D-N-formylkynurenine | 13441-52-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: D-N-formylkynurenine
• 英文别名: N-formylkynurenine；(2R)-2-ammonio-4-(2-formamidophenyl)-4-oxobutanoate；(2R)-2-azaniumyl-4-(2-formamidophenyl)-4-oxobutanoate
• CAS: 13441-52-6
• 化学式: C₁₁H₁₂N₂O₄
• 分子量: 236.227
• InChiKey: BYHJHXPTQMMKCA-MRVPVSSYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.3
• 重原子数：
  17
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  110
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  D-色氨酸 在 recombinant human indoleamine 2,3-dioxygenase 、 亚甲兰 、 L-dehydroascorbic acid 、 bovine liver catalase 作用下， 以 aq. phosphate buffer 为溶剂， 反应 0.5h， 生成 D-N-formylkynurenine
  参考文献：
  名称：

  Human indoleamine 2,3-dioxygenase-2 has substrate specificity and inhibition characteristics distinct from those of indoleamine 2,3-dioxygenase-1

  摘要：

  Indoleamine 2,3-dioxygenase-2 (IDO2) is one of three enzymes (alongside tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase (IDO1)) that catalyse dioxygenation of L-tryptophan as the first step in the kynurenine pathway. Despite the reported expression of IDO2 in tumours, some fundamental characteristics of the enzyme, such as substrate specificity and inhibition selectivity, are still to be clearly defined. In this study, we report the kinetic and inhibition characteristics of recombinant human IDO2. Choosing from a series of likely IDO2 substrates, we screened 54 tryptophan derivatives and tryptophan-like molecules, and characterised the 8 with which the enzyme was most active. Specificity of IDO2 for the two isomers of 1-methyltryptophan was also evaluated and the findings compared with those obtained in other studies on IDO2 and IDO1. Interestingly, IDO2 demonstrates behaviour distinct from that of IDO1 in terms of substrate specificity and affinity, such that we have identified tryptophan derivatives that are mutually exclusive as substrates for IDO1 and IDO2. Our results support the idea that the antitumour activity of 1-Me-D-Trp is unlikely to be related with competitive inhibition of IDO2, and also imply that there are subtle differences in active site structure in the two enzymes that may be exploited in the development of specific inhibitors of these enzymes, a route which may prove important in defining their role(s) in cancer.

  DOI：

  10.1007/s00726-014-1766-3

文献信息

• Novel Tryptophan Catabolic Enzyme IDO2 Is the Preferred Biochemical Target of the Antitumor Indoleamine 2,3-Dioxygenase Inhibitory Compound <scp>d</scp>-1-Methyl-Tryptophan
  作者：Richard Metz、James B. DuHadaway、Uma Kamasani、Lisa Laury-Kleintop、Alexander J. Muller、George C. Prendergast

  DOI：10.1158/0008-5472.can-07-1872

  日期：2007.8.1

  Small-molecule inhibitors of indoleamine 2,3-dioxygenase (IDO) are currently being translated to clinic for evaluation as cancer therapeutics. One issue related to trials of the clinical lead inhibitor, d-1-methyl-tryptophan (D-1MT), concerns the extent of its biochemical specificity for IDO. Here, we report the discovery of a novel IDO-related tryptophan catabolic enzyme termed IDO2 that is preferentially inhibited by D-1MT. IDO2 is not as widely expressed as IDO but like its relative is also expressed in antigen-presenting dendritic cells where tryptophan catabolism drives immune tolerance. We identified two common genetic polymorphisms in the human gene encoding IDO2 that ablate its enzymatic activity. Like IDO, IDO2 catabolizes tryptophan, triggers phosphorylation of the translation initiation factor eIF2α, and (reported here for the first time) mobilizes translation of LIP, an inhibitory isoform of the immune regulatory transcription factor NF-IL6. Tryptophan restoration switches off this signaling pathway when activated by IDO, but not IDO2, arguing that IDO2 has a distinct signaling role. Our findings have implications for understanding the evolution of tumoral immune tolerance and for interpreting preclinical and clinical responses to D-1MT or other IDO inhibitors being developed to treat cancer, chronic infection, and other diseases. [Cancer Res 2007;67(15):7082–7]

