Tao Chen, Wang Quyi, Ji Junyang, Zhou Ziyue, Yue Bingjie, Zhang Ran, Jiang Shu, Yuan Tianjie
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Jiangsu Collaborative Innovation Center of Chinese Medical Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, China.
Front Microbiol. 2024 Apr 16;15:1393073. doi: 10.3389/fmicb.2024.1393073. eCollection 2024.
Carbon catabolite repression (CCR) is a highly conserved mechanism that regulates carbon source utilization in . CCR has a negative impact on secondary metabolite fermentation, both in industrial and research settings. In this study, CCR was observed in the daunorubicin (DNR)-producing strain DM, which was cultivated in high concentration of carbohydrates. Unexpectedly, DM exhibited a high ability for anthraquinone glucuronidation biotransformation under CCR conditions with a maximum bioconversion rate of 95% achieved at pH 6, 30°C for 24 h. The co-utilization of glucose and sucrose resulted in the highest biotransformation rate compared to other carbon source combinations. Three novel anthraquinone glucuronides were obtained, with purpurin-O-glucuronide showing significantly improved water solubility, antioxidant activity, and antibacterial bioactivity. Comparative transcript analysis revealed that glucose and sucrose utilization were significantly upregulated as DM cultivated under CCR condition, which strongly enhance the biosynthetic pathway of the precursors Uridine diphosphate glucuronic acid (UDPGA). Meanwhile, the carbon metabolic flux has significantly enhanced the fatty acid biosynthesis, the exhaust of acetyl coenzyme A may lead to the complete repression of the biosynthesis of DNR, Additionally, the efflux transporter genes were simultaneously downregulated, which may contribute to the anthraquinones intracellular glucuronidation. Overall, our findings demonstrate that utilizing CCR can be a valuable strategy for enhancing the biotransformation efficiency of anthraquinone O-glucuronides by DM. This approach has the potential to improve the bioavailability and therapeutic potential of these compounds, opening up new possibilities for their pharmaceutical applications.
碳代谢物阻遏（CCR）是一种高度保守的机制，可调节[具体生物]中的碳源利用。CCR对工业和研究环境中的次级代谢产物发酵均有负面影响。在本研究中，在高浓度碳水化合物中培养的柔红霉素（DNR）产生菌株DM中观察到了CCR。出乎意料的是，DM在CCR条件下表现出高蒽醌葡萄糖醛酸化生物转化能力，在pH 6、30°C培养24小时时，最大生物转化率达到95%。与其他碳源组合相比，葡萄糖和蔗糖的共同利用导致了最高的生物转化率。获得了三种新型蒽醌葡萄糖醛酸苷，其中紫红素 - O - 葡萄糖醛酸苷的水溶性、抗氧化活性和抗菌生物活性显著提高。比较转录分析表明，在CCR条件下培养DM时，葡萄糖和蔗糖的利用显著上调，这强烈增强了前体尿苷二磷酸葡萄糖醛酸（UDPGA）的生物合成途径。同时，碳代谢通量显著增强了脂肪酸生物合成，乙酰辅酶A的排出可能导致DNR生物合成的完全抑制。此外，外排转运蛋白基因同时下调，这可能有助于蒽醌在细胞内的葡萄糖醛酸化。总体而言，我们的研究结果表明，利用CCR可能是提高DM对蒽醌O - 葡萄糖醛酸苷生物转化效率的一种有价值的策略。这种方法有可能提高这些化合物的生物利用度和治疗潜力，为其药物应用开辟新的可能性。
