10-decarboxymethylaclacinomycin T

• 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: 10-decarboxymethylaclacinomycin T
• 英文别名: (1R,2R,4S)-4-[(2R,4S,5S,6S)-4-(dimethylazaniumyl)-5-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-1,2,7-trihydroxy-6,11-dioxo-3,4-dihydro-1H-tetracen-5-olate
• 化学式: C28H33NO9
• 分子量: 527.6
• InChiKey: IWALHFMBCZSCRZ-SONOWFOZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  38
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  157
• 氢给体数：
  5
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  15-demethoxy-aclacinomycin T 、 AH₂ 、 氧气 生成 10-decarboxymethylaclacinomycin T 、 A 、 二氧化碳 、 水
  参考文献：
  名称：

  阿克拉霉素10-羟化酶是一种新型的底物辅助羟化酶，需要S-腺苷-L-蛋氨酸作为辅因子。

  摘要：

  Aclacinomycin 10-羟化酶是一种甲基转移酶同源物，可催化15-脱甲氧基-ε-紫红霉素的C-10碳原子的S-腺苷-L-蛋氨酸（AdoMet）依赖性羟基化，这是聚酮化合物抗生素β的生物合成步骤-红霉素。S-腺苷-L-高半胱氨酸是该酶的抑制剂，而AdoMet类似物西那芬净可以充当辅因子，表明催化需要正电荷。18O2实验表明羟基源自分子氧。该反应还需要硫醇试剂，例如谷胱甘肽或二硫苏糖醇。在不存在还原剂的情况下将酶与底物一起孵育会导致分子质量与过羟基化合物一致的中间体的积累。加入谷胱甘肽后，该中间体变成产物。流产酶-AdoMet产物三元复合物的晶体结构揭示了大的构象变化，该变化由域旋转组成，导致蒽环类配体结合后导致活性位点封闭。数据表明底物的脱羧作用导致形成碳负离子中间体的机理，该碳负离子中间体通过蒽环类底物的芳香环系统的共振得以稳定。辅因子AdoMet的正电荷有助于电子的离域。氧的活

  DOI：

  10.1074/jbc.m412095200

文献信息

• Modifications of aclacinomycin T by aclacinomycin methyl esterase (RdmC) and aclacinomycin-10-hydroxylase (RdmB) from Streptomyces purpurascens
  作者：Yulong Wang、Jarmo Niemi、Kalervo Airas、Kristiina Ylihonko、Juha Hakala、Pekka Mäntsälä

  DOI：10.1016/s0167-4838(00)00089-3

  日期：2000.7

  The genes rdmB and rdmC of Streptomyces purpurascens encoding aclacinomycin modifying enzymes RdmB and RdmC were expressed in Streptomyces lividans TK24. In contrast to the earlier suggestion that RdmC may be an esterase that causes the removal of the carbomethoxy group from the 10 position of aclacinomycins, RdmC functions as an aclacinomycin methyl esterase and catalyzes the removal of the methoxy group from the C-15 position of aclacinomycin T producing 15-demethoxyaclacinomycin T. RdmB acts upon C-10 of 15-demethoxyaclacinomycin T and is able to remove the carboxylic group from the C-10 position. It functions also as an aclacinomycin-10-hydroxylase being able to add a hydroxyl group at the same, C-10 position in vitro. Aclacinomycin methyl esterase was purified to apparent homogeneity from S. lividans carrying the rdmC and aclacinomycin-10-hydroxylase as a glutathione S-transferase fusion construct from Escherichia coli carrying the rdmB gene, respectively. Aclacinomycin methyl esterase functions as a monomer and aclacinomycin-10-hydroxylase as a tetramer. Aclacinomycin methyl esterase has an exceptionally high temperature stability and has an apparent K-m for aclacinomycin T of 15.5 mu M. The introduction of rdmC and rdmB in a Streptomyces galilaeus mutant HO38 produced the same modifications of aclacinomycin T in vivo as aclacinomycin methyl esterase and aclacinomycin-10-hydroxylase in vitro. (C) 2000 Elsevier Science B.V. All rights reserved.
• Crystal Structure of Aclacinomycin-10-Hydroxylase, a S -Adenosyl- l -Methionine-dependent Methyltransferase Homolog Involved in Anthracycline Biosynthesis in Streptomyces purpurascens
  作者：Anna Jansson、Jarmo Niemi、Ylva Lindqvist、Pekka Mäntsälä、Gunter Schneider