  摘要 吲哚胺 2,3-二氧化酶（IDO）的小分子抑制剂目前正被转化为临床癌症治疗药物。与临床先导抑制剂 d-1-甲基色氨酸（D-1MT）的试验有关的一个问题是其对 IDO 的生化特异性程度。在这里，我们报告发现了一种新的与 IDO 相关的色氨酸分解酶 IDO2，这种酶会优先受到 D-1MT 的抑制。IDO2 不像 IDO 那样广泛表达，但和它的亲戚一样，IDO2 也在抗原递呈树突状细胞中表达，在树突状细胞中色氨酸分解作用驱动免疫耐受。我们在编码 IDO2 的人类基因中发现了两种常见的基因多态性，它们会削弱 IDO2 的酶活性。与 IDO 一样，IDO2 也分解色氨酸，引发翻译起始因子 eIF2α 的磷酸化，并（在此首次报道）调动免疫调节转录因子 NF-IL6 的抑制性异构体 LIP 的翻译。色氨酸还原在被 IDO 激活时会关闭这一信号通路，但 IDO2 不会，这表明 IDO2 具有不同的信号作用。我们的发现对于理解肿瘤免疫耐受的演变，以及解释临床前和临床对 D-1MT 或其他正在开发的 IDO 抑制剂的反应，以治疗癌症、慢性感染和其他疾病都有意义。[癌症研究 2007；67（15）：7082-7］
• Antigen-binding molecules, the antigen-binding activity of which varies according to the concentration of compounds, and libraries of said molecules
  申请人：CHUGAI SEIYAKU KABUSHIKI KAISHA

  公开号：US10961530B2

  公开（公告）日：2021-03-30

  An objective of the present invention is to provide target tissue-specific antigen-binding molecules, antigen-binding molecules whose antigen-binding activity varies depending on the concentration of an unnatural compound, libraries comprising a plurality of the antigen-binding molecules which are different from one another, pharmaceutical compositions comprising the antigen-binding molecules, methods of screening for the antigen-binding molecules, and methods for producing the antigen-binding molecules. The present inventors created antigen-binding domains whose antigen-binding activity varies depending on the concentration of a small molecule compound or antigen-binding molecules containing an antigen-binding domain, and libraries comprising a plurality of the antigen-binding domains which are different from one another or antigen-binding domains, and demonstrated that the above-noted objective could be achieved by using the libraries. Various diseases originating from target tissues can be treated in a target tissue-specific manner by using the antigen-binding molecules of the present invention.

  本发明的目的是提供靶组织特异性抗原结合分子、抗原结合活性随非天然化合物浓度变化而变化的抗原结合分子、包含多种彼此不同的抗原结合分子的文库、包含抗原结合分子的药物组合物、筛选抗原结合分子的方法以及生产抗原结合分子的方法。本发明人创造了抗原结合活性随小分子化合物或含有抗原结合结构域的抗原结合分子的浓度而变化的抗原结合结构域，以及包含多个互不相同的抗原结合结构域或抗原结合结构域的文库，并证明使用这些文库可以实现上述目标。通过使用本发明的抗原结合分子，可以以靶组织特异性的方式治疗源于靶组织的各种疾病。
• Human Tryptophan Dioxygenase:  A Comparison to Indoleamine 2,3-Dioxygenase
  作者：Dipanwita Batabyal、Syun-Ru Yeh

