基于生物合成途径改造的一个三欣卡辛类似物的发现

Production of a Trioxacarcin Analogue by Engineering of Its Biosynthetic Pathway

三欣卡辛是一种来源于链霉菌的具有良好抗肿瘤活性的芳香聚酮类天然产物.我们通过对三欣卡辛的发酵和分离条件进行优化,显著地提高了其产量.通过对基因簇中一个酰基转移酶(Trx49)编码基因的敲除,改动了三欣卡辛的生物合成途径,获得了C-4位糖基上O-乙酰基缺失的三欣卡辛类似物1.体外细胞毒性测试考察糖基上的O-乙酰基修饰缺失对三欣卡辛的影响,发现化合物1的生物活性比三欣卡辛A有所降低,但仍具有IC50为4.86 nmol?L-1的优异抗肿瘤细胞活性.

Trioxacarcins, derived from streptomyces, are aromatic polyketide natural products with antitumor activity. The production of trioxacarcins was improved significantly by optimizing the fermentation and purification processes. The biosyn- thetic pathway of trioxacareins was changed by inactivating an acyltransferase （Trx49） gene in the trioxacarcin cluster, and an analogue compound I lacking the O-acetyl group of sugar on C-4 was obtained. The influence of the O-acetyl group on biological activity of trioxacarcins was investigated by in vitro cytotoxicity test. Compared with trioxacarcin A, the activity of compound 1 decreases to some extent but still persists an excellent anti-tumor activity level with IC50 value of 4.86 nmol.L-1.