Metabotropic glutamate receptor 3 protects neurons from glucose-induced oxidative injury by increasing intracellular glutathione concentration [O] . Berent-Spillson Alison, Russell James W. 2007

机译：代谢型谷氨酸受体3神经保护a. Berent-spillson和J. W. Russell于2006年6月12日收到;修订稿于2006年10月3日收到; 2006年10月5日接受。美国马里兰州巴尔的摩市南格林街22号，马里兰大学医学院神经病学系James W. Russell的地址通信和重印申请。电子邮件：jruss@umich.edu使用的缩写：apDC，2R，4R-4-氨基吡咯烷-2,4-二羧酸酯（特异性代谢型谷氨酸受体3激动剂）; BsO，丁硫氨酸亚砜亚胺（GsH合成抑制剂）;半胱天冬酶，半胱氨酸需要的天冬氨酸蛋白酶; CysGly，半胱氨酰甘氨酸（GsH降解产物）; DapI，4'-6-二脒基-2-苯基吲哚; DCF，二氯二氢荧光素; DCFDa，5-（和6） - 氯甲基-2'，7'-二氯二氢荧光素二乙酸酯，乙酰酯; DHE，二氢乙锭; DRG，背根神经节; FCCp，羰基氰化物4-（三氟甲氧基）苯腙（电子传输解偶联剂）; GCp II / III，谷氨酸羧肽酶II / III;谷胱甘肽;谷胱甘肽; GsH-EE，谷胱甘肽乙酯; GsT，谷胱甘肽-s-转移酶; H 2 O 2，过氧化氢; HBss，Hank的平衡盐溶液; JC-1,5,5'，6,6'-四氯-1,1'，3,3'-四乙基苯并咪唑基酞菁碘化物; mCB，monochlorobimane; mGluR，代谢型谷氨酸受体; NaaG，N-乙酰基 - 天冬氨酰谷氨酸; pBs，磷酸盐缓冲盐水; pCD，程序性细胞死亡; Rh123，罗丹明123;活性氧，活性氧; δψμ，线粒体内膜电位。代谢型谷氨酸受体3通过增加细胞内谷胱甘肽浓度来保护神经元免受葡萄糖诱导的氧化损伤
8. Flash kinetics in liquefied noble gases: Studies of alkane activation and liganddynamics at rhodium carbonyl centers, and a search for xenon-carbene adducts [R] . Yeston, J. S. 2001

机译：液化稀有气体中的闪光动力学：铑羰基中心的烷烃活化和配体动力学研究，以及寻找氙 - 卡宾加合物

Glutathione Adduct Patterns of Michael-Acceptor Carbonyls

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