{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:28:29Z","timestamp":1787218109775,"version":"build-2736575974"},"reference-count":50,"publisher":"Portland Press Ltd.","issue":"9","funder":[{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["UID\/04469\/2025"],"award-info":[{"award-number":["UID\/04469\/2025"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["LA\/P\/0029\/2020"],"award-info":[{"award-number":["LA\/P\/0029\/2020"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["TecTex COMPETE2030-FEDER-00821000"],"award-info":[{"award-number":["TecTex COMPETE2030-FEDER-00821000"]}]}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,9,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Flavonoids are plant-derived natural compounds belonging to the large group of polyphenols. These molecules have a wide range of applications in the pharmaceutical, nutraceutical, and cosmetic industries due to their well-documented antioxidant, anti-inflammatory, and antimicrobial properties. However, their extraction from plant sources is limited by low yields, seasonal variability, and complex purification processes, making large-scale production challenging. Chemical synthesis is often not a viable alternative because of high production costs and the environmental impact associated with the use of toxic reagents and solvents. Consequently, microbial bioproduction through metabolic engineering has emerged as a sustainable and efficient alternative. In this context, Escherichia coli has become a leading microbial chassis for flavonoid production. The present review summarizes the advances in engineering E. coli for the de novo heterologous biosynthesis of flavonoids, including de novo production of flavanones, flavones, flavonols, prenylflavonoids, glycosylated flavonoids, and methylated flavonoids. Furthermore, the present review discusses the major metabolic and enzymatic bottlenecks that currently limit industrial-scale de novo flavonoid production. These challenges include insufficient precursor supply, suboptimal performance of plant-derived enzymes, cofactor imbalance, accumulation of toxic intermediates, and product toxicity. Strategies to overcome these limitations and enhance flavonoid titers, yields, and structural diversity are also highlighted. By integrating these approaches, E. coli emerges as a robust, sustainable, and economically competitive platform for large-scale flavonoid production.<\/jats:p>","DOI":"10.1042\/bcj20250324","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:17:54Z","timestamp":1787217474000},"page":"1729-1745","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<i>De novo<\/i>\n                    flavonoid production in engineered\n                    <i>Escherichia coli<\/i>"],"prefix":"10.1042","volume":"483","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7703-2391","authenticated-orcid":false,"given":"Daniela","family":"Gomes","sequence":"first","affiliation":[{"name":"1CEB-Centre of Biological Engineering, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"2LABBELS\u2014Associate Laboratory, Braga\/Guimar\u00e3es, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3217-2320","authenticated-orcid":false,"given":"Joana\u00a0L.","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"1CEB-Centre of Biological Engineering, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"2LABBELS\u2014Associate Laboratory, Braga\/Guimar\u00e3es, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9265-0630","authenticated-orcid":false,"given":"Ligia\u00a0R.","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"1CEB-Centre of Biological Engineering, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"2LABBELS\u2014Associate Laboratory, Braga\/Guimar\u00e3es, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"2026082005174806400_B1","doi-asserted-by":"publisher","first-page":"56","DOI":"10.3390\/life10050056","article-title":"Synthetic biology approaches to engineer Saccharomyces cerevisiae towards the industrial production of valuable polyphenolic compounds","volume":"10","author":"Rainha","year":"2020","journal-title":"Life"},{"key":"2026082005174806400_B2","doi-asserted-by":"publisher","first-page":"111755","DOI":"10.1016\/j.cbi.2025.111755","article-title":"The biological potential and health-benefits of flavonoids: a review and development opportunities","volume":"421","author":"Duarte","year":"2025","journal-title":"Chem. Biol. Interact."},{"key":"2026082005174806400_B3","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1007\/s11101-018-9591-z","article-title":"Comprehensive review of antimicrobial activities of plant flavonoids","volume":"18","author":"G\u00f3rniak","year":"2019","journal-title":"Phytochem. Rev."