3-glutathionyl-4-hydroxynonanal | 204851-41-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 3-glutathionyl-4-hydroxynonanal
• 英文别名: 4-Hydroxynonenal glutathione conjugate；(2S)-2-amino-5-[[(2R)-1-(carboxymethylamino)-3-(5-hydroxy-2-pentyloxolan-3-yl)sulfanyl-1-oxopropan-2-yl]amino]-5-oxopentanoic acid
• CAS: 204851-41-2
• 化学式: C₁₉H₃₃N₃O₈S
• 分子量: 463.552
• InChiKey: ICRIFHIWWXQBPY-RQRWYUMJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.2
• 重原子数：
  31
• 可旋转键数：
  15
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  214
• 氢给体数：
  6
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  3-glutathionyl-4-hydroxynonanal 在 sodium tetrahydroborate 、 镍 作用下， 反应 1.0h， 生成 nonane-1,4-diol
  参考文献：
  名称：

  Analysis in the Rat of 4-Hydroxynonenal Metabolites Excreted in Bile: Evidence of Enterohepatic Circulation of These Byproducts of Lipid Peroxidation

  摘要：

  4-Hydroxynonenal (HNE) is a cytotoxic product resulting from the lipid peroxidation of membrane polyunsaturated fatty acids. In vitro, metabolism mainly leads to the corresponding alcohol (DHN), carboxylic acid (HNA), and the glutathione conjugate, whereas in vivo, mercapturic acid conjugates of HNE, DHN, HNA, and HNA-lactone and, more recently, dicarboxylic acids and related mercapturate conjugates were identified in urine of rats. In the study presented here, the identity of the HNE biotransformation products in the bile of rats following a single iv administration of [4-H-3]HNE and the potential for enterohepatic recycling of HNE metabolites were investigated. The identity of metabolites was assessed by comparison of their HPLC retention times with those of the corresponding synthesized standards and by mass spectrometry analysis. Five metabolites were present in the bile; two of them corresponded to HNE- and DHN-glutathione conjugates. Two others metabolites were identified as DHN- and HNA-lactone mercapturic acid conjugates. The fifth metabolite was isolated but remained unidentified. As previously observed for urinary elimination, the kinetic excretion of biliary metabolites exhibited a rapid metabolism of HNE in rats. Within 4 h of injection, the bile accounted for 19.5% (+/-2.8%) of the injected radioactivity, whereas only 3% was found in the feces within 48 h [Alary, J., et al. (1995) Chem. Res. Toxicol. 8, 34-39]. The extent of HNE enterohepatic recycling was estimated utilizing a modified version of the linked rat model in three animals. All rat recipients were found to have measurable levels of HNE metabolites in bile, confirming that HNE is likely to undergo enterohepatic recirculation in the rat. The extent of recycling was approximatly 7.7% of the total dose in this model. Two unknown metabolites were present in the bile of recipient rats and not found in the bile of donors rats, suggesting that intestinal microflora and/or intestinal mucosa could biotransform HNE-related compounds before or during the reabsorption process.

  DOI：

  10.1021/tx9900425
• 作为产物：
  描述：

  谷胱甘肽 、 (E)-4-Hydroxy-2-nonenal 以 phosphate buffer 为溶剂， 生成 3-glutathionyl-4-hydroxynonanal
  参考文献：
  名称：

  Identification of Intermediate Pathways of 4-Hydroxynonenal Metabolism in the Rat

  摘要：

  The formation of 4-hydroxy-2-nonenal (HNE) conjugates with glutathione (GSH) by Michael addition and subsequent cleavage to yield the related mercapturic acid (MA) conjugates are a major detoxication process. To characterize the metabolic pathways involved in the formation of urinary HNE-MA conjugates in the rat, the metabolism of HNE-thioethers (HNE-GSH, HNE-MA, and HNE-Cys) by rat liver and kidney cytosolic fractions was investigated. The experimental results showed that HNE-GSH is a good substrate for cytosolic incubations whereas HNE-MA and HNE-Cys are poorly metabolized. About 80% of the urinary MA conjugates originate from the primary and major HNE metabolite, namely, the hemiacetalized HNE-GSH. The direct reduction of HNE-GSH by a cytosolic aldo-keto reductase (NADPH) leads to 1,4-dihydroxynonene-GSH (DHN-GSH) and subsequently to DHN-MA. The direct oxidation of HNE-GSH by aldehyde dehydrogenase (NAD)(+) leads to 4-hydroxynonenoiclactone-GSH, the partial hydrolysis of which occurs at physiological pH and accounts for the corresponding 4-hydroxynonenoic-GSH. Both the spontaneous- and the glutathione S-transferases-catalyzed retro-Michael cleavages of HNE-GSH and HNA-lactone-GSH are the source of HNE and HNA-lactone, respectively. This latter compound, with both lipophilic and electrophilic properties, is available for microsomal omega-hydroxylation by cytochrome P450 4A enzymes and conjugation with thiol groups and therefore is the most likely candidate for the formation of omega-hydroxylated HNE-mercapturic acid conjugates excreted in rat urine.

