Precursor Supply for Erythromycin Biosynthesis: Engineering of Propionate Assimilation Pathway Based on Propionylation Modification.
Erythromycin is necessary in medical treatment and known to be biosynthesized with propionyl-CoA as direct precursor. Oversupply of propionyl-CoA induced hyperpropionylation, which was demonstrated as harmful for erythromycin synthesis in Saccharopolyspora erythraea. Herein, we identified three propionyl-CoA synthetases regulated by propionylation, and one propionyl-CoA synthetase SACE_1780 revealed resistance to propionylation. A practical strategy for raising the precursor (propionyl-CoA) supply bypassing the feedback inhibition caused by propionylation was developed through two approaches: deletion of the propionyltransferase AcuA, and SACE_1780 overexpression. The constructed Δ acuA strain presented a 10% increase in erythromycin yield; SACE_1780 overexpression strain produced 33% higher erythromycin yield than the wildtype strain NRRL2338 and 22% higher erythromycin yield than the industrial high yield Ab strain. These findings uncover the role of protein acylation in precursor supply for antibiotics biosynthesis and provide efficient post-translational modification-metabolic engineering strategy (named as PTM-ME) in synthetic biology for improvement of secondary metabolites.
['You|Di|D|', 'Wang|Miao-Miao|MM|', 'Yin|Bin-Cheng|BC|0000-0002-4011-4307', 'Ye|Bang-Ce|BC|0000-0002-5555-5359']
D000214:Acyl Coenzyme A D001426:Bacterial Proteins D004917:Erythromycin D060847:Metabolic Engineering D011422:Propionates D016930:Saccharopolyspora
precursor supply erythromycin biosynthesis propionate assimilation propionylation propionyl-CoA synthetase