butylmalonyl-CoA

• 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: butylmalonyl-CoA
• 英文别名: 2-[2-[3-[[(2R)-4-[[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-hydroxy-3-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-2-hydroxy-3,3-dimethylbutanoyl]amino]propanoylamino]ethylsulfanylcarbonyl]hexanoic acid
• 化学式: C₂₈H₄₆N₇O₁₉P₃S
• 分子量: 909.696
• InChiKey: OSSGQGDHVMDIST-XGGCCDIMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.9
• 重原子数：
  58
• 可旋转键数：
  25
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  426
• 氢给体数：
  10
• 氢受体数：
  24

反应信息

• 作为反应物：
  描述：

  butylmalonyl-CoA 、 戊硫酸,3-羟基-2-甲基-,S-[2-(乙酰基氨基)乙基]酯,(2S,3R)- 在 polyketide synthase of eryAI gene of Saccharopolyspora erythraea NRRL 2338 作用下， 以 aq. phosphate buffer 为溶剂， 生成 (4S,5R)-3-oxo-2-butyl-4-methyl-5-hydroxyheptanoic acid-d-lactone
  参考文献：
  名称：

  通过模块化聚酮合酶内的酰基转移酶域交换扩展非天然聚酮生物合成的扩展底物选择

  摘要：

  模块化聚酮合酶 (PKS) 是使用 α-羧基辅酶 A 作为增量底物的聚合酶。该酶家族包含多个催化模块，其中每个模块负责单轮聚酮化合物链延伸。尽管 PKS 模块通常使用丙二酰辅酶 A 或甲基丙二酰辅酶 A 进行链延长，但许多其他丙二酰辅酶 A 类似物用于使自然界中的聚酮化合物结构多样化。以前，我们开发了一种方法，通过在保持蛋白质折叠的同时交换酰基转移酶 (AT) 结构域来改变给定模块的延伸底物。在这里，我们报告了13 种 PKS（野生型 PKS 和 12 种具有异常 AT 的 AT 交换 PKS）和 14 种扩展底物的体外聚酮化合物生物合成。我们的 ~200体外反应产生了 13 种结构不同的聚酮化合物，其中包括几种尚未报道的聚酮化合物。在某些情况下，AT 交换的 PKS 产生的目标聚酮化合物是野生型 PKS 的 100 倍以上。这些数据还表明，大多数不寻常的 AT 结构域不包含丙二酰辅酶 A

  DOI：

  10.1021/jacs.2c11027
• 作为产物：
  描述：

  丁基丙二酸 在 碳酸氢钠 、 N,N'-二环己基碳二亚胺 、 sodium hydroxide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 butylmalonyl-CoA
  参考文献：
  名称：

  Identification of Middle Chain Fatty Acyl-CoA Ligase Responsible for the Biosynthesis of 2-Alkylmalonyl-CoAs for Polyketide Extender Unit

  摘要：

  Background: Fatty acyl-CoA ligases involved in polyketide biosynthesis remain uncharacterized.Results: RevS classified in fatty acyl-AMP ligase clade was the middle chain fatty acyl-CoA ligase.Conclusion: RevS was responsible for 2-alkylmalonyl-CoA biosynthesis through enzyme coupling with RevT carboxylase/reductase.Significance: 2-Alkylmalonyl-CoA biosynthesis was strongly supported by the function of RevR and RevS, which utilized fatty acids derived from de novo biosynthesis and degradation products, respectively.Understanding the biosynthetic mechanism of the atypical polyketide extender unit is important for the development of bioactive natural products. Reveromycin (RM) derivatives produced by Streptomyces sp. SN-593 possess several aliphatic extender units. Here, we studied the molecular basis of 2-alkyl-malonyl- CoA formation by analyzing the revR and revS genes, which form a transcriptional unit with the revT gene, a crotonyl-CoA carboxylase/reductase homolog. We mainly focused on the uncharacterized adenylate-forming enzyme (RevS). revS gene disruption resulted in the reduction of all RM derivatives, whereas reintroduction of the gene restored the yield of RMs. Although RevS was classified in the fatty acyl-AMP ligase clade based on phylogenetic analysis, biochemical characterization revealed that the enzyme catalyzed the middle chain fatty acyl-CoA ligase (FACL) but not the fatty acyl-AMP ligase activity, suggesting the molecular evolution for acyl-CoA biosynthesis. Moreover, we examined the in vitro conversion of fatty acid into 2-alkylmalonyl-CoA using purified RevS and RevT. The coupling reaction showed efficient conversion of hexenoic acid into butylmalonyl-CoA. RevS efficiently catalyzed C8-C10 middle chain FACL activity; therefore, we speculated that the acyl-CoA precursor was truncated via beta-oxidation and converted into (E)-2-enoyl-CoA, a RevT substrate. To determine whether the beta-oxidation process is involved between the RevS and RevT reaction, we performed the feeding experiment using [1,2,3,4-C-13] octanoic acid. C-13 NMR analysis clearly demonstrated incorporation of the [3,4-C-13] octanoic acid moiety into the structure of RM-A. Our results provide insight into the role of uncharacterized RevS homologs that may catalyze middle chain FACL to produce a unique polyketide extender unit.

