(1S,3S)-3-ethyl-3,5,10,12-tetrahydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-azaniumyl-2,3,6-trideoxy-alpha-L-lyxo-hexopyranoside

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 蒽环类药物
• 英文名称: (1S,3S)-3-ethyl-3,5,10,12-tetrahydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-azaniumyl-2,3,6-trideoxy-alpha-L-lyxo-hexopyranoside
• 英文别名: [(2S,3S,4S,6R)-6-[[(1S,3S)-3-ethyl-3,5,10,12-tetrahydroxy-6,11-dioxo-2,4-dihydro-1H-tetracen-1-yl]oxy]-3-hydroxy-2-methyloxan-4-yl]azanium
• 化学式: C26H30NO9+
• 分子量: 500.5
• InChiKey: UHYFCDBUKBJSFA-JYFLSIMMSA-O

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  36
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  181
• 氢给体数：
  6
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (1S,3S)-3-ethyl-3,5,10,12-tetrahydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-azaniumyl-2,3,6-trideoxy-alpha-L-lyxo-hexopyranoside 、 氢(+1)阳离子 、 NADPH(4-) 、 氧气 生成 (1S,3S)-3,5,10,12-tetrahydroxy-3-[(1R)-1-hydroxyethyl]-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-azaniumyl-2,3,6-trideoxy-alpha-L-lyxo-hexopyranoside 、 水 、 NADP⁺
  参考文献：
  名称：

  In vivo and in vitro bioconversion of epsilon-rhodomycinone glycoside to doxorubicin: functions of DauP, DauK, and DoxA

  摘要：

  我们最近确定了Streptomyces sp.菌株C5 doxA基因产物的功能，这是一种类似于细胞色素P-450的蛋白质，被确定为多柔比星C-14羟化酶(M. L. Dickens和W. R. Strohl，J. Bacteriol. 178: 3389-3395，1996)。在本研究中，我们展示了DoxA也可以催化13-去氧卡尔米霉素和13-去氧多柔比星的羟基化反应，分别形成13-二氢卡尔米霉素和13-二氢多柔比星，同时氧化13-二氢蒽环类化合物为它们相应的13-酮形式。Streptomyces sp.菌株C5 dauP基因产物也被明确地证明可以去除epsilon-洛多霉素酮-糖苷（洛多霉素D）的羧甲氧基，形成10-羧基-13-去氧卡尔米霉素。此外，发现Streptomyces sp.菌株C5 DauK可以在4-羟基位甲基化蒽环类化合物洛多霉素D，10-羧基-13-去氧卡尔米霉素和13-去氧卡尔米霉素，表明它具有比以前已知的更广泛的底物特异性。Streptomyces sp.菌株C5 doxA、dauK和dauP的产物足以并且必要地赋予Streptomyces lividans TK24将洛多霉素和多柔比星生物合成中的第一个糖苷洛多霉素D转化为多柔比星的能力。

  DOI：

  10.1128/jb.179.8.2641-2650.1997

文献信息

• Purification, Properties, and Characterization of Recombinant <i>Streptomyces</i> sp. Strain C5 DoxA, a Cytochrome P-450 Catalyzing Multiple Steps in Doxorubicin Biosynthesis
  作者：Robbie J. Walczak、Michael L. Dickens、Nigel D. Priestley、William R. Strohl

  DOI：10.1128/jb.181.1.298-304.1999

  日期：1999.1

  DoxA is a cytochrome P-450 monooxygenase involved in the late stages of daunorubicin and doxorubicin biosynthesis that has a broad substrate specificity for anthracycline glycone substrates. Recombinant DoxA was purified to homogeneity from Streptomyces lividans transformed with a plasmid containing the Streptomyces sp. strain C5 doxA gene under the control of the strong SnpR-activated snpA promoter. The purified enzyme was a monomeric, soluble protein with an apparent M _r of 47,000. Purified DoxA catalyzed the 13-hydroxylation of 13-deoxydaunorubicin, the 13-oxidation of 13-dihydrocarminomycin and 13-dihydrodaunorubicin, and the 14-hydroxylation of daunorubicin. The pH optimum for heme activation was pH 7.5, and the temperature optimum was 30°C. The k _cat / K _m values for the oxidation of anthracycline substrates by purified DoxA, incubated with appropriate electron-donating components, were as follows: for 13-deoxydaunorubicin, 22,000 M ⁻¹ · s ⁻¹ ; for 13-dihydrodaunorubicin, 14,000 M ⁻¹ · s ⁻¹ ; for 13-dihydrocarminomycin, 280 M ⁻¹ · s ⁻¹ ; and for daunorubicin, 130 M ⁻¹ · s ⁻¹ . Our results indicate that the conversion of daunorubicin to doxorubicin by this enzyme is not a favored reaction and that the main anthracycline flux through the late steps of the daunorubicin biosynthetic pathway catalyzed by DoxA is likely directed through the 4- O -methyl series of anthracyclines.

  摘要 DoxA 是一种细胞色素 P-450 单加氧酶，参与达柔比星和多柔比星生物合成的后期阶段，对蒽环类糖酮底物具有广泛的底物特异性。重组的 DoxA 可从铁锈色链霉菌（Streptomyces lividans）中纯化至均一。 重组 DoxA 转化了含有 Streptomyces 菌株 C5 doxA 基因的质粒进行转化。 snpA 启动子的控制下。纯化的酶是一种单体可溶性蛋白，其表观分子量为 M r 为 47,000。纯化的 DoxA 催化了 13-脱氧大柔比星的 13-羟基化、13-二氢金霉素和 13-二氢大柔比星的 13-氧化以及大柔比星的 14-羟基化。血红素活化的最佳 pH 值为 7.5，最佳温度为 30°C。在 k cat / K m 纯化的 DoxA 与适当的电子供能成分孵育后氧化蒽环类底物的值如下：13-脱氧腺苷酸，22,000 M -1 - s -1 ；13-二氢杜冷丁为 14,000 M -1 - s -1 ；对于 13-二氢金霉素，280 M -1 - s -1 ；而对于 daunorubicin，则为 130 M -1 - s -1 .我们的研究结果表明，该酶将 daunorubicin 转化为多柔比星并不是一个有利的反应，由 DoxA 催化的通过 daunorubicin 生物合成途径后期步骤的主要蒽环类通量很可能是通过 4- O. O -甲基系列蒽环类化合物。
• Bioconversion of the Anthracycline Analogue Desacetyladriamycin by Recombinant DoxA, a P450-Monooxygenase from <i>Streptomyces</i> sp. Strain C5
  作者：Robbie J. Walczak、Jennifer V. Hines、William R. Strohl、Nigel D. Priestley

  DOI：10.1021/ol015998x

  日期：2001.7.1

  [GRAPHICS]A recombinant P450-monooxygenase, DoxA, obtained from Streptomyces sp, strain C5, the producer of the anticancer compound daunorubicin, was expressed in S. lividans TK24 and therein used to catalyze the conversion of the anthracycline analogue desacetyladriamycin into the new anthracycline, 10-hydroxydesacetyladriamycin. This work establishes a new function for DoxA and demonstrates the use of a recombinant enzyme to prepare a new anthracycline analogue.