(R)-lipoate | 1200-22-2

• 物质功能分类: 化学试剂 - 有机试剂 - 芳香酸
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二硫杂环戊烷
• 英文名称: (R)-lipoate
• 英文别名: 5-[(3R)-dithiolan-3-yl]pentanoate
• CAS: 1200-22-2
• 化学式: C8H13O2S2-
• 分子量: 205.3
• InChiKey: AGBQKNBQESQNJD-SSDOTTSWSA-M

物化性质

• 熔点：
  48-52 °C(lit.)
• 比旋光度：
  D23 +104° (c = 0.88 in benzene)
• 沸点：
  185-195 °C(Press: 0.5 Torr)
• 密度：
  1.218±0.06 g/cm3(Predicted)
• 闪点：
  >230 °F
• 溶解度：
  乙腈（微溶）、氯仿（微溶）、DMSO
• LogP：
  2.160 (est)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  12
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  90.7
• 氢给体数：
  0
• 氢受体数：
  4

安全信息

• 安全说明：
  S20,S26,S35,S36
• 危险类别码：
  R22,R36/38
• WGK Germany：
  3
• 海关编码：
  2934999090
• 危险品运输编号：
  NONH for all modes of transport
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

发现R-(+)-硫辛酸是一种黄色结晶物质。它是一种具有生物活性的天然产物。1951年Raed等人首次从处理过的不溶肝组织残渣中分离得到一种生长促进酶的结晶型辅因子，并由于其高度脂溶性和pKa值为4.7而将其命名为硫辛酸。

生理功能 硫辛酸是一种内源性抗氧化剂，可以去除机体自由基。它能促进机体利用葡萄糖合成维生素C，促进谷胱甘肽合成，有效去除黑色素，还能协助辅酶进行有利于机体免疫力的生理代谢。此外，硫辛酸还具有抗炎作用，可抑制激酶、转化因子、肿瘤坏死因子和胶原酶的活性，具有抗衰老功效。它能保存和再生其他抗氧化剂，广泛应用于预防和治疗心脏病、糖尿病、肝病及老年痴呆症。

生物活性 R型对映异构体在硫辛酸中表现出更强的生物活性。这是因为代谢过程中大量R型硫辛酸可通过细胞膜及线粒体膜进入细胞和线粒体内被还原成二氢硫辛酸，而S型仅有少量进入细胞被还原。二氢硫辛酸具有比硫辛酸更强的抗氧化能力，并且是内源性抗氧化剂再生和氧化性损伤修复的重要形式。

靶点

• NF-κB
• LTR

体外研究 R-(+)-α-硫辛酸（(R)-(+)-α-Lipoic acid）是在人体中合成的一种强效抗氧化剂，对于减轻糖尿病神经症状具有优越的疗效。它是一种线粒体酶复合物的重要辅助因子，并且能够抑制NF-κB依赖性HIV-1 LTR活化。

用途 维生素类药物，效果优于硫辛酸。

反应信息

• 作为反应物：
  描述：

  (R)-lipoate 、 GTP 、 氢(+1)阳离子 生成 (R)-lipoyl-GMP(1-) 、 pyrophosphoric acid
  参考文献：
  名称：

  Purification, Characterization, and cDNA Cloning of Lipoate-activating Enzyme from Bovine Liver

  摘要：

  In mammals, lipoate-activating enzyme (LAE) catalyzes the activation of lipoate to lipoyl-nucleoside monophosphate. The lipoyl moiety is then transferred to the specific lysine residue of lipoate-dependent enzymes by the action of lipoyltransferase. We purified LAE from bovine liver mitochondria to apparent homogeneity. LAE activated lipoate with GTP at a 1000-fold higher rate than with ATP. The reaction absolutely required lipoate, GTP, and Mg2+ ion, and the reaction product was lipoyl-GMP. LAE activated both (R)- and (S)-lipoate to the respective lipoyl-GMP, although a preference for (R)-lipoate was observed. Similarly, lipoyltransferase equally transferred both the (R)- and (S)-lipoyl moieties from the respectively activated lipoates to apoH-protein. Interestingly, however, only H-protein carrying (R)-lipoate was active in the glycine cleavage reaction. cDNA clones encoding a precursor LAE with a mitochondrial presequence were isolated. The predicted amino acid sequence of LAE is identical with that of xenobiotic-metabolizing/medium-chain fatty acid:CoA ligase-Ill, but an amino acid substitution due to a single nucleotide polymorphism was found. These results indicate that the medium-chain acyl-CoA synthetase in mitochondria has a novel function, the activation of lipoate with GTP.

