Rui Zhe, Ye Min, Wang Shuoguo, Fujikawa Kaori, Akerele Bankole, Aung May, Floss Heinz G, Zhang Wenjun, Yu Tin-Wein
Department of Biological Science, Louisiana State University, Baton Rouge, LA 70803, USA.
Chem Biol. 2012 Sep 21;19(9):1116-25. doi: 10.1016/j.chembiol.2012.07.025.
Phenazine-type metabolites arise from either phenazine-1-carboxylic acid (PCA) or phenazine-1,6-dicarboxylic acid (PDC). Although the biosynthesis of PCA has been studied extensively, PDC assembly remains unclear. Esmeraldins and saphenamycin, the PDC originated products, are antimicrobial and antitumor metabolites isolated from Streptomyces antibioticus Tü 2706. Herein, the esmeraldin biosynthetic gene cluster was identified on a dispensable giant plasmid. Twenty-four putative esm genes were characterized by bioinformatics, mutagenesis, genetic complementation, and functional protein expressions. Unlike enzymes involved in PCA biosynthesis, EsmA1 and EsmA2 together decisively promoted the PDC yield. The resulting PDC underwent a series of conversions to give 6-acetylphenazine-1-carboxylic acid, saphenic acid, and saphenamycin through a unique one-carbon extension by EsmB1-B5, a keto reduction by EsmC, and an esterification by EsmD1-D3, the atypical polyketide sythases, respectively. Two transcriptional regulators, EsmT1 and EsmT2, are required for esmeraldin production.
吩嗪类代谢产物源自吩嗪 - 1 - 羧酸（PCA）或吩嗪 - 1,6 - 二羧酸（PDC）。尽管PCA的生物合成已得到广泛研究，但PDC的组装仍不清楚。埃斯梅拉定和沙芬霉素是源自PDC的产物，它们是从抗生链霉菌Tü 2706中分离出的抗菌和抗肿瘤代谢产物。在此，埃斯梅拉定生物合成基因簇在一个可移动的巨型质粒上被鉴定出来。通过生物信息学、诱变、遗传互补和功能性蛋白质表达对24个假定的esm基因进行了表征。与参与PCA生物合成的酶不同，EsmA1和EsmA2共同决定性地提高了PDC的产量。生成的PDC分别通过EsmB1 - B5进行独特的一碳延伸、EsmC进行酮还原以及EsmD1 - D3进行酯化（这些都是非典型聚酮合酶），经过一系列转化生成6 - 乙酰吩嗪 - 1 - 羧酸、沙芬酸和沙芬霉素。埃斯梅拉定的产生需要两个转录调节因子EsmT1和EsmT2。
