State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Road, P. O. Box 329#, Shanghai, 200237, People's Republic of China.
Bioprocess Biosyst Eng. 2019 Dec;42(12):1903-1913. doi: 10.1007/s00449-019-02184-9. Epub 2019 Aug 30.
Bitespiramycin is composed of nine main acylated spiramycin components with isovaleryspiramycin as the major component. However, even with excellent therapeutic effects, its application and industrialization are restricted due to its low titer. In this study, the exogenous addition of A-Factor analogue 1,4-butyrolactone (1,4-BL) stimulated an improvement in bitespiramycin biological titer by 29% with a tiny influence on concentration of major component. Moreover, the mechanism of 1,4-BL stimulating effect was preliminarily explored by the analyses of three key enzyme activities, intracellular metabolite profiling and metabolic flux distribution. All results coordinately revealed that the extensive accumulation of methylmalonyl-CoA and acetyl-CoA was the direct reason for the enhanced bitespiramycin biosynthesis. This study would provide theoretical and technical basis for the application of 1,4-BL addition strategy to industrial bitespiramycin production.
比替米星由九个主要酰化螺旋霉素组成，其中异戊酰螺旋霉素为主要成分。然而，尽管具有出色的治疗效果，但由于其低效价，其应用和产业化受到限制。在这项研究中，外源性添加 A 因子类似物 1,4-丁内酯（1,4-BL）刺激比替米星生物效价提高了 29%，而主要成分的浓度几乎没有影响。此外，通过分析三种关键酶活性、细胞内代谢物谱和代谢通量分布，初步探讨了 1,4-BL 刺激作用的机制。所有结果都共同表明，甲基丙二酰辅酶 A 和乙酰辅酶 A 的广泛积累是增强比替米星生物合成的直接原因。这项研究将为 1,4-BL 添加策略在工业比替米星生产中的应用提供理论和技术基础。
