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| Main Authors: | , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
2025
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/40788096/ |
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| _version_ | 1868266167299211264 |
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| author | Fan, Baoqiang Liu, Yinuo Chi, Lu-Ping Yang, Chaofan Li, Shengying Zhang, Wei |
| author_facet | Fan, Baoqiang Liu, Yinuo Chi, Lu-Ping Yang, Chaofan Li, Shengying Zhang, Wei Fan, Baoqiang Liu, Yinuo Chi, Lu-Ping Yang, Chaofan Li, Shengying Zhang, Wei |
| collection | PubMed - marine biology |
| contents | Enhancing the β-Oxidation-Like Pathway for the Optimal Production of the Immunosuppressant Mycophenolic Acid. Fan, Baoqiang Liu, Yinuo Chi, Lu-Ping Yang, Chaofan Li, Shengying Zhang, Wei Mycophenolic Acid Oxidation-Reduction Penicillium Immunosuppressive Agents Peroxisomes Metabolic Engineering The recruitment of catabolic β-oxidation enzyme cascades and their reaction logic for natural product biosynthesis remains underexplored, representing a significant opportunity for synthetic biology to engineer novel pathways for structurally unique metabolites. In this study, the first functional reconstitution of the fungal β-oxidative cascade responsible for assembling the immunosuppressant mycophenolic acid (MPA) is reported. Through in vitro enzyme assays, five peroxisomal enzymes are identified that cooperatively mediate two iterative rounds of side-chain cleavage of the biosynthetic precursor MFDHMP-3C and revealed a key oxidative strategy for pharmacophore formation of MPA. These enzymes catalyzed sequential oxidation, dehydrogenation, hydration, reduction, isomerization, and reverse Claisen condensation reactions, mirroring canonical β-oxidation while adapting it for biosynthetic purposes. Furthermore, integrated overexpression of the rate-limiting peroxisomal acyl-CoA oxidase PbACOX323, peroxisomal biogenesis factor PbPex337, and endoplasmic reticulum (ER)-localized oxygenase MpaB' in Penicillium brevicompactum NRRL864 increased MPA production by 50% (from 0.77 to 1.15 g L), demonstrating the biotechnological efficacy of pathway optimization. This work establishes the first example of a full β-oxidation-like enzyme cascade in fungal natural product biosynthesis, providing a paradigm for the evolutionary repurposing of catabolic modules to drive synthetic innovation. |
| format | Artículo científico |
| id | pubmed_40788096 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | Advanced science (Weinheim, Baden-Wurttemberg, Germany) |
| record_format | pubmed |
| spellingShingle | Enhancing the β-Oxidation-Like Pathway for the Optimal Production of the Immunosuppressant Mycophenolic Acid. Fan, Baoqiang Liu, Yinuo Chi, Lu-Ping Yang, Chaofan Li, Shengying Zhang, Wei Mycophenolic Acid Oxidation-Reduction Penicillium Immunosuppressive Agents Peroxisomes Metabolic Engineering Enhancing the β-Oxidation-Like Pathway for the Optimal Production of the Immunosuppressant Mycophenolic Acid. Fan, Baoqiang Liu, Yinuo Chi, Lu-Ping Yang, Chaofan Li, Shengying Zhang, Wei Mycophenolic Acid Oxidation-Reduction Penicillium Immunosuppressive Agents Peroxisomes Metabolic Engineering The recruitment of catabolic β-oxidation enzyme cascades and their reaction logic for natural product biosynthesis remains underexplored, representing a significant opportunity for synthetic biology to engineer novel pathways for structurally unique metabolites. In this study, the first functional reconstitution of the fungal β-oxidative cascade responsible for assembling the immunosuppressant mycophenolic acid (MPA) is reported. Through in vitro enzyme assays, five peroxisomal enzymes are identified that cooperatively mediate two iterative rounds of side-chain cleavage of the biosynthetic precursor MFDHMP-3C and revealed a key oxidative strategy for pharmacophore formation of MPA. These enzymes catalyzed sequential oxidation, dehydrogenation, hydration, reduction, isomerization, and reverse Claisen condensation reactions, mirroring canonical β-oxidation while adapting it for biosynthetic purposes. Furthermore, integrated overexpression of the rate-limiting peroxisomal acyl-CoA oxidase PbACOX323, peroxisomal biogenesis factor PbPex337, and endoplasmic reticulum (ER)-localized oxygenase MpaB' in Penicillium brevicompactum NRRL864 increased MPA production by 50% (from 0.77 to 1.15 g L), demonstrating the biotechnological efficacy of pathway optimization. This work establishes the first example of a full β-oxidation-like enzyme cascade in fungal natural product biosynthesis, providing a paradigm for the evolutionary repurposing of catabolic modules to drive synthetic innovation. |
| title | Enhancing the β-Oxidation-Like Pathway for the Optimal Production of the Immunosuppressant Mycophenolic Acid. |
| topic | Mycophenolic Acid Oxidation-Reduction Penicillium Immunosuppressive Agents Peroxisomes Metabolic Engineering |
| url | https://pubmed.ncbi.nlm.nih.gov/40788096/ |