Terpenoids are a class of natural compounds with many important functions and applications. They are synthesized from a long synthetic pathway of isoprenyl unit coupling with the myriads of terpene synthases. Owing to the catalytic divergence of terpenoids synthesis, microbial production of terpenoids is compromised to the complexity of pathway engineering and suffers from the metabolic engineering burden. In this work, the adaptive Escherichia coli HP variant exhibited a general cell fitness in terpenoid synthesis. Especially, it could yield taxadiene of 193.2 mg/L in a test tube culture, which is a five-fold increase over the production in the wild type E. coli DH5α. Mutational analyses indicated that IS10 insertion in adenylate cyclase CyaA (CyaA_HP) resulted in lowering intracellular cyclic AMP (cAMP), which could regulate its receptor protein CRP to rewire cell metabolism and contributed to the improved cell fitness. Our results suggested a way to manipulate cell fitness for terpenoids production and other products.

萜类化合物是一类具有许多重要功能和应用的天然化合物。它们是由异戊二烯基单元与无数萜烯合酶偶联的长合成途径合成的。由于萜类化合物合成的催化分歧，萜类化合物的微生物生产受到途径工程的复杂性的影响，并受到代谢工程负担的影响。在这项工作中，适应性大肠杆菌HP 变体在萜类化合物合成中表现出一般的细胞适应性。尤其是在试管培养中可产生193.2 mg/L的紫杉二烯，是野生型大肠杆菌DH5α的5倍。突变分析表明IS 10 插入腺苷酸环化酶 CyaA (CyaA_HP ) 导致细胞内环 AMP (cAMP) 降低，这可以调节其受体蛋白 CRP 以重新连接细胞代谢并有助于改善细胞适应性。我们的研究结果提出了一种控制萜类化合物生产和其他产品的细胞适应性的方法。