  DOI：

  10.1074/jbc.m101748200

文献信息

• Crystal Structure of Lipoate-Protein Ligase A Bound with the Activated Intermediate
  作者：Do Jin Kim、Kyoung Hoon Kim、Hyung Ho Lee、Sang Jae Lee、Jun Yong Ha、Hye Jin Yoon、Se Won Suh

  DOI：10.1074/jbc.m507284200

  日期：2005.11

  of the target proteins. The reaction catalyzed by LplA occurs in two steps. First, LplA activates exogenously supplied lipoic acid at the expense of ATP to lipoyl-AMP. Next, it transfers the enzyme-bound lipoyl-AMP to the epsilon-amino group of a specific lysine residue of the lipoyl domain to give an amide linkage. To gain insight into the mechanism of action by LplA, we have determined the crystal

  硫辛酸是几种能催化关键代谢反应的多组分酶复合物的共价结合辅因子。硫辛酸与脂酰依赖性酶的连接是通过硫辛酸脂蛋白连接酶（LPL）催化的。在大肠杆菌中，两种截然不同的酶脂酸酯-蛋白连接酶A（LplA）和lipB编码的脂酰转移酶（LipB）催化目标蛋白脂酰化的独立途径。LplA催化的反应分两个步骤进行。首先，LplA激活外源供应的硫辛酸，但以ATP取代硫酰-AMP的代价。接下来，将结合酶的脂酰-AMP转移至脂酰结构域的特定赖氨酸残基的ε-氨基，以提供酰胺键。为了深入了解LplA的作用机理，我们以三种形式确定了嗜酸嗜热丝菌LplA的晶体结构：（i）载脂蛋白表格；（ii）ATP复合物；（iii）脂酰-AMP复合物。LplA的总体折叠与大肠杆菌生物素全酶全酶合成酶/生物阻遏物（BirA）的生物素蛋白连接酶模块的相似。脂酰-AMP深深地结合在LplA的分叉口袋中，并呈U形构象。大部分脂肪族溶剂中的磷酸根基
• Assembly of the Covalent Linkage between Lipoic Acid and Its Cognate Enzymes
  作者：Xin Zhao、J.Richard Miller、Yanfang Jiang、Michael A Marletta、John E Cronan

  DOI：10.1016/j.chembiol.2003.11.016

  日期：2003.12

  insertion of sulfur atoms at carbons 6 and 8 and is covalently attached to a pyruvate dehydrogenase (PDH) subunit. We show that sulfur atoms can be inserted into octanoyl moieties attached to a PDH subunit or a derived domain.Escherichia coli lipBmutants grew well when supplemented with octanoate in place of lipoate. Octanoate growth required both lipoate protein ligase (LplA) and LipA, the sulfur insertion

  硫辛酸是通过在碳6和8上插入硫原子由辛酸合成的，并与丙酮酸脱氢酶（PDH）亚基共价连接。我们表明，硫原子可以插入连接到PDH亚基或衍生结构域的辛酰基部分中。当补充辛酸代替硫辛酸酯时，大肠杆菌的lipBmutants生长良好。辛酸的生长需要硫辛酸脂蛋白连接酶（LplA）和硫磺插入蛋白LipA，这表明LplA将辛酸脂与脱氢酶连接，然后LipA将辛酸脂转化为硫辛酸。通过在anE中用氘代辛酸酯标记PDH域来测试该途径。缺乏LipA活性的大肠杆菌。恢复LipA后，标记的辛酰基结构域被转化为脂酰化的结构域。而且，
• Crystal Structure of Lipoate-Protein Ligase A from Escherichia coli
  作者：Kazuko Fujiwara、Sachiko Toma、Kazuko Okamura-Ikeda、Yutaro Motokawa、Atsushi Nakagawa、Hisaaki Taniguchi

  DOI：10.1074/jbc.m505010200

  日期：2005.9

  equivalents between the active sites of the components of the complexes. We have determined the X-ray crystal structures of Escherichia coli LplA alone and in a complex with lipoic acid at 2.4 and 2.9 angstroms resolution, respectively. The structure of LplA consists of a large N-terminal domain and a small C-terminal domain. The structure identifies the substrate binding pocket at the interface between the

  脂酸酯蛋白连接酶A（LplA）催化由脂酸酯和ATP形成脂酰-AMP，然后将脂酰部分转移至α-酮酸脱氢酶复合物的酰基转移酶亚基上以及甘氨酸裂解系统的H蛋白上的特定赖氨酸残基上。赖氨酰赖氨酸臂通过穿梭反应中间体并减少复合物组分的活性位点之间的当量而在复合物中起关键作用。我们已经确定了单独的大肠埃希氏菌LplA的X射线晶体结构以及与硫辛酸的复合物分别在2.4和2.9埃分辨率下的X射线晶体结构。LplA的结构由一个大的N端结构域和一个小的C端结构域组成。该结构在两个结构域之间的界面处识别底物结合口袋。硫辛酸通过疏水相互作用和硫辛酸的羧基与LplA的Ser-72或Arg-140残基之间的弱氢键结合在N末端结构域的疏水腔中。硫辛酸结合后，在主链结构中未观察到大的构象变化。
• Crystal Structure of Bovine Lipoyltransferase in Complex with Lipoyl-AMP
  作者：Kazuko Fujiwara、Harumi Hosaka、Makoto Matsuda、Kazuko Okamura-Ikeda、Yutaro Motokawa、Mamoru Suzuki、Atsushi Nakagawa、Hisaaki Taniguchi