  DOI：

  10.1021/tx025671k

文献信息

• Detoxification of cytotoxic ?,?-unsaturated aldehydes by carnosine: characterization of conjugated adducts by electrospray ionization tandem mass spectrometry and detection by liquid chromatography/mass spectrometry in rat skeletal muscle
  作者：Giancarlo Aldini、Paola Granata、Marina Carini

  DOI：10.1002/jms.381

  日期：2002.12

  in biological systems, no data are available on HNE interactions with carnosine, a dipeptide (beta-alanyl-L-histidine) present in high concentration in skeletal muscle. The aim of this work was to study the quenching ability of carnosine towards HNE and to characterize the reaction products by electrospray ionization tandem mass spectrometry (ESI-MS/MS), using GSH as a model peptide. GSH incubation

  组织中含有磷脂的多不饱和脂肪酸的氧化会产生脂质氢过氧化物，脂质氢过氧化物会进一步降解为几种产物，其中不饱和醛（例如4-羟基-反-2-壬烯醛（HNE））在介导氧化性的病理作用中起重要作用压力。虽然HNE与谷胱甘肽（GSH）的反应是生物系统中公认的排毒途径，但尚无有关HNE与肌肽（肌酸是骨骼肌中高浓度存在的二肽（β-丙氨酰-L-组氨酸）的相互作用）的数据。这项工作的目的是研究肌肽对HNE的淬灭能力，并使用GSH作为模型肽，通过电喷雾电离串联质谱（ESI-MS / MS）表征反应产物。在1 mM磷酸盐缓冲液（pH 7。4）由于迈克尔加合物S-（4-羟基壬醛-3-基）谷胱甘肽的形成，导致HNE在1小时内完全消失。研究了HNE与肌肽的不同摩尔比，并通过高效液相色谱（HPLC）（HNE消耗），MS / MS（输液）和液相色谱质谱（LC / MS）实验监测长达24小时。肌肽虽然比GSH的反应性差，但可以显着淬灭HNE（1
• NADP+-dependent dehydrogenase activity of carbonyl reductase on glutathionylhydroxynonanal as a new pathway for hydroxynonenal detoxification
  作者：Roberta Moschini、Eleonora Peroni、Rossella Rotondo、Giovanni Renzone、Dominique Melck、Mario Cappiello、Massimo Srebot、Elio Napolitano、Andrea Motta、Andrea Scaloni、Umberto Mura、Antonella Del-Corso

  DOI：10.1016/j.freeradbiomed.2015.02.001

  日期：2015.6

  An NADP(+) -dependent dehydrogenase activity on 3-glutathiony1-4-hydroxynonanal (GSHNE) was purified to electrophoretic homogeneity from a line of human astrocytoma cells (ADF). Proteomic analysis identified this enzymatic activity as associated with carbonyl reductase 1 (EC 1.1.1.184). The enzyme is highly efficient at catalyzing the oxidation of GSHNE (K-M 33 mu M, k(cat) 405 min(-1)), as it is practically inactive toward trans-4-hydroxy-2-nonenal (HNE) and other HNE-adducted thiol-containing amino acid derivatives. Combined mass spectrometry and nuclear magnetic resonance spectroscopy analysis of the reaction products revealed that carbonyl reductase oxidizes the hydroxyl group of GSHNE in its hemiacetal form, with the formation of the corresponding 3-glutathionylnonanoic-delta-lactone. The relevance of this new reaction catalyzed by carbonyl reductase 1 is discussed in terms of HNE detoxification and the recovery of reducing power. (C) 2015 Published by Elsevier Inc.
• Analysis in the Rat of 4-Hydroxynonenal Metabolites Excreted in Bile: Evidence of Enterohepatic Circulation of These Byproducts of Lipid Peroxidation
  作者：Alexia Laurent、Jacques Alary、Laurent Debrauwer、Jean-Pierre Cravedi

