McGuire J C, Thomas M C, Stroshane R M, Hamilton B K, White R J
Antimicrob Agents Chemother. 1980 Sep;18(3):454-64. doi: 10.1128/AAC.18.3.454.
Daunorubicin (daunomycin; NSC 82151) is a fermentation-derived anthracycline antibiotic that is clinically useful in the treatment of human leukemias. Daunorubicin itself is found rarely in microbial fermentations, but is present normally in the form of glycoside derivatives that yield the free drug on simple acid hydrolysis. A major by-product of daunorubicin fermentations is usually the structurally related anthracyclinone epsilon-rhodomycinone. We have used mutants of a daunorubicin-producing Streptomyces species to study the biosynthetic relationship between epsilon-rhodomycinone and daunorubicin. We found that exogenously added epsilon-rhodomycinone can be converted to daunorubicin glycosides by a nonproducing mutant and by a mutant that produces daunorubicin glycosides but not epsilon-rhoeomycinone. Molar conversion efficiences were in the 15 to 30% range. The latter mutant was also shown to convert exogenous 14C-labeled epsilon-rhodomycinone to 14C-labeled daunorubicin glycosides, again at conversion efficiencies of about 25%. The same biotransformation was observed with daunorubicin production strain C5, which normally accumulates both epsilon-rhodomycinone and daunorubicin glycosides. A significant percentage (16 to 37%) of exogenously added epsilon-[14C]rhodomycinone was metabolized by strain C5, and 22 to 32% of the metabolized radioactivity could be recovered as daunorubicin glycosides. A mathematical model of epsilon-rhodomycinone metabolism was constructed based on plausible assumptions concerning the kinetics of epsilon-rhodomycinone accumulation and catabolsim. When analyzed according to this model, our data indicate that most (63 to 73%), but not all, of the daunorubicin glycosides accumulated in the experiments with production strain C5 derived from epsilon-rhodomycinone. A pathway network for the biosynthesis of daunorubicin glycosides is proposed that is in agreement with these data. In this proposed pathway network, epsilon-rhodomycinone is an intermediate in one of at least two pathways which yield daunorubicin glycosides.
柔红霉素（道诺霉素；NSC 82151）是一种通过发酵产生的蒽环类抗生素，在临床上可用于治疗人类白血病。柔红霉素本身在微生物发酵中很少见，但通常以糖苷衍生物的形式存在，这些衍生物在简单的酸水解后可产生游离药物。柔红霉素发酵的一种主要副产物通常是结构相关的蒽环酮ε-玫瑰霉素酮。我们利用一株产柔红霉素的链霉菌属突变体来研究ε-玫瑰霉素酮与柔红霉素之间的生物合成关系。我们发现，外源添加的ε-玫瑰霉素酮可被一株不产柔红霉素的突变体以及一株产柔红霉素糖苷但不产ε-玫瑰霉素酮的突变体转化为柔红霉素糖苷。摩尔转化率在15%至30%的范围内。还发现后一种突变体可将外源14C标记的ε-玫瑰霉素酮转化为14C标记的柔红霉素糖苷，转化率同样约为25%。在通常会积累ε-玫瑰霉素酮和柔红霉素糖苷的柔红霉素生产菌株C5中也观察到了相同的生物转化。外源添加的ε-[14C]玫瑰霉素酮有相当比例（16%至37%）被菌株C5代谢，其中22%至32%的代谢放射性可作为柔红霉素糖苷回收。基于关于ε-玫瑰霉素酮积累和分解代谢动力学的合理假设构建了ε-玫瑰霉素酮代谢的数学模型。根据该模型进行分析时，我们的数据表明，在使用生产菌株C5进行的实验中积累的柔红霉素糖苷大部分（63%至73%），但并非全部，源自ε-玫瑰霉素酮。提出了一个与这些数据相符的柔红霉素糖苷生物合成途径网络。在这个提出的途径网络中，ε-玫瑰霉素酮是至少两条产生柔红霉素糖苷的途径之一的中间体。
