{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:32Z","timestamp":1791331232026,"version":"4.3.1"},"reference-count":92,"publisher":"American Chemical Society (ACS)","issue":"34","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22177138"],"award-info":[{"award-number":["22177138"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82473810"],"award-info":[{"award-number":["82473810"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Fundamental Research Funds for the Central Universities, South-Central Minzu University","doi-asserted-by":"publisher","award":["CZQ24022"],"award-info":[{"award-number":["CZQ24022"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Crinipellins are a distinctive family of 5\/5\/5\/5 tetracyclic diterpenoids previously reported exclusively from mushrooms of the genus Crinipellis. Despite extensive synthetic studies, the biosynthetic machinery responsible for crinipellin formation has remained elusive. Here, we identify the crinipellin biosynthetic gene cluster (mfd) from the mushroom Marasmius fiardii PR-910, a member of the family Marasmiaceae to which Crinipellis also belongs, although M. fiardii PR-910 itself has not been previously reported to produce crinipellins. Using a combination of site-directed mutagenesis guided by an AlphaFold3-generated structural model, stable isotope-labeling studies, density functional theory (DFT) calculations, and ab initio molecular dynamics (AIMD) simulations, the cyclization mechanism of the diterpene synthase MfdB, which constructs the fused tetraquinane scaffolds 1 and 2, was elucidated. Mutagenesis of MfdB uncovered cryptic cyclization pathways that generate structurally diverse diterpenes, including unprecedented bridged and rearranged diterpene skeletons (4\u20136), whose formation is supported by computational analyses, and further revealed an unusual arginine-rich diphosphate-binding architecture. Heterologous expression studies in Aspergillus oryzae and Saccharomyces cerevisiae established the oxidative functions of the cytochrome P450 enzymes MfdC, MfdD, and MfdE, leading to the production of 19 previously undescribed oxidized metabolites (16\u201334). Notably, MfdE, a member of the largely unexplored CYP_FUM15-like subfamily, catalyzes an unusual oxidative demethylation through C\u2013C bond cleavage, expanding the known catalytic repertoire of fungal cytochrome P450 enzymes. Collectively, this work establishes the biosynthetic logic of crinipellin formation, reveals how terpene synthase plasticity generates cryptic diterpene scaffolds, and demonstrates how oxidative tailoring by multiple cytochrome P450 enzymes drives diterpene scaffold diversification.<\/jats:p>","DOI":"10.1021\/jacs.6c10016","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T20:12:44Z","timestamp":1787343164000},"page":"36942-36957","source":"Crossref","is-referenced-by-count":2,"title":["Biosynthesis of Crinipellin\nDiterpenes in Mushroom\n                    <i>Marasmius fiardii<\/i>\n                    PR-910"],"prefix":"10.1021","volume":"148","author":[{"given":"Li-Li","family":"Guo","sequence":"first","affiliation":[{"name":"South-Central Minzu University , , ,","place":["Wuhan, China, 430074"]},{"name":"South-Central Minzu University , , ,","place":["Wuhan, China, 430074"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Facheng","family":"Su","sequence":"additional","affiliation":[{"name":"South-Central Minzu University , , ,","place":["Wuhan, China, 430074"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjuan","family":"Wei","sequence":"additional","affiliation":[{"name":"South-Central Minzu University , , ,","place":["Wuhan, China, 430074"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyang","family":"Li","sequence":"additional","affiliation":[{"name":"South-Central Minzu University , , ,","place":["Wuhan, China, 430074"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Wang","sequence":"additional","affiliation":[{"name":"South-Central Minzu University , , ,","place":["Wuhan, China, 