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In this study, the first functional reconstitution of the fungal\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010oxidative 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\u2010chain cleavage of the biosynthetic precursor MFDHMP\u20103C 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\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010oxidation while adapting it for biosynthetic purposes. Furthermore, integrated overexpression of the rate\u2010limiting peroxisomal acyl\u2010CoA oxidase PbACOX323, peroxisomal biogenesis factor PbPex337, and endoplasmic reticulum (ER)\u2010localized oxygenase MpaB\u2019 in\n                    <jats:italic>Penicillium brevicompactum<\/jats:italic>\n                    NRRL864 increased MPA production by 50% (from 0.77 to 1.15\u00a0g\u00a0L\n                    <jats:sup>\u22121<\/jats:sup>\n                    ), demonstrating the biotechnological efficacy of pathway optimization. This work establishes the first example of a full\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010oxidation\u2010like enzyme cascade in fungal natural product biosynthesis, providing a paradigm for the evolutionary repurposing of catabolic modules to drive synthetic innovation.\n                  <\/jats:p>","DOI":"10.1002\/advs.202508826","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T13:22:15Z","timestamp":1754918535000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Enhancing the\n                    <i>\u03b2<\/i>\n                    \u2010Oxidation\u2010Like Pathway for the Optimal Production of the Immunosuppressant Mycophenolic Acid"],"prefix":"10.1002","volume":"12","author":[{"given":"Baoqiang","family":"Fan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Microbial Technology Shandong University  No. 72 Binhai Road Qingdao Shandong 266237 China"},{"name":"CAS and Shandong Province Key Laboratory of Experimental Marine Biology Institute of Oceanology Chinese Academy of Sciences  Qingdao Shandong 266071 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinuo","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Technology Shandong University  No. 72 Binhai Road Qingdao Shandong 266237 China"},{"name":"CAS and Shandong Province Key Laboratory of Experimental Marine Biology Institute of Oceanology Chinese Academy of Sciences  Qingdao Shandong 266071 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu\u2010ping","family":"Chi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Technology Shandong University  No. 72 Binhai Road Qingdao Shandong 266237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaofan","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Technology Shandong University  No. 72 Binhai Road Qingdao Shandong 266237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengying","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Technology Shandong University  No. 72 Binhai Road Qingdao Shandong 266237 China"},{"name":"Laboratory for Marine Biology and Biotechnology Qingdao Marine Science and Technology Center  Qingdao Shandong 266237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9459-680X","authenticated-orcid":false,"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Technology Shandong University  No. 72 Binhai Road Qingdao Shandong 266237 China"},{"name":"CAS and Shandong Province Key Laboratory of Experimental Marine Biology Institute of Oceanology Chinese Academy of Sciences  Qingdao Shandong 266071 China"},{"name":"Laboratory for Marine Biology and Biotechnology Qingdao Marine Science and Technology Center  Qingdao Shandong 266237 China"},{"name":"Shenzhen Research Institute of Shandong University  Shenzhen 518057 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,11]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ4300559v"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1039\/C4MB00443D"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymben.2010.10.007"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2024119"},{"key":"e_1_2_7_5_1","first-page":"176","volume":"348","author":"Cortes J.","year":"1990","journal-title":"ature"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-94-007-6889-5_16"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2013.11.010"},{"key":"e_1_2_7_8_1","first-page":"23","author":"Winter B. 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