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.