  DOI：

  10.1074/jbc.m115.677195

文献信息

• Establishing a Toolkit for Precursor-Directed Polyketide Biosynthesis: Exploring Substrate Promiscuities of Acid-CoA Ligases
  作者：Maybelle Kho Go、Jeng Yeong Chow、Vivian Wing Ngar Cheung、Yan Ping Lim、Wen Shan Yew

  DOI：10.1021/bi300425j

  日期：2012.6.5

  biosynthesized from acyl-CoA precursors by polyketide synthases. One of the limitations to combinatorial biosynthesis of polyketides has been the lack of a toolkit that describes the means of delivering novel acyl-CoA precursors necessary for polyketide biosynthesis. Using five acid-CoA ligases obtained from various plants and microorganisms, we biosynthesized an initial library of 79 acyl-CoA thioesters by screening

  聚酮化合物是化学上多样化且具有医学上重要意义的生物化学物质，它们是通过聚酮化合物合酶从酰基辅酶A前体生物合成的。聚酮化合物的组合生物合成的局限性之一是缺少工具包，该工具包描述了递送聚酮化合物生物合成所必需的新型酰基-CoA前体的方法。使用从各种植物和微生物中获得的5种酸性CoA连接酶，我们通过针对123种羧酸的文库筛选每种酸性CoA连接酶，生物合成了79种酰基CoA硫酯的初始文库。酰基-CoA硫酯库包括肉桂基-CoA，3-苯基丙酰基-CoA，苯甲酰基-CoA，苯乙酰基-CoA，丙二酰-CoA，饱和和不饱和脂族CoA硫酯和双环芳族CoA硫酯的衍生物。在我们对新型酰基辅酶A前体的生物合成路线的搜索中，我们发现了两种以前未报道过的丙二酰辅酶A衍生物（3-硫代苯丙氨酰辅酶A和苯基丙二酰辅酶A），无法通过规范的丙二酰辅酶A合成酶生产。该报告强调了确定常规底物池之外底物混杂的实用性和重要性，并描述了建
• Activating a Cryptic Ansamycin Biosynthetic Gene Cluster To Produce Three New Naphthalenic Octaketide Ansamycins with <i>n</i>-Pentyl and <i>n</i>-Butyl Side Chains
  作者：Shanren Li、Yaoyao Li、Chunhua Lu、Juanli Zhang、Jing Zhu、Haoxin Wang、Yuemao Shen

  DOI：10.1021/acs.orglett.5b01686

  日期：2015.8.7

  Genome mining is a rational approach to discovering new natural products. The genome sequence analysis of Streptomyces sp. LZ35 revealed the presence of a putative ansamycin gene cluster (nam). Constitutive overexpression of the pathway-specific transcriptional regulatory gene nam1 successfully activated the nam gene cluster, and three novel naphthalenic octaketide ansamycins were discovered with unprecedented n-pentylmalonyl-CoA or n-butylmalonyl-CoA extender units. This study represents the first example of discovering novel ansamycin scaffolds via activation of a cryptic gene cluster.
• Identification of Middle Chain Fatty Acyl-CoA Ligase Responsible for the Biosynthesis of 2-Alkylmalonyl-CoAs for Polyketide Extender Unit
  作者：Takeshi Miyazawa、Shunji Takahashi、Akihiro Kawata、Suresh Panthee、Teruo Hayashi、Takeshi Shimizu、Toshihiko Nogawa、Hiroyuki Osada

