D-(3-hydroxy-4-methyl)kynurenine

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: D-(3-hydroxy-4-methyl)kynurenine
• 英文别名: (2R)-2-amino-4-(2-amino-3-hydroxy-4-methylphenyl)-4-oxobutanoic acid
• 化学式: C₁₁H₁₄N₂O₄
• 分子量: 238.243
• InChiKey: BHPWCYYINLFUDE-SSDOTTSWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.5
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  131
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  DL-3-羟基犬尿氨酸 在 methyltransferase SibL 、 copper(II) sulfate 作用下， 以 水 、 异丙醇 为溶剂， 反应 2.0h， 生成 D-(3-hydroxy-4-methyl)kynurenine
  参考文献：
  名称：

  3,5-二羟基-4-甲基邻氨基苯甲酸形成并掺入抗肿瘤抗生素西比霉素的四酶途径

  摘要：

  抗肿瘤抗生素西伯霉素属于由多种放线菌产生的吡咯并[1,4]苯并二氮杂（PBDs）类。PBD是序列特异性DNA烷基化剂，具有显着的抗肿瘤特性。其中，西比霉素是两种已鉴定的糖基化PBD之一，显示出最高的DNA结合亲和力和最有效的抗肿瘤活性。在这项研究中，我们报道了从已知代谢物3-羟基犬尿氨酸（3HK）开始，阐明了导致在sibiromycin中发现的3,5-二羟基-4-甲基邻氨基苯甲酸构造单元的精​​确反应序列的过程。研究的途径由四种酶组成，这些酶在体外进行了生化表征。从3HK开始，SAM依赖性甲基转移酶SibL将底物转化为其4-甲基衍生物，然后通过PLP依赖性犬尿氨酸酶SibQ的作用进行水解，导致形成3-羟基-4-甲基邻氨基苯甲酸（3H4MAA）。随后，NRPS二结构域SibE激活3H4MAA，并将其束缚至其硫醇化结构域，在该结构中，其被CAD上的FAD / NADH依赖性羟化酶SibG羟基化

  DOI：

  10.1021/bi2006114

文献信息

• Aromatic <i>C-</i>Methyltransferases with Antipodal Stereoselectivity for Structurally Diverse Phenolic Amino Acids Catalyze the Methylation Step in the Biosynthesis of the Actinomycin Chromophore
  作者：Ivana Crnovčić、Roderich Süssmuth、Ullrich Keller

  DOI：10.1021/bi101422r

  日期：2010.11.16

  The actinomycin biosynthetic gene cluster of Streptomyces chrysomallus harbors two paralogous genes, acmI and acmL, encoding methyltransferases. To unveil their suspected role in the formation of 3-hydroxy-4-methyl-anthranilic acid (4-MHA), the building block of the actinomycin chromophore, each gene was expressed in Escherichia coli. Testing the resulting similar to 40 kDa His(6)-tagged proteins with compounds of biogenetic relevance as substrates and S-adenosyl-L-methionine revealed that each exclusively methylated 3-hydroxykynurenine (3-HK) with formation of 3-hydroxy-4-methylkynurenine (4-MHK) identified by its in vitro conversion to 4-MHA with hydroxykynureninase. AcmI and AcmL methylate also hydroxyphenylamino propanoic acids such as p-tyrosine, m-tyrosine, or 3,4-dihydroxy-L-phenylalanine (DOPA) but at a lower rate than 3-HK. The presence of the alpha-amino group was necessary for substrate recognition. Phenolic acids with shorter chains such as 4-hydoxyphenyl-L-glycine (HPG), 3-hydroxybenzoic acid (3-HB), or 3-hydroxyanthranilic acid (3-HA) gave no product. Both enzymes were stereospecific for the optical configuration at alpha-C with unprecedented antipodal selectivity for the D-enantiomer of 3-HK and the L-enantiomer of p-tyrosine or m-tyrosine. AcmI and AcmL show sequence similarity to various C- and O-methyltransferases from bacteria. Phylogenetic analysis places them into the clade of C-methyltransferases comprising among others orthologues involved in 4-MHA formation of other biosynthesis systems and methyltransferases putatively involved in the C-methylation of tyrosine. Remarkably, computational remodelling of AcmI and AcmL structures revealed significant similarity with the 3-D structures of type 1 O-methyltransferases from plants such as caffeic acid O-methyltransferase (COMT) and other phenylpro-panoid methyltransferases. The relevance of 3-HK or 3-HA methylation in the actinomycin biosynthesis pathways of different actinomycetes is discussed.
• A Four-Enzyme Pathway for 3,5-Dihydroxy-4-methylanthranilic Acid Formation and Incorporation into the Antitumor Antibiotic Sibiromycin
  作者：Tobias W. Giessen、Femke I. Kraas、Mohamed A. Marahiel

  DOI：10.1021/bi2006114

  日期：2011.6.28

  The antitumor antibiotic sibiromycin belongs to the class of pyrrolo[1,4]benzodiazepines (PBDs) that are produced by a variety of actinomycetes. PBDs are sequence-specific DNA-alkylating agents and possess significant antitumor properties. Among them, sibiromycin, one of two identified glycosylated PBDs, displays the highest DNA binding affinity and the most potent antitumor activity. In this study

  抗肿瘤抗生素西伯霉素属于由多种放线菌产生的吡咯并[1,4]苯并二氮杂（PBDs）类。PBD是序列特异性DNA烷基化剂，具有显着的抗肿瘤特性。其中，西比霉素是两种已鉴定的糖基化PBD之一，显示出最高的DNA结合亲和力和最有效的抗肿瘤活性。在这项研究中，我们报道了从已知代谢物3-羟基犬尿氨酸（3HK）开始，阐明了导致在sibiromycin中发现的3,5-二羟基-4-甲基邻氨基苯甲酸构造单元的精​​确反应序列的过程。研究的途径由四种酶组成，这些酶在体外进行了生化表征。从3HK开始，SAM依赖性甲基转移酶SibL将底物转化为其4-甲基衍生物，然后通过PLP依赖性犬尿氨酸酶SibQ的作用进行水解，导致形成3-羟基-4-甲基邻氨基苯甲酸（3H4MAA）。随后，NRPS二结构域SibE激活3H4MAA，并将其束缚至其硫醇化结构域，在该结构中，其被CAD上的FAD / NADH依赖性羟化酶SibG羟基化