  DOI：10.1021/ja076186k

  日期：2007.12.1

  In contrast to the diverse superfamily of monooxygenases, there are only two classes of hemecontaining dioxygenases in humans, One is tryptophan 2,3 dioxygenase (hTDO), and the other is indoleamine 2,3-dioxygenase (hlDO), both of which catalyze the oxidative degradation of Trp to N-formyl kynurenine. Although hTDO and hIDO catalyze the same reaction, they engage in distinct physiological functions. The molecular properties of hTDO, unlike hIDO, have never been explored in the past. Here, we report the first structural and functional characterization of hTDO with resonance Raman and optical absorption spectroscopies. We show that the proximal Fe-His stretching frequency of hTDO is 229 cm(-1), 7 cm-1 lower than that of hIDO, indicating its weaker imidazolate character as compared to hIDO. In the CO derivative of the L-Trp-bound enzyme, the Fe-CO stretching and C-O stretching frequencies are 488 and 1972 cm-1, respectively, suggesting that L-Trp binds to the distal pocket with its C-2-C-3 double bond facing the heme-bound ligand, in contrast to hIDO, in which the indole NH group forms an H-bond with the heme-bound ligand. Moreover, the Km values of hTDO for D-Trp and L-Trp are similar, but the k(cal) value for D-Trp is 10-fold lower than that for L-Trp. In contrast, in hIDO, the Km value for D-Trp is 700-fold higher than L-Trp, whereas the kat values are comparable for the two stereoisomers. Taken together, the data indicate that the initial deprotonation reaction of the indole NH group in hTDO is carried out by the evolutionarily conserved distal His, whereas that in hIDO is performed by the heme-bound dioxygen; in addition, the stereospecificity of hTDO is determined by the efficiency of the dioxygen chemistry, whereas that in hIDO is controlled by the substrate affinity.
• Redox reactions related to indoleamine 2,3-dioxygenase and tryptophan metabolism along the kynurenine pathway
  作者：S.R. Thomas、R. Stocker

  DOI：10.1179/135100099101534927

  日期：1999.10

  The heme enzyme indoleamine 2,3-dioxygenase (IDO) oxidizes the pyrrole moiety of L-tryptophan (Trp) and other indoleamines and represents the initial and rate-limiting enzyme of the kynurenine (Kyn) pathway. IDO is a unique enzyme in that it can utilize superoxide anion radical (O-2(.-)) as both a substrate and a co-factor. The latter role is due to the ability of O-2(.-) to reduce inactive ferric-IDO to the active ferrous form. Nitrogen monoxide ((NO)-N-.) and H2O2 inhibit the dioxygenase and various inter-relationships between the nitric oxide synthase- and IDO-initiated amino acid degradative pathways exist. Induction of IDO and metabolism of Trp along the Kyn pathway is implicated in a variety of physiological and pathophysiological processes, including anti-microbial and anti-tumor defense, neuropathology, immunoregulation and antioxidant activity. Antioxidant activity may arise from O-2(.-) scavenging by IDO and formation of the potent radical scavengers and Kyn pathway metabolites, 3-hydroxyanthranilic acid and 3-hydroxykynurenine. Under certain conditions, these aminophenols and other Kyn pathway metabolites may exhibit pro-oxidant activities. This article reviews findings indicating that redox reactions are involved in the regulation of IDO and Trp metabolism along the Kyn pathway and also participate in the biological activities exhibited by Kyn pathway metabolites.
• Molecular Evolution and Characterization of Fungal Indoleamine 2,3-Dioxygenases
  作者：Hajime J. Yuasa、Helen J. Ball

  DOI：10.1007/s00239-010-9412-5

  日期：2011.2

  Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are tryptophan-degrading enzymes. Mammalian IDO expression is induced by cytokines and has antimicrobial and immunomodulatory effects. A major role of mammalian TDO is to supply nicotinamide adenine dinucleotide (NAD(+)). In fungi, the IDO homologue is thought to be expressed constitutively and supply NAD(+), as TDO is absent from their genomes. Here, we reveal the distribution of IDO genes among fungal species and characterize their enzymatic activity. The yeast, Saccharomyces cerevisiae has only one IDO gene, whereas the koji-mold, Aspergillus oryzae has two genes, IDO alpha and IDO beta. The A. oryzae IDO alpha showed more similar enzymatic properties to those of S. cerevisiae IDO than IDO beta, suggesting that the A. oryzae IDO alpha is a functional homologue of the S. cerevisiae IDO. From the IDO beta gene, two isoforms, IDO beta and IDO beta(+) could be generated by alternative splicing. The latter contained a 17 amino acids insertion which were encoded by the first intron of IDO beta gene. In comparison to IDO beta(+), bacterially expressed IDO beta showed much lower K (m) value and more than five-times faster V (max) value, resulting in 85 times higher catalytic efficiency; i.e., the removal of the domain encoded by the first intron from IDO beta(+) increases its enzymatic activity drastically. This might be a unique regulation mechanism of the l-Trp metabolism in the A. oryzae. The levo-1-methyl tryptophan (l-1MT) is a good inhibitor of both IDO1 and IDO2. However, the activity of fungal IDOs tested was not inhibited at all by l-1MT.