430074"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0416-9535","authenticated-orcid":true,"given":"He-Ping","family":"Chen","sequence":"additional","affiliation":[{"name":"South-Central Minzu University , , ,","place":["Wuhan, China, 430074"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Kai","family":"Liu","sequence":"additional","affiliation":[{"name":"South-Central Minzu University , , ,","place":["Wuhan, China, 430074"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"2026090312103740800_cit1","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1039\/D2NP00020B","article-title":"Engineering Fungal Terpene Biosynthesis","volume":"40","author":"Yin","year":"2023","journal-title":"Nat. Prod. Rep."},{"key":"2026090312103740800_cit2","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1039\/D2NP00076H","article-title":"Terpene\nSynthases and Pathways in Animals: Enzymology and Structural Evolution\nin the Biosynthesis of Volatile Infochemicals","volume":"40","author":"Tholl","year":"2023","journal-title":"Nat. Prod. Rep."},{"key":"2026090312103740800_cit3","doi-asserted-by":"publisher","first-page":"12774","DOI":"10.1021\/acscatal.3c03047","article-title":"Decoding\nCatalysis by Terpene Synthases","volume":"13","author":"Whitehead","year":"2023","journal-title":"ACS Catal."},{"key":"2026090312103740800_cit4","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1021\/acs.biochem.3c00681","article-title":"Structure-Based\nEngineering of a Sesquiterpene Cyclase\nto Generate an Alcohol Product: Conversion of epi-Isozizaene Synthase\ninto \u03b1-Bisabolol Synthase","volume":"63","author":"Eaton","year":"2024","journal-title":"Biochemistry"},{"key":"2026090312103740800_cit5","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1038\/nm.2471","article-title":"The Discovery\nof Artemisinin (Qinghaosu) and Gifts from Chinese Medicine","volume":"17","author":"Tu","year":"2011","journal-title":"Nat. Med."},{"key":"2026090312103740800_cit6","doi-asserted-by":"publisher","first-page":"2325","DOI":"10.1021\/ja00738a045","article-title":"Plant Antitumor\nAgents. VI. Isolation and Structure of Taxol, A Novel Antileukemic\nand Antitumor Agent from Taxus brevifolia","volume":"93","author":"Wani","year":"1971","journal-title":"J. Am. Chem. Soc."},{"key":"2026090312103740800_cit7","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1007\/s00425-017-2749-x","article-title":"Volatile Terpenoids:\nMultiple Functions,\nBiosynthesis, Modulation and Manipulation by Genetic Engineering","volume":"246","author":"Abbas","year":"2017","journal-title":"Planta"},{"key":"2026090312103740800_cit8","doi-asserted-by":"publisher","first-page":"15926","DOI":"10.1021\/acs.jafc.3c05074","article-title":"Progress and Prospects of Natural Glycoside Sweetener\nBiosynthesis:\nA Review","volume":"71","author":"Qu","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"2026090312103740800_cit9","first-page":"1","article-title":"Secondary Metabolites\nfrom Higher Fungi","volume-title":"Progress in the Chemistry\nof Organic Natural Products","author":"Chen","year":"2017"},{"key":"2026090312103740800_cit10","doi-asserted-by":"publisher","first-page":"1389","DOI":"10.1021\/acs.jafc.4c10986","article-title":"Hericinosides A\u2013M,\nCyathane Diterpene Glycosides\nwith \u03b1-Glucosidase Inhibitory Activity from the Medicinal Fungus Hericium erinaceus","volume":"73","author":"Yuan","year":"2025","journal-title":"J. Agric.\nFood Chem."},{"key":"2026090312103740800_cit11","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1021\/acsinfecdis.5c00988","article-title":"Recent Advances in\nPleuromutilin Derivatives as Antimicrobial Agents (2015\u20132025)","volume":"12","author":"Liu","year":"2026","journal-title":"ACS Infect. Dis."