itaconate | 2964-00-3

• 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: itaconate
• 英文别名: Methylenesuccinate(2-)；2-methylidenebutanedioate
• CAS: 2964-00-3
• 化学式: C₅H₄O₄
• 分子量: 128.084
• InChiKey: LVHBHZANLOWSRM-UHFFFAOYSA-L

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  9
• 可旋转键数：
  1
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  80.3
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  itaconate 、 L-cysteine residue 生成 S-(2,3-dicarboxypropyl)-L-cysteine residue
  参考文献：
  名称：

  衣康酸盐是一种抗炎代谢物，可通过 KEAP1 的烷基化激活 Nrf2

  摘要：

  内源性代谢物衣康酸盐最近作为巨噬细胞功能的调节剂出现，但其确切的作用机制仍知之甚少。在这里，我们表明衣康酸是小鼠和人类巨噬细胞中脂多糖激活抗炎转录因子 Nrf2（也称为 NFE2L2）所必需的。我们发现衣康酸盐通过半胱氨酸残基的烷基化直接修饰蛋白质。衣康酸酯使 KEAP1 蛋白上的半胱氨酸残基 151、257、288、273 和 297 烷基化，使 Nrf2 能够增加具有抗氧化和抗炎能力的下游基因的表达。衣康酸盐的抗炎作用需要激活 Nrf2。我们描述了一种新的细胞渗透性衣康酸酯衍生物，4-辛基衣康酸酯的使用，它在体内可防止脂多糖诱导的致死性并减少细胞因子的产生。我们表明 I 型干扰素可促进 Irg1（也称为 Acod1）的表达和衣康酸的产生。此外，我们发现衣康酸盐的产生限制了 I 型干扰素的反应，表明涉及干扰素和衣康酸盐的负反馈回路。我们的研究结果表明，衣康酸盐是一种重要的抗炎代谢物，它通过

  DOI：

  10.1038/nature25986
• 作为产物：
  描述：

  cis-aconitate 、 氢(+1)阳离子 生成 二氧化碳 、 itaconate
  参考文献：
  名称：

  Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production

  摘要：

  免疫响应基因1（Irg1）在哺乳动物巨噬细胞炎症期间高度表达，但其生物功能尚未阐明。在这里，我们确定Irg1是编码酶的基因，该酶通过去羧化顺式-顺丁二酸（三羧酸循环中间体）产生顺式-丙烯酸（也称为甲基丁烯二酸）。通过在小鼠和人类免疫细胞中使用增益和失去功能方法，我们发现Irg1表达水平与顺式-丙烯酸的量相关，该代谢产物先前被认为具有抗微生物作用。我们纯化了IRG1蛋白，并在酶学测定中确定了其顺式-顺丁二酸去羧化活性。顺式-丙烯酸是一种有机化合物，可以抑制异柠檬酸裂解酶，这是甘氨酸循环关键酶，是特定条件下细菌生长的必要途径。在这里，我们展示了顺式-丙烯酸抑制表达异柠檬酸裂解酶的细菌（如沙门氏菌和结核分枝杆菌）的生长。此外，巨噬细胞中的Irg1基因沉默导致胞内顺式-丙烯酸水平显著降低，以及在细菌感染期间显著降低抗微生物活性。综上所述，我们的结果表明，IRG1通过催化顺式-丙烯酸的产生将细胞代谢与免疫防御联系起来。

  DOI：

  10.1073/pnas.1218599110

文献信息

• Properties of Succinyl-Coenzyme A: <scp>l</scp> -Malate Coenzyme A Transferase and Its Role in the Autotrophic 3-Hydroxypropionate Cycle of <i>Chloroflexus aurantiacus</i>
  作者：Silke Friedmann、Astrid Steindorf、Birgit E. Alber、Georg Fuchs

  DOI：10.1128/jb.188.7.2646-2655.2006

  日期：2006.4

  The 3-hydroxypropionate cycle has been proposed to operate as the autotrophic CO ₂ fixation pathway in the phototrophic bacterium Chloroflexus aurantiacus . In this pathway, acetyl coenzyme A (acetyl-CoA) and two bicarbonate molecules are converted to malate. Acetyl-CoA is regenerated from malyl-CoA by l -malyl-CoA lyase. The enzyme forming malyl-CoA, succinyl-CoA: l -malate coenzyme A transferase, was purified. Based on the N-terminal amino acid sequence of its two subunits, the corresponding genes were identified on a gene cluster which also contains the gene for l -malyl-CoA lyase, the subsequent enzyme in the pathway. Both enzymes were severalfold up-regulated under autotrophic conditions, which is in line with their proposed function in CO ₂ fixation. The two CoA transferase genes were cloned and heterologously expressed in Escherichia coli , and the recombinant enzyme was purified and studied. Succinyl-CoA: l -malate CoA transferase forms a large (αβ) _n complex consisting of 46- and 44-kDa subunits and catalyzes the reversible reaction succinyl-CoA + l -malate → succinate + l -malyl-CoA. It is specific for succinyl-CoA as the CoA donor but accepts l -citramalate instead of l -malate as the CoA acceptor; the corresponding d -stereoisomers are not accepted. The enzyme is a member of the class III of the CoA transferase family. The demonstration of the missing CoA transferase closes the last gap in the proposed 3-hydroxypropionate cycle.

