5-(octyl) D-glutamate | 149332-65-0

• 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: 5-(octyl) D-glutamate
• 英文别名: 5-Octyl D-Glutamate；(2R)-2-amino-5-octoxy-5-oxopentanoic acid
• CAS: 149332-65-0
• 化学式: C₁₃H₂₅NO₄
• 分子量: 259.346
• InChiKey: UCDDOKSXLQWTOD-LLVKDONJSA-N

物化性质

• 沸点：
  402.4±40.0 °C(Predicted)
• 密度：
  1.057±0.06 g/cm3(Predicted)
• 溶解度：
  甲醇：1 mg/ml（加热）

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  18
• 可旋转键数：
  12
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  89.6
• 氢给体数：
  2
• 氢受体数：
  5

制备方法与用途

5-癸基-D-谷氨酸是一种氨基酸及其衍生物。

反应信息

• 作为产物：
  描述：

  辛醇 、 D-谷氨酸 在 sodium sulfate 、 tetrafluoroboric acid dimethyl ether complex 作用下， 以 四氢呋喃 为溶剂， 生成 5-(octyl) D-glutamate
  参考文献：
  名称：

  The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR

  摘要：

  研究表明，补充δ-酮戊二酸可以延缓草履虫的衰老，这种作用可能是通过ATP合成酶和雷帕霉素靶标（TOR）产生的。限制热量摄入可以延长一系列生物的寿命，延缓与年龄相关的衰退。一些小分子代谢物已被证明能调节衰老过程，但人们对其中的机制知之甚少。黄晶及其同事在此报告说，三羧酸循环中间体δ-酮戊二酸（δ-KG）可使成年草履虫蛔虫的寿命延长约 50%。δ-KG的分子靶标是ATP酶的δ²亚基。δ-KG依赖于TOR（雷帕霉素靶标）途径，它不会延长饮食限制动物的寿命，这表明δ-KG的作用与饥饿/饮食限制之间存在联系。新陈代谢与衰老密切相关。在进化过程中，与自由摄食相比，饮食限制能持续延长生物的寿命并延缓与年龄相关的疾病1,2。类似的营养素限制条件和遗传或药物对营养素或能量代谢的扰动也有延年益寿的作用3,4。最近，人们发现了几种可调节衰老的代谢物5,6；然而，其分子机制在很大程度上尚未明确。在这里，我们发现三羧酸循环中间体δ-酮戊二酸（δ-KG）可延长成年秀丽隐杆线虫的寿命。ATP 合成酶亚基δ² 被确定为δ-KG 的新型结合蛋白，其采用的小分子靶标鉴定策略被称为药物亲和力反应靶标稳定性（DARTS）7。 ATP 合成酶又称线粒体电子传递链的复合体 V，是细胞的主要能量生成机制，在整个进化过程中高度保守8,9。虽然完全丧失线粒体功能是有害的，但部分抑制电子传递链已被证明能延长秀丽隐杆线虫的寿命10,11,12,13。我们发现δ-KG 可抑制 ATP 合成酶，与 ATP 合成酶敲除类似，δ-KG 的抑制作用可导致线虫和哺乳动物细胞中 ATP 含量降低、耗氧量减少以及自噬增加。我们提供的证据表明，δ-KG 延长寿命需要 ATP 合成酶亚基δ²，并依赖于下游的雷帕霉素靶标（TOR）。饥饿时内源性δ-KG水平升高，而δ-KG不能延长限食动物的寿命，这表明δ-KG是通过限食介导长寿的关键代谢物。我们的分析发现了一种常见的代谢物、一种普遍的细胞能量发生器和饮食限制在调节生物体寿命方面的新的分子联系，从而为预防和治疗衰老和与年龄相关的疾病提出了新的策略。

  DOI：

  10.1038/nature13264

文献信息

• COMPOSITIONS AND METHODS FOR TREATING AGING AND AGE-RELATED DISEASES AND SYMPTOMS
  申请人：THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

  公开号：EP3104852A1

  公开（公告）日：2016-12-21
• Compositions and Methods for Treating Aging and Age-Related Diseases and Symptoms
  申请人：THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

  公开号：US20160354334A1

  公开（公告）日：2016-12-08

  Disclosed herein are methods for (a) inhibiting, reducing, slowing, or preventing, the aging of a subject, (b) for treating, inhibiting, reducing, or preventing an age-related disease in the subject, and/or (c) for increasing the lifespan of the subject which comprise administering to the subject one or more glutamate compounds, such as α-ketoglutate, and/or one or more glutamate compounds, such as 2 -hydroxypentanedioate, and compositions thereof.
• [EN] COMPOSITIONS AND METHODS FOR TREATING AGING AND AGE-RELATED DISEASES AND SYMPTOMS<br/>[FR] COMPOSITIONS ET PROCÉDÉS DE TRAITEMENT DES MALADIES ET SYMPTÔMES DU VIEILLISSEMENT ET LIÉS À L'ÂGE
  申请人：UNIV CALIFORNIA