},{"key":"2026090312103740800_cit12","doi-asserted-by":"publisher","DOI":"10.3390\/jof8030244","article-title":"Diterpenes Specially Produced by\nFungi: Structures, Biological Activities,\nand Biosynthesis (2010\u20132020)","volume":"8","author":"Zhang","year":"2022","journal-title":"J. Fungi"},{"key":"2026090312103740800_cit13","doi-asserted-by":"publisher","first-page":"21250","DOI":"10.1021\/jacs.4c07900","article-title":"Concise Total Syntheses\nof (\u2212)-Crinipellins A and B Enabled by a Controlled Cargill\nRearrangement","volume":"146","author":"Xu","year":"2024","journal-title":"J. Am. Chem. Soc."},{"key":"2026090312103740800_cit14","doi-asserted-by":"publisher","first-page":"4827","DOI":"10.1002\/ange.201700565","article-title":"Discovery\nand Characterization of a New Family of Diterpene Cyclases in Bacteria\nand Fungi","volume":"129","author":"Yang","year":"2017","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090312103740800_cit15","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01659-1","article-title":"Heterologous\nExpression\nReveals the Biosynthesis of the Antibiotic Pleuromutilin and Generates\nBioactive Semi-Synthetic Derivatives","volume":"8","author":"Alberti","year":"2017","journal-title":"Nat. Commun."},{"key":"2026090312103740800_cit16","doi-asserted-by":"publisher","first-page":"5345","DOI":"10.1021\/acs.orglett.3c01924","article-title":"Biochemical\nand Genetic Basis of\nGuanacastane Diterpene Biosynthesis in Basidiomycete Fungi","volume":"25","author":"He","year":"2023","journal-title":"Org. Lett."},{"key":"2026090312103740800_cit17","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.1021\/jo802319e","article-title":"Biosynthetic Gene-Based\nSecondary\nMetabolite Screening: A New Diterpene, Methyl Phomopsenonate, from\nthe Fungus Phomopsis amygdali","volume":"74","author":"Toyomasu","year":"2009","journal-title":"J. Org. Chem."},{"key":"2026090312103740800_cit18","doi-asserted-by":"publisher","first-page":"8280","DOI":"10.1002\/anie.201803800","article-title":"Two Bacterial Diterpene Synthases\nfrom Allokutzneria albata Produce Bonnadiene,\nPhomopsene, and Allokutznerene","volume":"57","author":"Lauterbach","year":"2018","journal-title":"Angew. Chem.,\nInt. Ed."},{"key":"2026090312103740800_cit19","doi-asserted-by":"publisher","first-page":"3238","DOI":"10.1002\/anie.20180038","article-title":"Two Diterpene\nSynthases for Spiroalbatene and Cembrene A from Allokutzneria albata","volume":"57","author":"Rinkel","year":"2018","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090312103740800_cit20","doi-asserted-by":"publisher","first-page":"11943","DOI":"10.1002\/anie.202004691","article-title":"Two Diterpene\nSynthases from Chryseobacterium: Chryseodiene Synthase\nand Wanjudiene Synthase","volume":"59","author":"Lauterbach","year":"2020","journal-title":"Angew. Chem., Int.\nEd."},{"key":"2026090312103740800_cit21","doi-asserted-by":"publisher","first-page":"20781","DOI":"10.1002\/anie.202109465","article-title":"Functional Switch and Ethyl Group\nFormation in the Bacterial Polytrichastrene Synthase from Chryseobacterium polytrichastri","volume":"60","author":"Hou","year":"2021","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090312103740800_cit22","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202507752","article-title":"Biosynthesis of the Red Algal Diterpene Peyssonnosol in Bacteria","volume":"64","author":"Yin","year":"2025","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090312103740800_cit23","doi-asserted-by":"publisher","first-page":"4513","DOI":"10.1021\/ja00167a059","article-title":"Biosynthesis of Pentalenene and Pentalenolactone","volume":"112","author":"Cane","year":"1990","journal-title":"J. Am. Chem. Soc."},{"key":"2026090312103740800_cit24","doi-asserted-by":"publisher","first-page":"2239","DOI":"10.1016\/0031-9422(81)80121-5","article-title":"Eriolanolides,\nEudesmanolides, and a Rearranged Sesquiterpene from Eriophyllum Species","volume":"20","author":"Bohlmann","year":"1981","journal-title":"Phytochemistry"},{"key":"2026090312103740800_cit25","doi-asserted-by":"publisher","first-page":"130","DOI":"10.7164\/antibiotics.32.130","article-title":"Antibiotics from Basidiomycetes.