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Notably, ibrexafungerp, a semi\u2010chemically synthesized analogue of enfumafungin, has recently received approval as a novel antifungal drug. Thus, reconstituting the heterologous biosynthesis of enfumafungin holds great significance, as it offers a promising route for high\u2010level production. Herein, the\n                    <jats:italic>Aspergillus oryzae<\/jats:italic>\n                    S184 chassis is first optimized. By deleting\n                    <jats:italic>ku80<\/jats:italic>\n                    gene and refining counter\u2010selection procedure, site\u2010specific gene integration and substantially shortened the time required for selection marker recycling are significantly enhanced. Subsequently, an artificial biosynthetic pathway potentially involved in enfumafungin biosynthesis is successfully reconstructed. Crucially, the native terpene cyclase (TC)\u2010glycosyltransferase (GT) fusion enzyme, EfuA, involved in enfumafungin biosynthesis, lost its functionality in\n                    <jats:italic>A. oryzae<\/jats:italic>\n                    . Conversely, a designed fusion enzyme EfuA\n                    <jats:sub>(TC)<\/jats:sub>\n                    FsoA\n                    <jats:sub>(GT)<\/jats:sub>\n                    , which combines the TC domain of EfuA with the GT domain of FsoA (involved in fuscoatroside biosynthesis), along with FsoD\/E\/F, efficiently produced the putative enfumafungin intermediate. The functional analysis further revealed that while the fusion of the TC and GT domains is critical for maintaining dual enzymatic activity, these fusion enzymes catalyze unconventional, non\u2010consecutive terpene cyclization and glycosylation steps during the biosynthesis of enfumafungin\u2010type antibiotics, differing from other canonical fusion enzymes.\n                  <\/jats:p>","DOI":"10.1002\/advs.202507531","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T03:15:06Z","timestamp":1756869306000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Engineered Fusion Enzyme\u2010Mediated Non\u2010Consecutive Cyclization\u2010Glycosylation Enables Heterologous Synthesis of Antifungal Enfumafungin"],"prefix":"10.1002","volume":"12","author":[{"given":"Yaohui","family":"Gao","sequence":"first","affiliation":[{"name":"School of Traditional Chinese Materia Medica Shenyang Pharmaceutical University  Shenyang 110016 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianming","family":"Lv","sequence":"additional","affiliation":[{"name":"Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy\/State Key Laboratory of Bioactive Molecules and Druggability Assessment\/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China\/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research Jinan University  Guangzhou 510632 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhong","sequence":"additional","affiliation":[{"name":"Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy\/State Key Laboratory of Bioactive Molecules and Druggability Assessment\/International Cooperative Laboratory of 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