},{"key":"2026082005174806400_B4","doi-asserted-by":"publisher","first-page":"5445291","DOI":"10.1155\/2022\/5445291","article-title":"Flavonoids a bioactive compound from medicinal plants and its therapeutic applications","volume":"2022","author":"Roy","year":"2022","journal-title":"Biomed Res. Int."},{"key":"2026082005174806400_B5","doi-asserted-by":"publisher","first-page":"55","DOI":"10.3390\/foods14020155","article-title":"Biological functions and health benefits of flavonoids in fruits and vegetables: a contemporary review","volume":"14","author":"Zheng","year":"2025","journal-title":"Foods"},{"key":"2026082005174806400_B6","doi-asserted-by":"publisher","first-page":"922","DOI":"10.3390\/antiox13080922","article-title":"Flavonoids: antioxidant powerhouses and their role in nanomedicine","volume":"13","author":"Zahra","year":"2024","journal-title":"Antioxidants"},{"key":"2026082005174806400_B7","doi-asserted-by":"publisher","first-page":"391","DOI":"10.3390\/nu6010391","article-title":"Recent advances and uses of grape flavonoids as nutraceuticals","volume":"6","author":"Georgiev","year":"2014","journal-title":"Nutrients"},{"key":"2026082005174806400_B8","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1002\/ptr.6208","article-title":"Antibacterial activity of flavonoids and their structure\u2013activity relationship: An update review","volume":"33","author":"Farhadi","year":"2019","journal-title":"Phytother. Res."},{"key":"2026082005174806400_B9","author":"Grand View Research","year":"2024"},{"key":"2026082005174806400_B10","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1007\/s12257-024-00125-2","article-title":"Recent advancements in flavonoid production through engineering microbial systems","volume":"29","author":"Hwang","year":"2024","journal-title":"Biotechnol. Bioprocess Eng."},{"key":"2026082005174806400_B11","doi-asserted-by":"publisher","first-page":"e0132","DOI":"10.1199\/tab.0132","article-title":"The biosynthetic pathways for shikimate and aromatic amino acids in Arabidopsis thaliana","volume":"8","author":"Tzin","year":"2010","journal-title":"Arabidopsis Book"},{"key":"2026082005174806400_B12","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1016\/j.tibtech.2019.11.007","article-title":"Metabolic engineering of Escherichia coli for natural product biosynthesis","volume":"38","author":"Yang","year":"2020","journal-title":"Trends Biotechnol."},{"key":"2026082005174806400_B13","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1016\/j.biotechadv.2016.02.012","article-title":"Microbial production of natural and non-natural flavonoids: Pathway engineering, directed evolution and systems\/synthetic biology","volume":"34","author":"Pandey","year":"2016","journal-title":"Biotechnol. Adv."},{"key":"2026082005174806400_B14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fpls.2019.00943","article-title":"The origin and evolution of plant flavonoid metabolism","volume":"10","author":"Yonekura-Sakakibara","year":"2019","journal-title":"Front. Plant Sci."},{"key":"2026082005174806400_B15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/metabo13010124","article-title":"Flavonoid production: current trends in plant metabolic engineering and de novo microbial production","volume":"13","author":"Tariq","year":"2023","journal-title":"Metabolites"},{"key":"2026082005174806400_B16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fceng.2022.880694","article-title":"Plant flavonoid production in bacteria and yeasts","volume":"4","author":"Isogai","year":"2022","journal-title":"Front. Chem. Eng."},{"key":"2026082005174806400_B17","doi-asserted-by":"publisher","first-page":"349","DOI":"10.3390\/molecules27020349","article-title":"Modern approaches in the discovery and development of plant-based natural products and their analogues as potential therapeutic agents","volume":"27","author":"Najmi","year":"2022","journal-title":"Molecules"},{"key":"2026082005174806400_B18","doi-asserted-by":"publisher","first-page":"109588","DOI":"10.1016\/j.ijfoodmicro.2022.109588","article-title":"Perspectives on the design of microbial cell factories to produce prenylflavonoids","volume":"367","author":"Gomes","year":"2022","journal-title":"Int. J. Food Microbiol."},{"key":"2026082005174806400_B19","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.greenca.2024.11.005","article-title":"Harnessing aromatic properties for sustainable bio-valorization of lignin derivatives into flavonoids","volume":"3","author":"Zhu","year":"2025","journal-title":"Green Carbon"},{"key":"2026082005174806400_B20","doi-asserted-by":"publisher","first-page":"4615","DOI":"10.1039\/D0CS00155D","article-title":"Tools and strategies of systems metabolic engineering for the development of microbial cell factories for chemical production","volume":"49","author":"Ko","year":"2020","journal-title":"Chem. Soc. Rev."},{"key":"2026082005174806400_B21","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1016\/j.tibtech.2020.01.002","article-title":"Microbial chassis development for natural product biosynthesis","volume":"38","author":"Xu","year":"2020","journal-title":"Trends Biotechnol."