  摘要 有人提出 3-羟基丙酸循环作为自养型 CO 2 固定途径。 的自养二氧化碳固定途径。 .在这一途径中，乙酰辅酶 A（乙酰-CoA）和两个碳酸氢分子被转化为苹果酸。乙酰辅酶 A 通过以下途径从苹果酸中再生 l -丙二酸裂解酶从丙二酸中再生。形成丙二酰-CoA、琥珀酰-CoA 的酶： l -丙二酸辅酶 A 转移酶。根据其两个亚基的 N 端氨基酸序列，在一个基因簇上确定了相应的基因，该基因簇还包括 l -丙二酰-CoA：l -丙二酸辅酶 A 转移酶的基因。 l -丙二酰-CoA 裂解酶的基因。在自养条件下，这两种酶都有数倍的上调，这与它们在 CO 2 固定的功能。这两种 CoA 转移酶基因被克隆并异源表达于 大肠杆菌 对重组酶进行了纯化和研究。琥珀酰-CoA： l 琥珀酰-CoA：l-苹果酸 CoA 转移酶形成一个大的 (αβ) n 复合物，催化琥珀酰-CoA + l -苹果酸的可逆反应。 l -丙二酸 → 琥珀酸 + l -丙二酸。它专门以琥珀酰-CoA 作为 CoA 供体，但也接受 l -柠檬醛酸，而不是 l -丙二酸作为 CoA 受体；相应的 d -立体异构体不被接受。该酶属于 CoA 转移酶家族第三类。缺失的 CoA 转移酶的发现填补了 3-羟基丙酸循环中的最后一个空白。
• BENTLEY R.; THIESSEN C.P., J Biol Chem, 1957, 0021-9258, 703-20
  作者：BENTLEY R.、THIESSEN C.P.

  DOI：——

  日期：——
• Cloning and functional characterization of the cis-aconitic acid decarboxylase (CAD) gene from Aspergillus terreus
  作者：Shin Kanamasa、Lies Dwiarti、Mitsuyasu Okabe、Enoch Y. Park

  DOI：10.1007/s00253-008-1523-1

  日期：2008.8

  A filamentous fungus Aspergillus terreus produces itaconic acid, which is predicted to be derived from cis-aconitic acid via catalysis by cis-aconitic acid decarboxylase (CAD) in the carbon metabolism of the fungus. To clarify the enzyme's function and a pathway for itaconic acid biosynthesis, we cloned a novel gene encoding the enzyme. The open reading frame of this gene (CAD1) consists of 1,529 bp encoding 490 amino acids and is interrupted by a single intron. Among the identified proteins in the database, the primary structure of the protein encoded by CAD1 shared high identity with the MmgE/PrpD family of proteins, including a number of 2-methylcitrate dehydratases of bacteria. The cloned gene excluding an intron was introduced into the expression plasmid pAUR-CAD1 controlled by the ADH1 promoter. The CAD activity in Saccharomyces cerevisiae was confirmed by directly detecting itaconic acid as a product from cis-aconitic acid as a substrate. This result reveals for the first time that this gene encodes CAD, which is essential for itaconic acid production in A. terreus.
• <i>Ustilago maydis</i>produces itaconic acid via the unusual intermediate<i>trans</i>‐aconitate
  作者：Elena Geiser、Sandra K Przybilla、Alexandra Friedrich、Wolfgang Buckel、Nick Wierckx、Lars M Blank、Michael Bölker

  DOI：10.1111/1751-7915.12329

  日期：2016.1

  SummaryItaconic acid is an important biomass‐derived chemical building block but has also recently been identified as a metabolite produced in mammals, which has antimicrobial activity. The biosynthetic pathway of itaconic acid has been elucidated in the ascomycetous fungus Aspergillus terreus and in human macrophages. In both organisms itaconic acid is generated by decarboxylation of the tricarboxylic acid (TCA) cycle intermediate cis‐aconitate. Here, we show that the basidiomycetous fungus Ustilago maydis uses an alternative pathway and produces itaconic acid via trans‐aconitate, the thermodynamically favoured isomer of cis‐aconitate. We have identified a gene cluster that contains all genes involved in itaconic acid formation. Trans‐aconitate is generated from cis‐aconitate by a cytosolic aconitate‐Δ‐isomerase (Adi1) that belongs to the PrpF family of proteins involved in bacterial propionate degradation. Decarboxylation of trans‐aconitate is catalyzed by a novel enzyme, trans‐aconitate decarboxylase (Tad1). Tad1 displays significant sequence similarity with bacterial 3‐carboxy‐cis,cis‐muconate lactonizing enzymes (CMLE). This suggests that U. maydis has evolved an alternative biosynthetic pathway for itaconate production using the toxic intermediate trans‐aconitate. Overexpression of a pathway‐specific transcription factor (Ria1) or a mitochondrial tricarboxylic acid transporter (Mtt1) resulted in a twofold increase in itaconate yield. Therefore, our findings offer new strategies for biotechnological production of this valuable biomass‐derived chemical.