2-methyl-3-ketobutyric acid-N-acetylcysteamine thioester | 220173-80-8

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: 2-methyl-3-ketobutyric acid-N-acetylcysteamine thioester
• 英文别名: (2RS)-methyl-3-oxobutanoyl-N-acetylcysteamine thioester；2-methyl-3-oxobutyric acid N-acetylcysteamine thioester；S-(2-acetamidoethyl) 2-methyl-3-oxobutanethioate
• CAS: 220173-80-8
• 化学式: C₉H₁₅NO₃S
• 分子量: 217.289
• InChiKey: VTDLBNMDPSCLKG-UHFFFAOYSA-N

物化性质

• 沸点：
  395.524±27.00 °C(Press: 760.00 Torr)(predicted)
• 密度：
  1.134±0.06 g/cm3(Temp: 25 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.61
• 重原子数：
  14.0
• 可旋转键数：
  5.0
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  63.24
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  2-methyl-3-ketobutyric acid-N-acetylcysteamine thioester 在 glucose dehydrogenase 、 D-葡萄糖 、 amphotericin ketoreductase 1 、 甘油 、 还原型辅酶II(NADPH)四钠盐 、 sodium chloride 作用下， 反应 24.0h， 生成 anti-(2S,3S)-3-hydroxy-2-methylbutyric acid N-acetylcysteamine thioester
  参考文献：
  名称：

  在二酮化合物手性结构单元的化学合成中使用模块化聚酮化合物合酶酮还原酶作为生物催化剂。

  摘要：

  手性构件是天然产物和药物合成中的有价值的中间体。已开发出一种可扩展的手性二酮化学反应路线，包括一般合成α-取代的β-酮酰基N-乙酰半胱胺硫酯，然后进行生物催化循环，其中葡萄糖驱动的NADPH再生系统驱动由分离的模块化聚酮合酶催化的还原反应（PKS）酮还原酶（KRs）。为了鉴定起活性，立体定向生物催化剂作用的KR，将11个分离的KR与5个二酮化合物一起孵育，并通过手性色谱法分析其产物。天然还原小的聚酮化合物中间体的KR对双酮化合物面板最为活跃，且立体定向性最高。扩大了几种生物催化反应的规模，以生产超过100毫克的产品。

  DOI：

  10.1016/j.chembiol.2011.07.021
• 作为产物：
  描述：

  2-甲基乙酰乙酸 、 N-乙酰基半胱胺 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 20.0h， 以30%的产率得到2-methyl-3-ketobutyric acid-N-acetylcysteamine thioester
  参考文献：
  名称：

  Tyl-KR1的底物依赖性立体特异性：来自链霉菌的分离的聚酮化合物合酶酮还原酶结构域

  摘要：

  酶促反应的立体特异性取决于底物及其对映异构体与活性位点结合的方式。这些绑定模式无法轻易预测。我们通过分析五种不同的酮酸酯底物还原的立体化学结果，研究了来自链霉菌的酪酮聚酮化合物合酶的酮还原酶结构域Tyl-KR1的立体特异性和立体选择性。通过使用振动圆二色性（VCD）光谱结合量子化学计算来确定Tyl-KR1还原产物的绝对构型。仅一种被测底物2甲基3氧代戊酸N乙酰半胱胺硫酯的转化提供了预期的抗（2 R，3 R）α-甲基-β-羟基酯产物的构型，代表观察到的生理学聚酮化合物酪酸内酯的立体化学。对于所有其他根据酯的类型和/或链长（C 4代替C 5）进行修饰的底物，获得了对映体相反的构型（anti-（2 S，3 S）），对映体和非对映选择性。两个立体中心的倒置表明完全不同的结合模式仅通过对底物结构的微小修改即可调用。

  DOI：

  10.1002/chem.201300554

文献信息

• α-Methylation follows condensation in the gephyronic acid modular polyketide synthase
  作者：Drew T. Wagner、D. Cole Stevens、M. Rachel Mehaffey、Hannah R. Manion、Richard E. Taylor、Jennifer S. Brodbelt、Adrian T. Keatinge-Clay

  DOI：10.1039/c6cc04418b

  日期：——

  C-methyltransferases (MTs) from modular polyketide synthase assembly lines are relatively rare and unexplored domains that are responsible for installing [small alpha]-methyl groups into nascent polyketide backbones. The stage at which these...

