{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T05:19:58Z","timestamp":1788326398027,"version":"build-2803163510"},"reference-count":45,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100000154","name":"Division of Integrative Organismal Systems","doi-asserted-by":"publisher","award":["2545921"],"award-info":[{"award-number":["2545921"]}],"id":[{"id":"10.13039\/100000154","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Elucidating natural products encoded by cryptic biosynthetic gene clusters (BGCs) in agriculturally important biocontrol fungi such as Trichoderma afroharzianum T22 (ThT22) could lead to the discovery of new compounds that may be explored as potential agrochemicals. Herein, we discovered new lipopeptide natural products, trichopeptide A\u2013D, via genome mining and heterologous reconstitution of the tep BGC from ThT22. Comprehensive NMR, high-resolution mass spectrometry (HRMS), tandem mass spectrometry (MS\/MS), Marfey\u2019s analysis, and chemical synthesis experiments established the structures of trichopeptides as linear pentapeptides acylated with a conjugated triene acid at the N-terminus. A notable structural feature of trichopeptides is the presence of a nonproteinogenic amino acid residue, (Z)-dehydrobutyrine, in the linear peptide. The residue is proposed to be derived from threonine by the action of a noncanonical dehydrating condensation domain (DhC) in the nonribosomal peptide synthetase (NRPS) TepB. This represents only the second example in which a fungal NRPS is responsible for the biosynthesis of dehydroamino acids in a peptide product. Our results expand the chemical inventory of an agriculturally important fungus and pave the way for the future investigation of possible plant\u2013ThT22 interactions mediated by lipopeptides.<\/jats:p>","DOI":"10.1021\/acs.jnatprod.6c00702","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:14:15Z","timestamp":1785849255000},"page":"2396-2404","source":"Crossref","is-referenced-by-count":0,"title":["Genome Mining\nof the Biocontrol Fungus\n                    <i>Trichoderma afroharzianum<\/i>\n                    T22 Led to the Discovery\nof Dehydrobutyrine-Containing Lipopeptides"],"prefix":"10.1021","volume":"89","author":[{"given":"Zuodong","family":"Sun","sequence":"first","affiliation":[{"name":"University of California, Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Wong","sequence":"additional","affiliation":[{"name":"University of California, Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Choi","sequence":"additional","affiliation":[{"name":"University of California, Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camron","family":"Neville","sequence":"additional","affiliation":[{"name":"University of California, Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6951-5323","authenticated-orcid":true,"given":"Zuwei","family":"Wang","sequence":"additional","affiliation":[{"name":"University of California, Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1597-0141","authenticated-orcid":true,"given":"Yi","family":"Tang","sequence":"additional","affiliation":[{"name":"University of California, Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]},{"name":"University of California, Los Angeles , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"2026090200084941400_cit1","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1094\/PDIS.2000.84.4.377","article-title":"Myths and\nDogmas of Biocontrol Changes in Perceptions Derived from Research\non Trichoderma Harzinum T-22","volume":"84","author":"Harman","year":"2000","journal-title":"Plant Dis."},{"key":"2026090200084941400_cit2","doi-asserted-by":"publisher","DOI":"10.1093\/femsec\/fiw036","article-title":"Ecological\nFunctions of Trichoderma Spp. and Their Secondary Metabolites in the\nRhizosphere: Interactions with Plants","volume":"92","author":"Contreras-Cornejo","year":"2016","journal-title":"FEMS\nMicrobiol. Ecol."