Work

Metabolic engineering of Glarea lozoyensis for high-level production of pneumocandin B0

Year: 2024

Type: article

Abstract: Pneumocandin B 0 (PB 0 ) is a lipohexapeptide synthesized by Glarea lozoyensis and serves as the precursor for the widely used antifungal drug caspofungin acetate (Cancidas®). However, the low titer of PB 0 results in fermentation and purification costs during caspofungin production, limiting its widespread clinical application. Here, we engineered an efficient PB 0 -producing strain of G. lozoyensis by systems metabolic engineering strategies, including multi-omics analysis and multilevel metabolic engineering. We overexpressed four rate-limiting enzymes: thioesterase GLHYD, two cytochrome P450s GLP450s, and chorismate synthase GLCS; knocked out two competing pathways responsible for producing 6-methylsalicylic acid and pyranidine E; and overexpressed the global transcriptional activator GLHYP. As a result, the PB 0 titer increased by 108.7 % to 2.63 g/L at the shake-flask level through combinatorial strategies. Our study provides valuable insights into achieving high-level production of PB 0 and offers general guidance for developing efficient fungal cell factories to produce polyketide synthase-non-ribosomal peptide synthetase hybrid metabolites.

Source: Synthetic and Systems Biotechnology

DOI: 10.1016/j.synbio.2024.12.008