Enhancing the β ‐Oxidation‐Like Pathway for the Optimal Production of the Immunosuppressant Mycophenolic Acid
Year: 2025
Type: article
Abstract: 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 −1 ), 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.
Source: Advanced Science
Authors: Baoqiang Fan, Yinuo Liu, Lu‐ping Chi, Chaofan Yang, Shengying Li, Wei Zhang
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,730
Funders: Shandong University, National Natural Science Foundation of China, Chinese Academy of Sciences, Natural Science Foundation of Shandong Province, Peking University, Shenzhen Fundamental Research Program, Institute of Oceanology, Chinese Academy of Sciences, National Key Research and Development Program of China
OpenAlex ID: W4413102328