},{"key":"2026082005174806400_B22","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.copbio.2020.06.001","article-title":"Combining protein and metabolic engineering to construct efficient microbial cell factories","volume":"66","author":"Xu","year":"2020","journal-title":"Curr. Opin. Biotechnol."},{"key":"2026082005174806400_B23","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.copbio.2014.12.004","article-title":"Production of natural products through metabolic engineering of Saccharomyces cerevisiae","volume":"35","author":"Krivoruchko","year":"2015","journal-title":"Curr. Opin. Biotechnol."},{"key":"2026082005174806400_B24","doi-asserted-by":"publisher","first-page":"1781","DOI":"10.1021\/jacsau.2c00344","article-title":"Designing microbial cell factories for the production of chemicals","volume":"2","author":"Cho","year":"2022","journal-title":"J. Am. Chem. Soc."},{"key":"2026082005174806400_B25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/life11010013","article-title":"CRISPR\u2013Cas9: a powerful tool to efficiently engineer Saccharomyces cerevisiae","volume":"11","author":"Rainha","year":"2020","journal-title":"Life"},{"key":"2026082005174806400_B26","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.1021\/acssynbio.6b00256","article-title":"The next generation of synthetic biology chassis: moving synthetic biology from the laboratory to the field","volume":"5","author":"Adams","year":"2016","journal-title":"ACS Synth. Biol."},{"key":"2026082005174806400_B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12934-024-02582-z","article-title":"Engineering an Escherichia coli strain for enhanced production of flavonoids derived from pinocembrin","volume":"23","author":"Hanko","year":"2024","journal-title":"Microb. Cell Fact."},{"key":"2026082005174806400_B28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00253-024-13271-7","article-title":"Step-by-step optimization of a heterologous pathway for de novo naringenin production in Escherichia coli","volume":"108","author":"Gomes","year":"2024","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"2026082005174806400_B29","doi-asserted-by":"publisher","first-page":"5302","DOI":"10.1021\/acs.jafc.3c00297","article-title":"Production of four flavonoid C-glucosides in Escherichia coli","volume":"71","author":"Chong","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"2026082005174806400_B30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fbioe.2023.1275651","article-title":"Expanding flavone and flavonol production capabilities in Escherichia coli","volume":"11","author":"Yiakoumetti","year":"2023","journal-title":"Front. Bioeng. Biotechnol."},{"key":"2026082005174806400_B31","doi-asserted-by":"publisher","first-page":"3320","DOI":"10.1007\/s12010-022-03880-1","article-title":"Production of flavonoid 7-O-glucosides by bioconversion using Escherichia coli expressing a 7-O-glucosyltransferase from tobacco (Nicotiana tabacum)","volume":"194","author":"Dorjjugder","year":"2022","journal-title":"Appl. Biochem. Biotechnol."},{"key":"2026082005174806400_B32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/synbio\/ysaa012","article-title":"Engineering Escherichia coli towards de novo production of gatekeeper (2S)-flavanones: naringenin, pinocembrin, eriodictyol and homoeriodictyol","volume":"5","author":"Dunstan","year":"2020","journal-title":"Synth. Biol."},{"key":"2026082005174806400_B33","doi-asserted-by":"publisher","first-page":"9826","DOI":"10.1021\/acs.jafc.3c02071","article-title":"Restricting promiscuity of plant flavonoid 3\u2032-hydroxylase and 4\u2032-O-methyltransferase improves the biosynthesis of (2S)-hesperetin in E. coli","volume":"71","author":"Liu","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"2026082005174806400_B34","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1016\/j.ymben.2011.02.002","article-title":"Optimization of a heterologous pathway for the production of flavonoids from glucose","volume":"13","author":"Santos","year":"2011","journal-title":"Metab. Eng."},{"key":"2026082005174806400_B35","first-page":"1","article-title":"Modular optimization of heterologous pathways for de novo synthesis of (2S)-naringenin in Escherichia coli","volume":"9","author":"Wu","year":"2014","journal-title":"PloS One"},{"key":"2026082005174806400_B36","doi-asserted-by":"publisher","first-page":"1574","DOI":"10.4014\/jmb.2008.08005","article-title":"Fermentation and metabolic pathway optimization to de novo synthesize (2S)-naringenin in Escherichia coli","volume":"30","author":"Zhou","year":"2020","journal-title":"J. Microbiol. Biotechnol."