},{"key":"2026090200084941400_cit3","doi-asserted-by":"publisher","first-page":"11502","DOI":"10.1021\/acs.jafc.3c03240","article-title":"Assessing the Biosynthetic Inventory of the Biocontrol Fungus Trichoderma\nAfroharzianum T22","volume":"71","author":"Han","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"2026090200084941400_cit4","doi-asserted-by":"publisher","first-page":"4364","DOI":"10.1128\/aem.60.12.4364-4370.1994","article-title":"Parallel Formation\nand Synergism of Hydrolytic Enzymes and Peptaibol Antibiotics, Molecular\nMechanisms Involved in the Antagonistic Action of Trichoderma Harzianum\nagainst Phytopathogenic Fungi","volume":"60","author":"Schirmbo\u0308ck","year":"1994","journal-title":"Appl. Environ.\nMicrobiol."},{"key":"2026090200084941400_cit5","doi-asserted-by":"publisher","first-page":"19538","DOI":"10.1021\/jacs.9b09669","article-title":"Fungal Highly Reducing Polyketide\nSynthases Biosynthesize Salicylaldehydes That Are Precursors to Epoxycyclohexenol\nNatural Products","volume":"141","author":"Liu","year":"2019","journal-title":"J. Am. Chem. Soc."},{"key":"2026090200084941400_cit6","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1111\/j.1472-765X.2006.01939.x","article-title":"Major Secondary\nMetabolites Produced\nby Two Commercial Trichoderma Strains Active against Different Phytopathogens","volume":"43","author":"Vinale","year":"2006","journal-title":"Lett. Appl. Microbiol."},{"key":"2026090200084941400_cit7","doi-asserted-by":"publisher","first-page":"9575","DOI":"10.1021\/jacs.1c03988","article-title":"Harzianic\nAcid from Trichoderma Afroharzianum\nIs a Natural Product Inhibitor of Acetohydroxyacid Synthase","volume":"143","author":"Xie","year":"2021","journal-title":"J. Am. Chem. Soc."},{"key":"2026090200084941400_cit8","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1073\/pnas.0237315100","article-title":"Atpenins, Potent and Specific Inhibitors\nof Mitochondrial Complex II (Succinate-Ubiquinone Oxidoreductase)","volume":"100","author":"Miyadera","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090200084941400_cit9","doi-asserted-by":"publisher","first-page":"3148","DOI":"10.1074\/jbc.273.6.3148","article-title":"Elongation Factor 2\nas a Novel Target\nfor Selective Inhibition of Fungal Protein Synthesis","volume":"273","author":"Justice","year":"1998","journal-title":"J. Biol. 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Genet."},{"key":"2026090200084941400_cit12","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1021\/acschembio.1c00867","article-title":"Differential Biosynthesis\nand Roles of Two Ferrichrome-Type\nSiderophores, ASP2397\/AS2488053 and Ferricrocin, in Acremonium Persicinum","volume":"17","author":"Asai","year":"2022","journal-title":"ACS Chem. Biol."},{"key":"2026090200084941400_cit13","doi-asserted-by":"publisher","first-page":"5499","DOI":"10.1073\/pnas.1819998116","article-title":"Genome Mining\nand Biosynthesis of a Polyketide from a Biofertilizer Fungus That\nCan Facilitate Reductive Iron Assimilation in Plant","volume":"116","author":"Chen","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090200084941400_cit14","doi-asserted-by":"publisher","first-page":"25080","DOI":"10.1021\/jacs.3c10179","article-title":"Genome Mining\nfrom Agriculturally Relevant Fungi Led to a D-Glucose Esterified Polyketide\nwith a Terpene-like Core Structure","volume":"145","author":"Yan","year":"2023","journal-title":"J. Am. Chem.\nSoc."},{"key":"2026090200084941400_cit15","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202400846","article-title":"D-Galactose-Esterification\nof a Fungal Polyketide Catalyzed by a Carnitine Acyltransferase Domain","volume":"26","author":"Nagasawa","year":"2025","journal-title":"ChemBioChem"},{"key":"2026090200084941400_cit16","doi-asserted-by":"publisher","first-page":"8574","DOI":"10.1039\/C5CC01535A","article-title":"Lipopeptides:\nFrom Self-Assembly to Bioactivity","volume":"51","author":"Hamley","year":"2015","journal-title":"Chem. Commun."