\nVII. Crinipellin, a New Antibiotic from the Basidiomycetous Fungus Crinipellis stipitaria (Fr.) Pat","volume":"32","author":"Kupka","year":"1979","journal-title":"J. Antibiot."},{"key":"2026090312103740800_cit26","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1002\/anie.198507091","article-title":"Crinipellins, the First\nNatural Products with a Tetraquinane\nSkeleton","volume":"24","author":"Anke","year":"1985","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090312103740800_cit27","doi-asserted-by":"publisher","first-page":"2151","DOI":"10.1002\/hlca.200900470","article-title":"Four Novel Diterpenoids\nfrom Crinipellis sp. 113","volume":"93","author":"Li","year":"2010","journal-title":"Helv.\nChim. Acta"},{"key":"2026090312103740800_cit28","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1016\/j.bmc.2016.11.016","article-title":"Anti-Inflammatory Tetraquinane Diterpenoids from a Crinipellis Species","volume":"25","author":"Rohr","year":"2017","journal-title":"Bioorg. Med. Chem."},{"key":"2026090312103740800_cit29","doi-asserted-by":"publisher","DOI":"10.3390\/molecules23092377","article-title":"Crinipellins\nA and I, Two Diterpenoids from the Basidiomycete Fungus Crinipellis rhizomaticola, as Potential Natural Fungicides","volume":"23","author":"Han","year":"2018","journal-title":"Molecules"},{"key":"2026090312103740800_cit30","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1021\/jo00053a005","article-title":"Total Synthesis of the Tetraquinane\nDiterpenoid (\u00b1)-Crinipellin\nB","volume":"58","author":"Piers","year":"1993","journal-title":"J. Org. Chem."},{"key":"2026090312103740800_cit31","doi-asserted-by":"publisher","first-page":"10274","DOI":"10.1021\/ja5054412","article-title":"Total Synthesis\nof (\u2212)-Crinipellin A","volume":"136","author":"Kang","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"2026090312103740800_cit32","doi-asserted-by":"publisher","first-page":"8744","DOI":"10.1002\/anie.201805143","article-title":"Total Syntheses of\nCrinipellins Enabled by Cobalt-Mediated and Palladium-Catalyzed\nIntramolecular Pauson\u2013Khand Reactions","volume":"57","author":"Yang","year":"2018","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090312103740800_cit33","doi-asserted-by":"publisher","first-page":"2495","DOI":"10.1021\/jacs.1c13370","article-title":"Divergent Total Syntheses of (\u2212)-Crinipellins\nFacilitated by a HAT-Initiated Dowd\u2013Beckwith Rearrangement","volume":"144","author":"Zhao","year":"2022","journal-title":"J. Am. Chem. Soc."},{"key":"2026090312103740800_cit34","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202501008","article-title":"Divergent Total Syntheses of Six Crinipellin-Type Diterpenoids\nthrough Tandem 4\u03c0-Electrocyclization\/Dicycloexpansion","volume":"64","author":"Ke","year":"2025","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090312103740800_cit35","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18795-w","article-title":"Large-Scale Genome Sequencing\nof Mycorrhizal Fungi Provides Insights into the Early Evolution of\nSymbiotic Traits","volume":"11","author":"Miyauchi","year":"2020","journal-title":"Nat. Commun."},{"key":"2026090312103740800_cit36","doi-asserted-by":"publisher","first-page":"45168","DOI":"10.1021\/jacs.5c14400","article-title":"Vinigrol Tricyclic\nScaffold Biosynthesis Employs an Atypical Terpene Cyclase and a Multipotent\nCyclization Cascade","volume":"147","author":"Tsukada","year":"2025","journal-title":"J. Am. Chem. Soc."},{"key":"2026090312103740800_cit37","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202416795","article-title":"Biosynthesis of (\u2212)-Vinigrol","volume":"64","author":"Xu","year":"2025","journal-title":"Angew.\nChem., Int. Ed."},{"key":"2026090312103740800_cit38","doi-asserted-by":"publisher","DOI":"10.1007\/s13659-025-00578-9","article-title":"Genome Mining and\nFunctional Characterization of Four Type I Sesquiterpene Synthases\nfrom the Tiger Milk Mushroom Lignosus rhinocerus","volume":"16","author":"Gao","year":"2026","journal-title":"Nat. Prod. Bioprospect."