  公开号：WO2015123229A1

  公开（公告）日：2015-08-20

  Disclosed herein are methods for (a) inhibiting, reducing, slowing, or preventing, the aging of a subject, (b) for treating, inhibiting, reducing, or preventing an age-related disease in the subject, and/or (c) for increasing the lifespan of the subject which comprise administering to the subject one or more glutamate compounds, such as α-ketoglutate, and/or one or more glutamate compounds, such as 2-hydroxypentanedioate, and compositions thereof.
• The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR
  作者：Randall M. Chin、Xudong Fu、Melody Y. Pai、Laurent Vergnes、Heejun Hwang、Gang Deng、Simon Diep、Brett Lomenick、Vijaykumar S. Meli、Gabriela C. Monsalve、Eileen Hu、Stephen A. Whelan、Jennifer X. Wang、Gwanghyun Jung、Gregory M. Solis、Farbod Fazlollahi、Chitrada Kaweeteerawat、Austin Quach、Mahta Nili、Abby S. Krall、Hilary A. Godwin、Helena R. Chang、Kym F. Faull、Feng Guo、Meisheng Jiang、Sunia A. Trauger、Alan Saghatelian、Daniel Braas、Heather R. Christofk、Catherine F. Clarke、Michael A. Teitell、Michael Petrascheck、Karen Reue、Michael E. Jung、Alison R. Frand、Jing Huang

  DOI：10.1038/nature13264

  日期：2014.6

  Ageing in the worm Caenorhabditis elegans is shown to be delayed by supplementation with α-ketoglutarate, an effect that is probably mediated by ATP synthase—which is identified as a direct target of α-ketoglutarate—and target of rapamycin (TOR). Calorie restriction can extend lifespan and delay age-related deterioration in a range of organisms. A few small-molecule metabolites have been shown to regulate the ageing process, but little is known about the mechanisms involved. Here Jing Huang and colleagues report that the tricarboxylic acid cycle intermediate α-ketoglutarate (α-KG) extends the lifespan of adult Caenorhabditis elegans roundworms by approximately 50%. The molecular target of α-KG is the β subunit of ATPase. α-KG is dependent on the TOR (target of rapamycin) pathway and it does not extend the lifespan of dietary-restricted animals, suggesting a link between the effects of α-KG and starvation/dietary restriction. Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms1,2. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits3,4. Recently, several metabolites have been identified that modulate ageing5,6; however, the molecular mechanisms underlying this are largely undefined. Here we show that α-ketoglutarate (α-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit β is identified as a novel binding protein of α-KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS)7. The ATP synthase, also known as complex V of the mitochondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution8,9. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan10,11,12,13. We show that α-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by α-KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells. We provide evidence that the lifespan increase by α-KG requires ATP synthase subunit β and is dependent on target of rapamycin (TOR) downstream. Endogenous α-KG levels are increased on starvation and α-KG does not extend the lifespan of dietary-restricted animals, indicating that α-KG is a key metabolite that mediates longevity by dietary restriction. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator and dietary restriction in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases.

  研究表明，补充δ-酮戊二酸可以延缓草履虫的衰老，这种作用可能是通过ATP合成酶和雷帕霉素靶标（TOR）产生的。限制热量摄入可以延长一系列生物的寿命，延缓与年龄相关的衰退。一些小分子代谢物已被证明能调节衰老过程，但人们对其中的机制知之甚少。黄晶及其同事在此报告说，三羧酸循环中间体δ-酮戊二酸（δ-KG）可使成年草履虫蛔虫的寿命延长约 50%。δ-KG的分子靶标是ATP酶的δ²亚基。δ-KG依赖于TOR（雷帕霉素靶标）途径，它不会延长饮食限制动物的寿命，这表明δ-KG的作用与饥饿/饮食限制之间存在联系。新陈代谢与衰老密切相关。在进化过程中，与自由摄食相比，饮食限制能持续延长生物的寿命并延缓与年龄相关的疾病1,2。类似的营养素限制条件和遗传或药物对营养素或能量代谢的扰动也有延年益寿的作用3,4。最近，人们发现了几种可调节衰老的代谢物5,6；然而，其分子机制在很大程度上尚未明确。在这里，我们发现三羧酸循环中间体δ-酮戊二酸（δ-KG）可延长成年秀丽隐杆线虫的寿命。ATP 合成酶亚基δ² 被确定为δ-KG 的新型结合蛋白，其采用的小分子靶标鉴定策略被称为药物亲和力反应靶标稳定性（DARTS）7。 ATP 合成酶又称线粒体电子传递链的复合体 V，是细胞的主要能量生成机制，在整个进化过程中高度保守8,9。虽然完全丧失线粒体功能是有害的，但部分抑制电子传递链已被证明能延长秀丽隐杆线虫的寿命10,11,12,13。我们发现δ-KG 可抑制 ATP 合成酶，与 ATP 合成酶敲除类似，δ-KG 的抑制作用可导致线虫和哺乳动物细胞中 ATP 含量降低、耗氧量减少以及自噬增加。我们提供的证据表明，δ-KG 延长寿命需要 ATP 合成酶亚基δ²，并依赖于下游的雷帕霉素靶标（TOR）。饥饿时内源性δ-KG水平升高，而δ-KG不能延长限食动物的寿命，这表明δ-KG是通过限食介导长寿的关键代谢物。我们的分析发现了一种常见的代谢物、一种普遍的细胞能量发生器和饮食限制在调节生物体寿命方面的新的分子联系，从而为预防和治疗衰老和与年龄相关的疾病提出了新的策略。