红霉素作为一种在医药畜牧业抗菌治疗中具有重要作用的天然广谱抗生素，具有广泛的市场需求。工业上主要通过添加正丙醇增强红霉素合成前体--丙酰CoA供应的方式提高红霉素的发酵单位。我们研究发现，在红霉素生产菌红霉糖多孢菌中丙酰CoA的累积会导致丙酸代谢酶的酰基化水平升高，抑制红霉素合成。本项目基于酰基化调控机制，利用代谢工程技术和高选择性、高灵敏度的新型分析手段，系统研究正丙醇（红霉素发酵生产添加）代谢过程中蛋白质酰基化对红霉素合成前体供应的影响：筛选酰基化修饰的靶标丙酸代谢酶，分析酰基化对丙酸代谢酶的作用机制；研究丙酸代谢酶酰基化水平对丙酸代谢产物（丙酰CoA/甲基丙二酰CoA）及红霉素产量的影响；建立消除酰基化修饰反馈抑制的改造策略，强化前体供应及红霉素合成，实现优质工程菌种的培育和推广。本项目预期能够促进我国红霉素发酵产业的发展，为代谢工程改造和合成生物学领域提供模式参考和新思路。

Erythromycin is an efficient natural broad-spectrum antibiotic widespread used in animal husbandry and medical treatment. Addition of n-propanol is the industrial way to improve the production of erythromycin by increasing the precursor(propionyl CoA) supply.Our previous work showed that the accumulation of propionyl CoA in Saccharopolyspora erythraea caused high acylation of enzymes involved in propionate metabolism, which repressed erythromycin synthesis. This study is based on the acylation regulatory mechanism, combines metabolic engineering technology with new analysis methods of high selectivity and sensitivity, and systematically studies the effects of acylation on precursors supply during n-propanol metabolism. The mechanism of protein acylation on propionate metabolites(propionyl CoA and malonyl CoA) and erythromycin production will be investigated by screening and analyzing the acylated propionate metabolic enzymes. Depend on which, the novel strategy will be established to eliminate the feedback inhibition of acylation, strengthen the synthesis of erythromycin precursors and cultivate excellent strains. This research will be of great benefit for the erythromycin fermentation industry as same as the metabolic engineering and synthetic biology.