},{"key":"2026090200084941400_cit17","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/473050","article-title":"Lipopeptides as\nthe Antifungal and Antibacterial Agents:\nApplications in Food Safety and Therapeutics","volume":"2015","author":"Meena","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"2026090200084941400_cit18","doi-asserted-by":"publisher","first-page":"2342","DOI":"10.1021\/jacs.2c11107","article-title":"Ecological Niche-Inspired Genome\nMining Leads to the Discovery of Crop-Protecting Nonribosomal Lipopeptides\nFeaturing a Transient Amino Acid Building Block","volume":"145","author":"Go\u0308tze","year":"2023","journal-title":"J. Am. Chem. Soc."},{"key":"2026090200084941400_cit19","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1016\/j.chembiol.2010.08.001","article-title":"Adding the Lipo to Lipopeptides: Do More with Less","volume":"17","author":"Chooi","year":"2010","journal-title":"Chem. 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Commun."},{"key":"2026090200084941400_cit23","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1002\/cbic.200400282","article-title":"Structure\nand Biosynthesis of Myxochromides S1\u20133 in Stigmatella Aurantiaca:\nEvidence for an Iterative Bacterial Type I Polyketide Synthase and\nfor Module Skipping in Nonribosomal Peptide Biosynthesis","volume":"6","author":"Wenzel","year":"2005","journal-title":"ChemBioChem"},{"key":"2026090200084941400_cit24","doi-asserted-by":"publisher","first-page":"1550","DOI":"10.1039\/D3NP00003F","article-title":"Structural\nAdvances toward Understanding the Catalytic Activity and Conformational\nDynamics of Modular Nonribosomal Peptide Synthetases","volume":"40","author":"Patel","year":"2023","journal-title":"Nat. Prod. Rep."},{"key":"2026090200084941400_cit25","doi-asserted-by":"publisher","first-page":"1767","DOI":"10.1021\/acs.analchem.3c04958","article-title":"Facile Method for Determining Lanthipeptide\nStereochemistry","volume":"96","author":"Luo","year":"2024","journal-title":"Anal. Chem."},{"key":"2026090200084941400_cit26","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1073\/pnas.1115983109","article-title":"Unveiling\nthe Biosynthetic Puzzle of Destruxins in Metarhizium Species","volume":"109","author":"Wang","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090200084941400_cit27","doi-asserted-by":"publisher","first-page":"2342","DOI":"10.1002\/chem.201103479","article-title":"Determination of the Absolute Configuration\nof Peptide\nNatural Products by Using Stable Isotope Labeling and Mass Spectrometry","volume":"18","author":"Bode","year":"2012","journal-title":"Chem. - Eur. J."},{"key":"2026090200084941400_cit28","doi-asserted-by":"publisher","first-page":"2541","DOI":"10.1021\/jacs.6b10792","article-title":"Structure\u2013Activity Relationship\nand Molecular Mechanics Reveal the Importance of Ring Entropy in the\nBiosynthesis and Activity of a Natural Product","volume":"139","author":"Tran","year":"2017","journal-title":"J. Am. Chem. Soc."},{"key":"2026090200084941400_cit29","doi-asserted-by":"publisher","first-page":"5457","DOI":"10.1021\/acs.chemrev.6b00591","article-title":"Mechanistic\nUnderstanding of Lanthipeptide Biosynthetic Enzymes","volume":"117","author":"Repka","year":"2017","journal-title":"Chem. Rev."},{"key":"2026090200084941400_cit30","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1016\/0014-5793(95)00888-G","article-title":"The Cyanobacterial Toxin Microcystin\nBinds Covalently\nto Cysteine-273 on Protein Phosphatase 1","volume":"371","author":"MacKintosh","year":"1995","journal-title":"FEBS\nLett."},{"key":"2026090200084941400_cit31","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1039\/D3NP00041A","article-title":"Dehydroamino Acid Residues in Bioactive\nNatural Products","volume":"41","author":"Wang","year":"2024","journal-title":"Nat. Prod. Rep."},{"key":"2026090200084941400_cit32","doi-asserted-by":"publisher","first-page":"1657","DOI":"10.1021\/jo982376p","article-title":"Probing Host-Selective Phytotoxicity:\nSynthesis and Biological Activity of Phomalide, Isophomalide, and\nDihydrophomalide","volume":"64","author":"Ward","year":"1999","journal-title":"J. Org. Chem."