Metabolic engineering of Glarea lozoyensis for high-level production of pneumocandin B0
Pneumocandin B0 (PB0) 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 PB0 results in fermentation and purification costs during caspofungin production, limiting its widesp...
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| Format: | Article |
| Language: | English |
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KeAi Communications Co., Ltd.
2025-06-01
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| Series: | Synthetic and Systems Biotechnology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405805X24001601 |
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| author | Xinyi Zhang Shu Cheng Jing Yang Li Lu Zixin Deng Guangkai Bian Tiangang Liu |
| author_facet | Xinyi Zhang Shu Cheng Jing Yang Li Lu Zixin Deng Guangkai Bian Tiangang Liu |
| author_sort | Xinyi Zhang |
| collection | DOAJ |
| description | Pneumocandin B0 (PB0) 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 PB0 results in fermentation and purification costs during caspofungin production, limiting its widespread clinical application. Here, we engineered an efficient PB0-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 PB0 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 PB0 and offers general guidance for developing efficient fungal cell factories to produce polyketide synthase-non-ribosomal peptide synthetase hybrid metabolites. |
| format | Article |
| id | doaj-art-4852c6ff608e4119bbf0482bd29755f3 |
| institution | Kabale University |
| issn | 2405-805X |
| language | English |
| publishDate | 2025-06-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Synthetic and Systems Biotechnology |
| spelling | doaj-art-4852c6ff608e4119bbf0482bd29755f32025-08-20T03:47:20ZengKeAi Communications Co., Ltd.Synthetic and Systems Biotechnology2405-805X2025-06-0110238139010.1016/j.synbio.2024.12.008Metabolic engineering of Glarea lozoyensis for high-level production of pneumocandin B0Xinyi Zhang0Shu Cheng1Jing Yang2Li Lu3Zixin Deng4Guangkai Bian5Tiangang Liu6Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and School of Pharmaceutical Sciences, Wuhan University, 430072, Wuhan, China; Center of Materials Synthetic Biology, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, 518055, Shenzhen, ChinaKey Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and School of Pharmaceutical Sciences, Wuhan University, 430072, Wuhan, ChinaKey Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and School of Pharmaceutical Sciences, Wuhan University, 430072, Wuhan, ChinaKey Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and School of Pharmaceutical Sciences, Wuhan University, 430072, Wuhan, ChinaKey Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and School of Pharmaceutical Sciences, Wuhan University, 430072, Wuhan, China; State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200030, Shanghai, ChinaCenter of Materials Synthetic Biology, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, 518055, Shenzhen, China; Corresponding author.Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and School of Pharmaceutical Sciences, Wuhan University, 430072, Wuhan, China; State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200030, Shanghai, China; Corresponding author. Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and School of Pharmaceutical Sciences, Wuhan University, 430072, Wuhan, China.Pneumocandin B0 (PB0) 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 PB0 results in fermentation and purification costs during caspofungin production, limiting its widespread clinical application. Here, we engineered an efficient PB0-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 PB0 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 PB0 and offers general guidance for developing efficient fungal cell factories to produce polyketide synthase-non-ribosomal peptide synthetase hybrid metabolites.http://www.sciencedirect.com/science/article/pii/S2405805X24001601Antifungal drugEchinocandinsPneumocandin B0Multi-omicsSystems metabolic engineering |
| spellingShingle | Xinyi Zhang Shu Cheng Jing Yang Li Lu Zixin Deng Guangkai Bian Tiangang Liu Metabolic engineering of Glarea lozoyensis for high-level production of pneumocandin B0 Synthetic and Systems Biotechnology Antifungal drug Echinocandins Pneumocandin B0 Multi-omics Systems metabolic engineering |
| title | Metabolic engineering of Glarea lozoyensis for high-level production of pneumocandin B0 |
| title_full | Metabolic engineering of Glarea lozoyensis for high-level production of pneumocandin B0 |
| title_fullStr | Metabolic engineering of Glarea lozoyensis for high-level production of pneumocandin B0 |
| title_full_unstemmed | Metabolic engineering of Glarea lozoyensis for high-level production of pneumocandin B0 |
| title_short | Metabolic engineering of Glarea lozoyensis for high-level production of pneumocandin B0 |
| title_sort | metabolic engineering of glarea lozoyensis for high level production of pneumocandin b0 |
| topic | Antifungal drug Echinocandins Pneumocandin B0 Multi-omics Systems metabolic engineering |
| url | http://www.sciencedirect.com/science/article/pii/S2405805X24001601 |
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