  来自模块化聚酮化合物合酶组装线的C-甲基转移酶（MT）是相对罕见且未开发的域，其负责将[小α-甲基]安装到新生的聚酮化合物主链中。这些阶段...
• Mechanism and Stereospecificity of a Fully Saturating Polyketide Synthase Module: Nanchangmycin Synthase Module 2 and Its Dehydratase Domain
  作者：Xun Guo、Tiangang Liu、Chiara R. Valenzano、Zixin Deng、David E. Cane

  DOI：10.1021/ja1073432

  日期：2010.10.27

  Recombinant nanchangmycin synthase module 2 (NANS module 2), with the thioesterase domain from the 6-deoxyerythronolide B synthase (DEBS TE) appended to the C-terminus, was cloned and expressed in Escherichia coli. Incubation of NANS module 2+TE with (+/-)-2-methyl-3-keto-butyryl-N-acetylcysteamine thioester (1), the SNAC analog of the natural ACP-bound substrate, with methylmalonyl-CoA (MM-CoA) in the absence of NADPH gave 3,5,6-trimethy1-4-hydroxypyrone (2), identified by direct comparison with synthetic 2 by radio-TLC-phosphorimaging and LC-ESI(+)-MS-MS. The reaction showed K(cat) 0.5 +/- 0.1 min(-1) and K(m)(1) 19 +/- 5 mM at 0.5 mM MM-CoA and k(cat)(app) 0.26 +/- 0.02 min(-1) and K(m)(MM-CoA) 0.11 +/- 0.02 mM at 8 mM 1. Incubation in the presence of NADPH generated the fully saturated triketide chain elongation product as a 5:3 mixture of (2S,4R)-2,4-dimethy1-5-ketohexanoic acid (3a) and the diastereomeric (2S, 4S)-3b. The structure and stereochemistry of each product was established by comparison with synthetic 3a and 3b by a combination of radio-TLC-phosphorimaging and LC-ESI(-)-MS-MS, as well as chiral capillary GC-MS analysis of the corresponding methyl esters 3a-Me and 3b-Me. The recombinant dehydratase domain from NANS module 2, NANS DH2, was shown to catalyze the formation of an (E)-double bond by syndehydration of the ACP-bound substrate anti-(2R,3R,4S,5R)-2,4-dimethyl-3,5-dihydroxyheptanoyl-ACP6 (4), generated in situ by incubation of (2S,3R)-2-methyl-3-hydroxypentanoyl-SNAC (5), methylmalonyl-CoA, and NADPH with the recombinant [KS6][AT6] didomain and ACP6 from DEBS module 6 along with the ketoreductase from the tylactone synthase module 1 (TYLS KR1). These results also indirectly establish the stereochemistry of the reactions catalyzed by the KR and enoylreductase (ER) domains of NANS module 2.
• Essential Role of the Donor Acyl Carrier Protein in Stereoselective Chain Translocation to a Fully Reducing Module of the Nanchangmycin Polyketide Synthase
  作者：Xun Guo、Tiangang Liu、Zixin Deng、David E. Cane

  DOI：10.1021/bi201768v

  日期：2012.1.31

  Incubation of recombinant module 2 of the polyether nanchangmycin synthase (NANS), carrying an appended thioesterase domain, with the ACP-bound substrate (2RS)-2-methyl-3-ketobutyryl-NANS_ACP1 (2-ACP1) and methylmalonyl-CoA in the presence of NADPH gave diastereomerically pure (25,4R)-2,4-dimethyl-5-ketohexanoic acid (4a). These results contrast with the previously reported weak discrimination by NANS module 2+TE between the enantiomers of the corresponding N-acetylcysteamine-conjugated substrate analogue (+/-)-2-methyl-3-ketobutyryl-SNAC (2-SNAC), which resulted in formation of a 5:3 mixture of 4a and its (2S,4S)-diastereomer 4h. Incubation of NANS module 2+TE with 2-ACP1 in the absence of NADPH gave unreduced 3,5,6-trimethyl-4-hydroxypyrone (3) with a K-cat of 4.4 +/- 0.9 min(-1) and a k(cat)/K-m of 67 min(-1) mM(-1), corresponding to a similar to 2300-fold increase compared to the k(cat)/K-m for the diffusive substrate 2-SNAC. Covalent tethering of the 2-methyl-3-ketobutyryl thioester substrate to the NANS ACP1 domain derived from the natural upstream PKS module of the nanchangmycin synthase significantly enhanced both the stereospecificity and the kinetic efficiency of the sequential polyketide chain translocation and condensation reactions catalyzed by the ketosynthase domain of NANS module 2.
• Expanding the Structural Diversity of Polyketides by Exploring the Cofactor Tolerance of an Inline Methyltransferase Domain
  作者：Jaclyn M. Winter、Grace Chiou、Ian R. Bothwell、Wei Xu、Neil K. Garg、Minkui Luo、Yi Tang

  DOI：10.1021/ol401723h

  日期：2013.7.19

  A strategy for introducing structural diversity into polyketides by exploiting the promiscuity of an in-line methyltransferase domain in a multidomain polyketide synthase is reported. In vitro investigations using the highly-reducing fungal polyketide synthase CazF revealed that its methyltransferase domain accepts the nonnatural cofactor propargylic Se-adenosyl-L-methionine and can transfer the propargyl moiety onto its growing polyketide chain. This propargylated polyketide product can then be further chain-extended and cyclized to form propargyl-alpha pyrone or be processed fully into the alkyne-containing 4'-propargyl-chaetoviridin A.
• Methyltransferases excised from trans-AT polyketide synthases operate on N-acetylcysteamine-bound substrates
  作者：D Cole Stevens、Drew T Wagner、Hannah R Manion、Bradley K Alexander、Adrian T Keatinge-Clay

  DOI：10.1038/ja.2016.66

  日期：2016.7