  DOI：10.1016/j.jmb.2003.09.061

  日期：2003.11

  Anthracyclines are aromatic polyketide antibiotics, and several of these compounds are widely used as anti-tumor drugs in chemotherapy. Aclacinomycin-10-hydroxylase (RdmB) is one of the tailoring enzymes that modify the polyketide backbone in the biosynthesis of these metabolites. RdmB, a S-adenosyl-L-methionine-dependent methyltransferase homolog, catalyses the hydroxylation of 15-demethoxy-epsilon-rhodomycin to beta-rhodomycin, one step in rhodomycin biosynthesis in Streptomyces purpurascens. The crystal structure of RdmB, determined by multiwavelength anomalous diffraction to 2.1A resolution, reveals that the enzyme subunit has a fold similar to methyltransferases and binds S-adenosyl-L-methionine. The N-terminal domain, which consists almost exclusively of alpha-helices, is involved in dimerization. The C-terminal domain contains a typical alpha/beta nucleotide-binding fold, which binds S-adenosyl-L-methionine, and several of the residues interacting with the cofactor are conserved in O-methyltransferases. Adjacent to the S-adenosyl-L-methionine molecule there is a large cleft extending to the enzyme surface of sufficient size to bind the substrate. Analysis of the putative substrate-binding pocket suggests that there is no enzymatic group in proximity of the substrate 15-demethoxy-epsilon-rhodomycin, which could assist in proton abstraction and thus facilitate methyl transfer. The lack of a suitably positioned catalytic base might thus be one of the features responsible for the inability of the enzyme to act as a methyltransferase.
• Aclacinomycin 10-Hydroxylase Is a Novel Substrate-assisted Hydroxylase Requiring S-Adenosyl-l-methionine as Cofactor
  作者：Anna Jansson、Hanna Koskiniemi、Anna Erola、Jessy Wang、Pekka Mäntsälä、Gunter Schneider、Jarmo Niemi

  DOI：10.1074/jbc.m412095200

  日期：2005.2

  changes consisting of a domain rotation leading to active site closure upon binding of the anthracycline ligand. The data suggest a mechanism where decarboxylation of the substrate results in the formation of a carbanion intermediate, which is stabilized by resonance through the aromatic ring system of the anthracycline substrate. The delocalization of the electrons is facilitated by the positive charge

  Aclacinomycin 10-羟化酶是一种甲基转移酶同源物，可催化15-脱甲氧基-ε-紫红霉素的C-10碳原子的S-腺苷-L-蛋氨酸（AdoMet）依赖性羟基化，这是聚酮化合物抗生素β的生物合成步骤-红霉素。S-腺苷-L-高半胱氨酸是该酶的抑制剂，而AdoMet类似物西那芬净可以充当辅因子，表明催化需要正电荷。18O2实验表明羟基源自分子氧。该反应还需要硫醇试剂，例如谷胱甘肽或二硫苏糖醇。在不存在还原剂的情况下将酶与底物一起孵育会导致分子质量与过羟基化合物一致的中间体的积累。加入谷胱甘肽后，该中间体变成产物。流产酶-AdoMet产物三元复合物的晶体结构揭示了大的构象变化，该变化由域旋转组成，导致蒽环类配体结合后导致活性位点封闭。数据表明底物的脱羧作用导致形成碳负离子中间体的机理，该碳负离子中间体通过蒽环类底物的芳香环系统的共振得以稳定。辅因子AdoMet的正电荷有助于电子的离域。氧的活