},{"key":"2026090200084941400_cit33","doi-asserted-by":"publisher","first-page":"9091","DOI":"10.1039\/D2SC00860B","article-title":"Macrophage-Targeting\nOligopeptides from Mortierella Alpina","volume":"13","author":"Wurlitzer","year":"2022","journal-title":"Chem.\nSci."},{"key":"2026090200084941400_cit34","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1039\/C8RA09880H","article-title":"Application of Dehydroalanine\nas a Building Block for\nthe Synthesis of Selenocysteine-Containing Peptides","volume":"9","author":"Reddy","year":"2019","journal-title":"RSC Adv."},{"key":"2026090200084941400_cit35","doi-asserted-by":"publisher","first-page":"3229","DOI":"10.1002\/anie.202012902","article-title":"Discovery and Biosynthetic Investigation of a New Antibacterial Dehydrated\nNon-Ribosomal Tripeptide","volume":"60","author":"Wang","year":"2021","journal-title":"Angew. Chem., Int.\nEd."},{"key":"2026090200084941400_cit36","doi-asserted-by":"publisher","first-page":"6043","DOI":"10.1021\/jacs.1c01516","article-title":"Targeted Genome Mining Reveals the\nBiosynthetic Gene Clusters of Natural Product CYP51 Inhibitors","volume":"143","author":"Liu","year":"2021","journal-title":"J. Am. Chem. Soc."},{"key":"2026090200084941400_cit37","doi-asserted-by":"publisher","first-page":"151","DOI":"10.7164\/antibiotics.45.151","article-title":"A New Series of Natural Antifungals That Inhibit P450\nLanosterol C-14 Demethylase. I. Taxonomy, Fermentation, Isolation\nand Structural Elucidation","volume":"45","author":"Matsukuma","year":"1992","journal-title":"J. Antibiot."},{"key":"2026090200084941400_cit38","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-30288-6","article-title":"Discovery\nand Characterization of a Terpene Biosynthetic Pathway Featuring a\nNorbornene-Forming Diels-Alderase","volume":"13","author":"Sun","year":"2022","journal-title":"Nat. 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Microbiol."},{"key":"2026090200084941400_cit41","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz310","article-title":"AntiSMASH 5.0: Updates\nto the Secondary Metabolite Genome Mining Pipeline","volume":"47","author":"Blin","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"2026090200084941400_cit42","doi-asserted-by":"publisher","first-page":"D265","DOI":"10.1093\/nar\/gkz991","article-title":"CDD\/SPARCLE: The Conserved Domain\nDatabase in 2020","volume":"48","author":"Lu","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"2026090200084941400_cit43","unstructured":"2ndFind. https:\/\/biosyn.nih.go.jp\/2ndfind\/."},{"key":"2026090200084941400_cit44","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate Structure\nPrediction of\nBiomolecular Interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"2026090200084941400_cit45","doi-asserted-by":"publisher","first-page":"3247","DOI":"10.1038\/nprot.2007.454","article-title":"Solid-Phase Peptide Synthesis: From\nStandard Procedures to the Synthesis of Difficult Sequences","volume":"2","author":"Coin","year":"2007","journal-title":"Nat. Protoc."}],"container-title":["Journal of Natural Products"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jnatprod.6c00702","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jnprdf\/article-pdf\/89\/8\/2396\/66319858\/acs.jnatprod.6c00702.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jnprdf\/article-pdf\/89\/8\/2396\/66319858\/acs.jnatprod.6c00702.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T04:29:36Z","timestamp":1788323376000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jnprdf\/article\/89\/8\/2396\/5236158\/Genome-Mining-of-the-Biocontrol-Fungus-Trichoderma"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,28]]},"references-count":45,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,7,28]]},"published-print":{"date-parts":[[2026,8,28]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jnatprod.6c00702","relation":{},"ISSN":["0163-3864","1520-6025"],"issn-type":[{"value":"0163-3864","type":"print"},{"value":"1520-6025","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,28]]}}}