},{"key":"2026090312103740800_cit39","doi-asserted-by":"publisher","first-page":"7239","DOI":"10.1021\/jo970695v","article-title":"Investigations of\nTerpenoid Biosynthesis\nby the Dorid Nudibranch Cadlina luteomarginata","volume":"62","author":"Kubanek","year":"1997","journal-title":"J. Org. Chem."},{"key":"2026090312103740800_cit40","doi-asserted-by":"publisher","first-page":"16293","DOI":"10.1021\/jacs.5c01828","article-title":"Avoidance of Secondary\nCarbocations, Unusual Deprotonation, and Nonstatistical Dynamic Effects\nin the Cyclization Mechanism of Tetraisoquinane","volume":"147","author":"Wei","year":"2025","journal-title":"J. Am. Chem. Soc."},{"key":"2026090312103740800_cit41","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202517373","article-title":"Mechanistic\nCharacterisation of Bacterial Terpene Synthases from Chitinophagaceae\nProducing Marine-Type Diterpenes","volume":"64","author":"Li","year":"2025","journal-title":"Angew. Chem.,\nInt. Ed."},{"key":"2026090312103740800_cit42","doi-asserted-by":"publisher","first-page":"10011","DOI":"10.1021\/jacs.6b05799","article-title":"Genome-Based\nDiscovery\nof an Unprecedented Cyclization Mode in Fungal Sesterterpenoid Biosynthesis","volume":"138","author":"Okada","year":"2016","journal-title":"J. Am. Chem. Soc."},{"key":"2026090312103740800_cit43","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/bs.mie.2024.01.011","article-title":"Isotopic Labelings for Mechanistic Studies","volume":"699","author":"Xu","year":"2024","journal-title":"Methods Enzymol."},{"key":"2026090312103740800_cit44","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202513149","article-title":"Mechanistic\nCharacterisation of a Diterpene Synthase for Chryseojoostenes A\u2013E\nfrom Chryseobacterium joostei","volume":"64","author":"Tabekoueng","year":"2025","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090312103740800_cit45","doi-asserted-by":"publisher","first-page":"4128","DOI":"10.1016\/S0021-9258(19)50638-X","article-title":"COQ2 Is a Candidate for the Structural Gene Encoding para-Hydroxybenzoate: Polyprenyltransferase","volume":"267","author":"Ashby","year":"1992","journal-title":"J. Biol. Chem."},{"key":"2026090312103740800_cit46","doi-asserted-by":"publisher","first-page":"23262","DOI":"10.1074\/jbc.271.38.23262","article-title":"Abietadiene\nSynthase\nfrom Grand Fir (Abies grandis): cDNA\nIsolation, Characterization, and Bacterial Expression of a Bifunctional\nDiterpene Cyclase Involved in Resin Acid Biosynthesis","volume":"271","author":"Vogel","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2026090312103740800_cit47","doi-asserted-by":"publisher","first-page":"8974","DOI":"10.1021\/ja010670k","article-title":"Bifunctional Abietadiene\nSynthase: Free Diffusive Transfer of the (+)-Copalyl Diphosphate Intermediate\nbetween Two Distinct Active Sites","volume":"123","author":"Peters","year":"2001","journal-title":"J. Am. Chem.\nSoc."},{"key":"2026090312103740800_cit48","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1039\/c2np20059g","article-title":"Terpenoid\nSynthase Structures: A\nSo Far Incomplete View of Complex Catalysis","volume":"29","author":"Gao","year":"2012","journal-title":"Nat. Prod. Rep."},{"key":"2026090312103740800_cit49","doi-asserted-by":"publisher","first-page":"1551","DOI":"10.1055\/a-1675-8208","article-title":"Mechanistic Investigations on Microbial Type I Terpene\nSynthases through Site-Directed Mutagenesis","volume":"54","author":"Xu","year":"2022","journal-title":"Synthesis"},{"key":"2026090312103740800_cit50","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate Structure Prediction of Biomolecular\nInteractions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"2026090312103740800_cit51","doi-asserted-by":"publisher","first-page":"3891","DOI":"10.1021\/acs.jcim.1c00203","article-title":"AutoDock Vina 1.2.0:\nNew Docking Methods, Expanded Force Field, and Python Bindings","volume":"61","author":"Eberhardt","year":"2021","journal-title":"J. Chem. Inf. 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