},{"key":"2026082005174806400_B37","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.ymben.2021.05.007","article-title":"Development of a growth coupled dynamic regulation network balancing malonyl-CoA node to enhance (2-S)-naringenin synthesis in E. coli","volume":"67","author":"Zhou","year":"2021","journal-title":"Metabolic Engineering"},{"key":"2026082005174806400_B38","doi-asserted-by":"publisher","first-page":"4849","DOI":"10.1007\/s00253-020-10576-1","article-title":"De novo biosynthesis of complex natural product sakuranetin using modular co-culture engineering","volume":"104","author":"Wang","year":"2020","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"2026082005174806400_B39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jbiotec.2020.04.002","article-title":"Constructing E. coli co-cultures for de novo biosynthesis of natural product acacetin","volume":"15","author":"Wang","year":"2020","journal-title":"Biotechnol. J."},{"key":"2026082005174806400_B40","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.jbiotec.2025.05.017","article-title":"De novo production of prenylnaringenin compounds by a metabolically engineered Escherichia coli","volume":"405","author":"Gomes","year":"2025","journal-title":"J. Biotech."},{"key":"2026082005174806400_B41","doi-asserted-by":"publisher","first-page":"3913","DOI":"10.1021\/acssynbio.5c00221","article-title":"De novo production of xanthohumol by a metabolically engineered Escherichia coli","volume":"14","author":"Gomes","year":"2025","journal-title":"ACS Synth. Biol."},{"key":"2026082005174806400_B42","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s44307-024-00018-8","article-title":"Strategies to increase the robustness of microbial cell factories","volume":"2","author":"Xu","year":"2024","journal-title":"Advanced Biotechnol."},{"key":"2026082005174806400_B43","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/AEM.00525-20","article-title":"Chromosome engineering to generate plasmid-free phenylalanine- and tyrosine-overproducing Escherichia coli strains that can be applied in the generation of aromatic-compound-producing bacteria","volume":"86","author":"Koma","year":"2020","journal-title":"Appl. Environ. Microbiol."},{"key":"2026082005174806400_B44","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.ymben.2025.02.001","article-title":"Metabolic division engineering of Escherichia coli consortia for de novo biosynthesis of flavonoids and flavonoid glycosides","volume":"89","author":"Qiu","year":"2025","journal-title":"Metab. Eng."},{"key":"2026082005174806400_B45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-3-030-81403-8_20-1","article-title":"Microbial production of naringenin","volume-title":"Microbial Production of Food Bioactive Compounds","author":"Gomes","year":"2024"},{"key":"2026082005174806400_B46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fbioe.2020.589069","article-title":"Metabolic engineering of microorganisms for the production of flavonoids","volume":"8","author":"Sheng","year":"2020","journal-title":"Front. Bioeng. Biotechnol."},{"key":"2026082005174806400_B47","doi-asserted-by":"publisher","first-page":"28588","DOI":"10.1021\/acs.jafc.5c09273","article-title":"From plants to microbes: harnessing enzyme promiscuity for natural product synthesis","volume":"73","author":"Hu","year":"2025","journal-title":"J. Agric. Food Chem."},{"key":"2026082005174806400_B48","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12934-024-02436-8","article-title":"Transcending membrane barriers: advances in membrane engineering to enhance the production capacity of microbial cell factories","volume":"23","author":"Wu","year":"2024","journal-title":"Microb. Cell Fact."},{"key":"2026082005174806400_B49","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1016\/j.tim.2019.01.006","article-title":"Engineering robust production microbes for large-scale cultivation","volume":"27","author":"Wehrs","year":"2019","journal-title":"Trends Microbiol."},{"key":"2026082005174806400_B50","doi-asserted-by":"publisher","first-page":"2735","DOI":"10.1002\/jctb.6797","article-title":"In situ product recovery as a strategy for bioprocess integration and depletion of inhibitory products","volume":"10","author":"Salas-Villalobos","year":"2021","journal-title":"J. Chem. Technol. Biotechnol."}],"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/483\/9\/1729\/991170\/bcj-2025-0324c.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/483\/9\/1729\/991170\/bcj-2025-0324c.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:17:55Z","timestamp":1787217475000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/483\/9\/1729\/237959\/De-novo-flavonoid-production-in-engineered"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,20]]},"references-count":50,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9,2]]}},"URL":"https:\/\/doi.org\/10.1042\/bcj20250324","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,9]]},"published":{"date-parts":[[2026,8,20]]}}}