  DOI：10.1021/tx9900425

  日期：1999.10.1

  4-Hydroxynonenal (HNE) is a cytotoxic product resulting from the lipid peroxidation of membrane polyunsaturated fatty acids. In vitro, metabolism mainly leads to the corresponding alcohol (DHN), carboxylic acid (HNA), and the glutathione conjugate, whereas in vivo, mercapturic acid conjugates of HNE, DHN, HNA, and HNA-lactone and, more recently, dicarboxylic acids and related mercapturate conjugates were identified in urine of rats. In the study presented here, the identity of the HNE biotransformation products in the bile of rats following a single iv administration of [4-H-3]HNE and the potential for enterohepatic recycling of HNE metabolites were investigated. The identity of metabolites was assessed by comparison of their HPLC retention times with those of the corresponding synthesized standards and by mass spectrometry analysis. Five metabolites were present in the bile; two of them corresponded to HNE- and DHN-glutathione conjugates. Two others metabolites were identified as DHN- and HNA-lactone mercapturic acid conjugates. The fifth metabolite was isolated but remained unidentified. As previously observed for urinary elimination, the kinetic excretion of biliary metabolites exhibited a rapid metabolism of HNE in rats. Within 4 h of injection, the bile accounted for 19.5% (+/-2.8%) of the injected radioactivity, whereas only 3% was found in the feces within 48 h [Alary, J., et al. (1995) Chem. Res. Toxicol. 8, 34-39]. The extent of HNE enterohepatic recycling was estimated utilizing a modified version of the linked rat model in three animals. All rat recipients were found to have measurable levels of HNE metabolites in bile, confirming that HNE is likely to undergo enterohepatic recirculation in the rat. The extent of recycling was approximatly 7.7% of the total dose in this model. Two unknown metabolites were present in the bile of recipient rats and not found in the bile of donors rats, suggesting that intestinal microflora and/or intestinal mucosa could biotransform HNE-related compounds before or during the reabsorption process.
• Identification of Intermediate Pathways of 4-Hydroxynonenal Metabolism in the Rat
  作者：Jacques Alary、Yvette Fernandez、Laurent Debrauwer、Elisabeth Perdu、Françoise Guéraud

  DOI：10.1021/tx025671k

  日期：2003.3.1

  The formation of 4-hydroxy-2-nonenal (HNE) conjugates with glutathione (GSH) by Michael addition and subsequent cleavage to yield the related mercapturic acid (MA) conjugates are a major detoxication process. To characterize the metabolic pathways involved in the formation of urinary HNE-MA conjugates in the rat, the metabolism of HNE-thioethers (HNE-GSH, HNE-MA, and HNE-Cys) by rat liver and kidney cytosolic fractions was investigated. The experimental results showed that HNE-GSH is a good substrate for cytosolic incubations whereas HNE-MA and HNE-Cys are poorly metabolized. About 80% of the urinary MA conjugates originate from the primary and major HNE metabolite, namely, the hemiacetalized HNE-GSH. The direct reduction of HNE-GSH by a cytosolic aldo-keto reductase (NADPH) leads to 1,4-dihydroxynonene-GSH (DHN-GSH) and subsequently to DHN-MA. The direct oxidation of HNE-GSH by aldehyde dehydrogenase (NAD)(+) leads to 4-hydroxynonenoiclactone-GSH, the partial hydrolysis of which occurs at physiological pH and accounts for the corresponding 4-hydroxynonenoic-GSH. Both the spontaneous- and the glutathione S-transferases-catalyzed retro-Michael cleavages of HNE-GSH and HNA-lactone-GSH are the source of HNE and HNA-lactone, respectively. This latter compound, with both lipophilic and electrophilic properties, is available for microsomal omega-hydroxylation by cytochrome P450 4A enzymes and conjugation with thiol groups and therefore is the most likely candidate for the formation of omega-hydroxylated HNE-mercapturic acid conjugates excreted in rat urine.