  DOI：10.1074/jbc.m115.677195

  日期：2015.11

  Background: Fatty acyl-CoA ligases involved in polyketide biosynthesis remain uncharacterized.Results: RevS classified in fatty acyl-AMP ligase clade was the middle chain fatty acyl-CoA ligase.Conclusion: RevS was responsible for 2-alkylmalonyl-CoA biosynthesis through enzyme coupling with RevT carboxylase/reductase.Significance: 2-Alkylmalonyl-CoA biosynthesis was strongly supported by the function of RevR and RevS, which utilized fatty acids derived from de novo biosynthesis and degradation products, respectively.Understanding the biosynthetic mechanism of the atypical polyketide extender unit is important for the development of bioactive natural products. Reveromycin (RM) derivatives produced by Streptomyces sp. SN-593 possess several aliphatic extender units. Here, we studied the molecular basis of 2-alkyl-malonyl- CoA formation by analyzing the revR and revS genes, which form a transcriptional unit with the revT gene, a crotonyl-CoA carboxylase/reductase homolog. We mainly focused on the uncharacterized adenylate-forming enzyme (RevS). revS gene disruption resulted in the reduction of all RM derivatives, whereas reintroduction of the gene restored the yield of RMs. Although RevS was classified in the fatty acyl-AMP ligase clade based on phylogenetic analysis, biochemical characterization revealed that the enzyme catalyzed the middle chain fatty acyl-CoA ligase (FACL) but not the fatty acyl-AMP ligase activity, suggesting the molecular evolution for acyl-CoA biosynthesis. Moreover, we examined the in vitro conversion of fatty acid into 2-alkylmalonyl-CoA using purified RevS and RevT. The coupling reaction showed efficient conversion of hexenoic acid into butylmalonyl-CoA. RevS efficiently catalyzed C8-C10 middle chain FACL activity; therefore, we speculated that the acyl-CoA precursor was truncated via beta-oxidation and converted into (E)-2-enoyl-CoA, a RevT substrate. To determine whether the beta-oxidation process is involved between the RevS and RevT reaction, we performed the feeding experiment using [1,2,3,4-C-13] octanoic acid. C-13 NMR analysis clearly demonstrated incorporation of the [3,4-C-13] octanoic acid moiety into the structure of RM-A. Our results provide insight into the role of uncharacterized RevS homologs that may catalyze middle chain FACL to produce a unique polyketide extender unit.
• Expanding Extender Substrate Selection for Unnatural Polyketide Biosynthesis by Acyltransferase Domain Exchange within a Modular Polyketide Synthase
  作者：Elias Englund、Matthias Schmidt、Alberto A. Nava、Anna Lechner、Kai Deng、Renee Jocic、Yingxin Lin、Jacob Roberts、Veronica T. Benites、Ramu Kakumanu、Jennifer W. Gin、Yan Chen、Yuzhong Liu、Christopher J. Petzold、Edward E. K. Baidoo、Trent R. Northen、Paul D. Adams、Leonard Katz、Satoshi Yuzawa、Jay D. Keasling

  DOI：10.1021/jacs.2c11027

  日期：2023.4.26

  Modular polyketide synthases (PKSs) are polymerases that employ α-carboxyacyl-CoAs as extender substrates. This enzyme family contains several catalytic modules, where each module is responsible for a single round of polyketide chain extension. Although PKS modules typically use malonyl-CoA or methylmalonyl-CoA for chain elongation, many other malonyl-CoA analogues are used to diversify polyketide structures

  模块化聚酮合酶 (PKS) 是使用 α-羧基辅酶 A 作为增量底物的聚合酶。该酶家族包含多个催化模块，其中每个模块负责单轮聚酮化合物链延伸。尽管 PKS 模块通常使用丙二酰辅酶 A 或甲基丙二酰辅酶 A 进行链延长，但许多其他丙二酰辅酶 A 类似物用于使自然界中的聚酮化合物结构多样化。以前，我们开发了一种方法，通过在保持蛋白质折叠的同时交换酰基转移酶 (AT) 结构域来改变给定模块的延伸底物。在这里，我们报告了13 种 PKS（野生型 PKS 和 12 种具有异常 AT 的 AT 交换 PKS）和 14 种扩展底物的体外聚酮化合物生物合成。我们的 ~200体外反应产生了 13 种结构不同的聚酮化合物，其中包括几种尚未报道的聚酮化合物。在某些情况下，AT 交换的 PKS 产生的目标聚酮化合物是野生型 PKS 的 100 倍以上。这些数据还表明，大多数不寻常的 AT 结构域不包含丙二酰辅酶 A