  DOI：10.1016/j.jmb.2007.05.059

  日期：2007.8

  C10 atom of lipoyl-AMP, and consequently facilitate the nucleophilic attack by the lysine residue of the lipoate-acceptor protein, accompanying the bond cleavage between the carbonyl group and the phosphate group. We discuss the structural differences between bLT and the lipoate-protein ligase A from Escherichia coli and Thermoplasma acidophilum. We further demonstrate that bLT in mitochondria also

  硫辛酸是α-酮酸脱氢酶复合物和甘氨酸裂解系统必不可少的辅助因子。它共价附于复合物亚基的特定赖氨酸残基。牛脂酰转移酶（bLT）以脂酰-AMP为底物催化硫辛酸的附着反应，形成脂酰化的蛋白质和AMP。为了深入了解原子级的反应机理，我们确定了2.10 A分辨率下bLT的晶体结构。出乎意料的是，纯化的重组bLT含有内源性脂酰-AMP。bLT的结构由N末端和C末端结构域组成，并且脂酰AMP结合到N末端结构域中的活性位点，呈U形构象。硫辛基部分埋在疏水口袋中，形成范德华相互作用，AMP部分与bLT在另一个隧道状腔中形成许多氢键。这些相互作用共同作用，使脂酰-AMP的C10原子暴露于bLT分子的表面。脂酰-AMP的羰基氧原子与不变的Lys135相互作用。相互作用可能会刺激脂酰-AMP的C10原子带正电荷，因此，伴随着羰基和磷酸酯基之间的键断裂，硫辛酸酯-受体蛋白的赖氨酸残基会促进亲核攻击。我们讨论了bLT
• Purification and properties of the lipoate protein ligase of <i>Escherichia coli</i>
  作者：D E Green、T W Morris、J Green、J E Cronan、J R Guest

  DOI：10.1042/bj3090853

  日期：1995.8.1

  Lipoate is an essential component of the 2-oxoacid dehydrogenase complexes and the glycine-cleavage system of Escherichia coli. It is attached to specific lysine residues in the lipoyl domains of the E2p (lipoate acetyltransferase) subunit of the pyruvate dehydrogenase complex by a Mg(2+)- and ATP-dependent lipoate protein ligase (LPL). LPL was purified from wild-type E. coli, where its abundance is extremely low (&lt; 10 molecules per cell) and from a genetically amplified source. The purified enzyme is a monomeric protein (M(r) 38,000) which forms irregular clusters of needle-like crystals. It is stable at -20 degrees C, but slowly oxidizes to an inactive form containing at least one intramolecular disulphide bond at 4 degrees C. The inactive form could be re-activated by reducing agents or by an as-yet unidentified component (reactivation factor) which is resolved from LPL at the final stage of purification. The pI is 5.80, and the Km values for ATP, Mg2+ and DL-lipoate were determined. Selenolipoate and 6-thio-octanoate were alternative but poorer substrates. Lipoylation was reversibly inhibited by the 6- and 8-seleno-octanoates and 8-thio-octanoate, which reacted with the six cysteine thiol groups of LPL. LPL was inactivated by Cu2+ ions in a process that involved the formation of inter- and intra-molecular disulphide bonds. Studies with lplA mutants lacking LPL activity indicated that E. coli possesses another distinct lipoylation system, although no such activity could be detected in vitro.

  Lipoate是大肠杆菌2-氧酸脱氢酶复合物和甘氨酸裂解系统的必需组分。它通过Mg（2+）和ATP依赖的脂肪酸蛋白配体酶（LPL）附着于E2p（脂肪酸乙酰转移酶）亚单位的脂肪酰域的特定赖氨酸残基上。LPL从野生型大肠杆菌中纯化，其丰度极低（＜10个分子/细胞），也从遗传放大的来源中纯化。纯化的酶是单体蛋白质（M（r）38000），形成不规则的针状晶体团。它在-20℃时稳定，但在4℃时缓慢氧化成至少含有一个分子内二硫键的不活性形式。还原剂或尚未确定的组分（重激活因子）可以重新激活不活性形式，在纯化的最后阶段与LPL分离。其等电点为5.80，ATP、Mg2+和DL-脂肪酸的Km值已确定。硒脂肪酸和6-硫辛酸是可替代但较差的底物。6-和8-硒辛酸和8-硫辛酸可可逆地抑制脂肪酰化，它们与LPL的六个半胱氨酸巯基反应。Cu2+离子使LPL失活，这涉及到形成分子间和分子内二硫键。缺乏LPL活性的LplA突变体的研究表明，大肠杆菌具有另一种独特的脂肪酰化系统，尽管在体外无法检测到这种活性。