{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T09:27:49Z","timestamp":1786354069966,"version":"build-2736575974"},"reference-count":40,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"publisher","award":["2023YFC3402000"],"award-info":[{"award-number":["2023YFC3402000"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"publisher","award":["2019YFA0905700"],"award-info":[{"award-number":["2019YFA0905700"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Shandong Provincial Natural Science Foundation","doi-asserted-by":"publisher","award":["ZR2023ZD29"],"award-info":[{"award-number":["ZR2023ZD29"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Key R&D Program of Shandong Province","award":["2025CXPT191"],"award-info":[{"award-number":["2025CXPT191"]}]},{"name":"Young Talent Development Program of SKLMT","award":["M2025YA03"],"award-info":[{"award-number":["M2025YA03"]}]},{"name":"Intramural Joint Program Fund of State Key Laboratory of Microbial Technology","award":["SKLMTIJP-2024-04"],"award-info":[{"award-number":["SKLMTIJP-2024-04"]}]},{"award":["SKLMTIJP-2024-04"],"award-info":[{"award-number":["SKLMTIJP-2024-04"]}],"id":[{"id":"https:\/\/ror.org\/03x08qn04","id-type":"ROR","asserted-by":"publisher"}]},{"name":"SKLMT Frontiers and Challenges Project","award":["SKLMTFCP-2023-05"],"award-info":[{"award-number":["SKLMTFCP-2023-05"]}]},{"DOI":"10.13039\/501100013314","name":"111 Project","doi-asserted-by":"crossref","award":["B16030"],"award-info":[{"award-number":["B16030"]}],"id":[{"id":"10.13039\/501100013314","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Genome mining of the marine-derived Streptomyces sp. S42 uncovered a type II polyketide synthetase (T2 PKS) biosynthetic gene cluster (BGC) harboring a gene for 3-ketoacyl-ACP synthase III (KAS III), a hallmark of non-acetate starter unit incorporation, suggesting that the BGC may produce previously unidentified aromatic polyketides. Heterologous expression and promoter engineering of this prioritized BGC in host Streptomyces albus J1074 activated the biosynthetic pathway, leading to the isolation of eight new polycyclic aromatic derivatives, verrucones A\u2013H (1\u20138). Comprehensive structural elucidation via NMR and HRESIMS revealed that these compounds feature either a 2-methylbutyryl or an isobutyryl starter unit and can be classified into three distinct skeletal types. Based on these findings and bioinformatic analysis, a plausible biosynthetic pathway for 1\u20138 involving divergent spontaneous cyclization from a common nascent polyketide intermediate was proposed. Among the isolated compounds, 1\u20135 exhibited inhibitory activity against several protein tyrosine phosphatases (PTPs) with IC50 values ranging from 1.84 \u03bcM to 24.82 \u03bcM. This study presents a successful case study demonstrating that combining KAS III-targeted genome mining with heterologous expression is a viable approach for discovering non-acetate-primed aromatic polyketides.<\/jats:p>","DOI":"10.3390\/microorganisms14081669","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:38:54Z","timestamp":1785411534000},"page":"1669","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Verrucones A\u2013H, Non-Acetate Starter Aromatic Polyketides Discovered by Heterologous Expression of a Type II PKS Gene Cluster"],"prefix":"10.3390","volume":"14","author":[{"given":"Xingkun","family":"Hao","sequence":"first","affiliation":[{"name":"Helmholtz International Lab for Anti-Infectives, Shandong University-Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Yang","sequence":"additional","affiliation":[{"name":"Helmholtz International Lab for Anti-Infectives, Shandong University-Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Yan","sequence":"additional","affiliation":[{"name":"Helmholtz International Lab for Anti-Infectives, Shandong University-Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiyao","family":"Shen","sequence":"additional","affiliation":[{"name":"Helmholtz International Lab for Anti-Infectives, Shandong University-Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Helmholtz International Lab for Anti-Infectives, Shandong University-Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Helmholtz International Lab for Anti-Infectives, Shandong University-Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1356-3211","authenticated-orcid":false,"given":"Xiaoying","family":"Bian","sequence":"additional","affiliation":[{"name":"Helmholtz International Lab for Anti-Infectives, Shandong University-Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9656-6479","authenticated-orcid":false,"given":"Haibo","family":"Zhou","sequence":"additional","affiliation":[{"name":"Helmholtz International Lab for Anti-Infectives, Shandong University-Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1039\/D1NP00059D","article-title":"Anthracyclines: Biosynthesis, engineering and clinical applications","volume":"39","author":"Hulst","year":"2022","journal-title":"Nat. Prod. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"110749","DOI":"10.1016\/j.jbc.2025.110749","article-title":"Type II polyketide synthases: Impact on human health, current knowledge, and future directions","volume":"301","author":"Wolff","year":"2025","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1039\/B507395M","article-title":"Type II polyketide synthases: Gaining a deeper insight into enzymatic teamwork","volume":"24","author":"Hertweck","year":"2007","journal-title":"Nat. Prod. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1038\/s41586-023-06575-7","article-title":"The PTPN2\/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity","volume":"622","author":"Baumgartner","year":"2023","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2836","DOI":"10.1021\/acs.jnatprod.2c00879","article-title":"Selective Inhibition of PTP1B by New Anthraquinone Glycosides from Knoxia valerianoides","volume":"85","author":"Zhang","year":"2022","journal-title":"J. Nat. Prod."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s10555-008-9126-y","article-title":"The tyrosine phosphatase Shp2 (PTPN11) in cancer","volume":"27","author":"Chan","year":"2008","journal-title":"Cancer Metastasis Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1042\/BST20150251","article-title":"SHP-1: The next checkpoint target for cancer immunotherapy?","volume":"44","author":"Watson","year":"2016","journal-title":"Biochem. Soc. Trans."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1517\/14728222.10.1.135","article-title":"Shp2 as a therapeutic target for leptin resistance and obesity","volume":"10","author":"Feng","year":"2006","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9595","DOI":"10.1039\/C7OB02562A","article-title":"Cell-permeable bicyclic peptidyl inhibitors against T-cell protein tyrosine phosphatase from a combinatorial library","volume":"15","author":"Liao","year":"2017","journal-title":"Org. Biomol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1021\/ar8002249","article-title":"Biosynthesis of Aromatic Polyketides in Bacteria","volume":"42","author":"Das","year":"2009","journal-title":"Acc. Chem. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1039\/b911518h","article-title":"Cyclization of aromatic polyketides from bacteria and fungi","volume":"27","author":"Zhou","year":"2010","journal-title":"Nat. Prod. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1039\/b911956f","article-title":"Post-PKS tailoring steps in natural product-producing actinomycetes from the perspective of combinatorial biosynthesis","volume":"27","author":"Olano","year":"2010","journal-title":"Nat. Prod. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7196","DOI":"10.1021\/acs.orglett.6c01650","article-title":"Discovery of antibacterial tetracycline-type natural products misiomycins E\u2013H through KASIII genome mining and regulator overexpression","volume":"28","author":"Tan","year":"2026","journal-title":"Org. Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"29462","DOI":"10.1021\/jacs.4c08803","article-title":"Hybrid type I and II polyketide synthases yield distinct aromatic polyketides","volume":"146","author":"Zhao","year":"2024","journal-title":"J. Am. Chem. Soc."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Schwarzer, P., Tsypik, O., Zuo, C., Alali, A., Wunsch-Palasis, J., Heitzler, T., Derochefort, J., Bernhardt, M., Yan, X., and Paululat, T. (2020). Early steps in the biosynthetic pathway of rishirilide B. Molecules, 25.","DOI":"10.3390\/molecules25081955"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e202202286","DOI":"10.1002\/anie.202202286","article-title":"Investigation of the Molecular Landscape of Bacterial Aromatic Polyketides by Global Analysis of Type II Polyketide Synthases","volume":"61","author":"Chen","year":"2022","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1039\/C8NP00091C","article-title":"Heterologous expression of bacterial natural product biosynthetic pathways","volume":"36","author":"Huo","year":"2019","journal-title":"Nat. Prod. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"100137","DOI":"10.1016\/j.engmic.2023.100137","article-title":"Heterologous expression facilitates the discovery and characterization of marine microbial natural products","volume":"4","author":"Zhao","year":"2024","journal-title":"Eng. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"W32","DOI":"10.1093\/nar\/gkaf334","article-title":"antiSMASH 8.0: Extended gene cluster detection capabilities and analyses of chemistry, enzymology, and regulation","volume":"53","author":"Blin","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.synbio.2018.09.001","article-title":"Activation of microbial secondary metabolic pathways: Avenues and challenges","volume":"3","author":"Baral","year":"2018","journal-title":"Synth. Syst. Biotechnol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1039\/D5NP00036J","article-title":"Streptomyces as a versatile host platform for heterologous production of microbial natural products","volume":"43","author":"Lasch","year":"2026","journal-title":"Nat. Prod. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2987","DOI":"10.1021\/acs.orglett.5c00514","article-title":"Genome mining and targeted discovery of twistane-containing angucyclinones from marine Streptomyces phaeochromogenes XSA2","volume":"27","author":"Hao","year":"2025","journal-title":"Org. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5324","DOI":"10.1021\/acs.orglett.5b02683","article-title":"Heterologous expression of fluostatin gene cluster leads to a bioactive heterodimer","volume":"17","author":"Yang","year":"2015","journal-title":"Org. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1021\/acs.jnatprod.4c01433","article-title":"(\u00b1)-Feionemycin A and Chromonemycins A\u2013D, Rearranged Aromatic Polyketides Uncovered by Type II Polyketide Gene Cluster Expression","volume":"88","author":"Huang","year":"2025","journal-title":"J. Nat. Prod."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2914","DOI":"10.1021\/acs.jafc.2c06928","article-title":"Genome Mining and Heterologous Expression Guided the Discovery of Antimicrobial Naphthocyclinones from Streptomyces eurocidicus CGMCC 4.1086","volume":"71","author":"Li","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2875","DOI":"10.1021\/acs.jnatprod.1c00617","article-title":"Genome-guided discovery of highly oxygenated aromatic polyketides, saccharothrixins D\u2013M, from the rare marine actinomycete Saccharothrix sp. D09","volume":"84","author":"Shen","year":"2021","journal-title":"J. Nat. Prod."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1039\/C5SC00116A","article-title":"Biosynthesis of trioxacarcin revealing a different starter unit and complex tailoring steps for type II polyketide synthase","volume":"6","author":"Zhang","year":"2015","journal-title":"Chem. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2322","DOI":"10.1021\/acs.orglett.9b00610","article-title":"Discovery of druggability-improved analogues by investigation of the LL-D49194\u03b11 biosynthetic pathway","volume":"21","author":"Dong","year":"2019","journal-title":"Org. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1038\/nprot.2016.054","article-title":"RecET direct cloning and red\u03b1\u03b2 recombineering of biosynthetic gene clusters, large operons or single genes for heterologous expression","volume":"11","author":"Wang","year":"2016","journal-title":"Nat. Protoc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0022-2836(05)80360-2","article-title":"Basic local alignment search tool","volume":"215","author":"AltschuP","year":"1990","journal-title":"J. Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e28","DOI":"10.1093\/nar\/gkx1249","article-title":"ExoCET: Exonuclease in vitro assembly combined with RecET recombination for highly efficient direct DNA cloning from complex genomes","volume":"46","author":"Wang","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_32","unstructured":"Keiser, T., Bibb, M.J., Buttner, M.J., Charter, K.F., and Hopwood, D.A. (2000). Practical Streptomyces Genetics, The John Innes Foundation."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e37","DOI":"10.1093\/nar\/gkt1339","article-title":"Improved seamless mutagenesis by recombineering using ccdB for counterselection","volume":"42","author":"Wang","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1039\/a809656b","article-title":"A water-soluble tetrazolium salt useful for colorimetric cell viability assay","volume":"36","author":"Tominaga","year":"1999","journal-title":"Anal. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3371","DOI":"10.1021\/acscatal.1c05131","article-title":"Characterization of a cryptic NRPS gene cluster in Bacillus velezensis FZB42 reveals a discrete oxidase involved in multithiazole biosynthesis","volume":"12","author":"Shen","year":"2022","journal-title":"ACS Catal."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1039\/C9MD00162J","article-title":"3-ketoacyl-ACP synthase (KAS) III homologues and their roles in natural product biosynthesis","volume":"10","author":"Nofiani","year":"2019","journal-title":"MedChemComm"},{"key":"ref_37","unstructured":"Chemical Abstracts Service (CAS) (2026, June 20). SciFinder-n. Available online: https:\/\/scifinder-n.cas.org."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3622","DOI":"10.1073\/pnas.96.7.3622","article-title":"Ectopic expression of the minimal whiE polyketide synthase generates a library of aromatic polyketides of diverse sizes and shapes","volume":"96","author":"Shen","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4688","DOI":"10.1002\/anie.200806121","article-title":"The biosynthetic logic of polyketide diversity","volume":"48","author":"Hertweck","year":"2009","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"117498","DOI":"10.1016\/j.ejmech.2025.117498","article-title":"Piperidine polyketide alkaloids of bacterial origin: Occurrence, bioactivity, and biosynthesis","volume":"289","author":"Xiong","year":"2025","journal-title":"Eur. J. Med. Chem."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/14\/8\/1669\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T08:28:23Z","timestamp":1786350503000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/14\/8\/1669"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,30]]},"references-count":40,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["microorganisms14081669"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms14081669","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,30]]}}}