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anti-inflammatory, and anti-viral properties. Methylated flavonoids are particularly significant due to their enhanced oral bioavailability, improved intestinal absorption, and greater stability. The heterologous production of plant flavonoids in bacterial factories involves the need for enough biosynthetic precursors to allow for high production levels. These biosynthetic precursors are malonyl-CoA and l-tyrosine. In this work, to enhance flavonoid biosynthesis in Streptomyces albidoflavus, we conducted a transcriptomics study for the identification of candidate genes involved in l-tyrosine catabolism. The hypothesis was that the bacterial metabolic machinery would detect an excess of this amino acid if supplemented with the conventional culture medium and would activate the genes involved in its catabolism towards energy production. Then, by inactivating those overexpressed genes (under an excess of l-tyrosine), it would be possible to increase the intracellular pools of this precursor amino acid and eventually the final flavonoid titers in this bacterial factory. The RNAseq data analysis in the S. albidoflavus wild-type strain highlighted the hppD gene encoding 4-hydroxyphenylpyruvate dioxygenase as a promising target for knock-out, exhibiting a 23.2-fold change (FC) in expression upon l-tyrosine supplementation in comparison to control cultivation conditions. The subsequent knock-out of the hppD gene in S. albidoflavus resulted in a 1.66-fold increase in the naringenin titer, indicating enhanced flavonoid biosynthesis. Leveraging the improved strain of S. albidoflavus, we successfully synthesized the methylated flavanones hesperetin, homoeriodictyol, and homohesperetin, achieving titers of 2.52 mg\/L, 1.34 mg\/L, and 0.43 mg\/L, respectively. In addition, the dimethoxy flavanone homohesperetin was produced as a byproduct of the endogenous metabolism of S. albidoflavus. To our knowledge, this is the first time that hppD deletion was utilized as a strategy to augment the biosynthesis of flavonoids. Furthermore, this is the first report where hesperetin and homoeriodictyol have been synthesized from l-tyrosine as a precursor. Therefore, transcriptomics is, in this case, a successful approach for the identification of catabolism reactions affecting key precursors during flavonoid biosynthesis, allowing the generation of enhanced production strains.<\/jats:p>","DOI":"10.3390\/ijms25074053","type":"journal-article","created":{"date-parts":[[2024,4,5]],"date-time":"2024-04-05T08:27:52Z","timestamp":1712305672000},"page":"4053","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Biosynthesis of Hesperetin, Homoeriodictyol, and Homohesperetin in a Transcriptomics-Driven Engineered Strain of Streptomyces albidoflavus"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4560-3847","authenticated-orcid":false,"given":"\u00c1lvaro","family":"P\u00e9rez-Valero","sequence":"first","affiliation":[{"name":"Research Group BIONUC (Biotechnology of Nutraceuticals and Bioactive Compounds), Area of Microbiology, Department of Functional Biology, University of Oviedo, 33006 Oviedo, Principality of Asturias, Spain"},{"name":"Instituto Universitario de Oncolog\u00eda del Principado de Asturias (IUOPA), 33006 Oviedo, Principality of Asturias, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA), 33006 Oviedo, Principality of Asturias, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1820-8064","authenticated-orcid":false,"given":"Juan","family":"Serna-Diestro","sequence":"additional","affiliation":[{"name":"Research Group BIONUC (Biotechnology of Nutraceuticals and Bioactive Compounds), Area of Microbiology, Department of Functional Biology, University of Oviedo, 33006 Oviedo, Principality of Asturias, Spain"},{"name":"Instituto Universitario de Oncolog\u00eda del Principado de Asturias (IUOPA), 33006 Oviedo, Principality of Asturias, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA), 33006 Oviedo, Principality of Asturias, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9428-183X","authenticated-orcid":false,"given":"Albert","family":"Tafur Rangel","sequence":"additional","affiliation":[{"name":"Department of Biology and Biological Engineering, Chalmers University of Technology, SE-412 96 Gothenburg, Sweden"},{"name":"Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, DK-2800 Kongens Lyngby, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9126-5869","authenticated-orcid":false,"given":"Simona","family":"Barbuto Ferraiuolo","sequence":"additional","affiliation":[{"name":"Section of Biotechnology and Molecular Biology, Department of Experimental Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, Via De Crecchio 7, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1066-843X","authenticated-orcid":false,"given":"Chiara","family":"Schiraldi","sequence":"additional","affiliation":[{"name":"Section of Biotechnology and Molecular Biology, Department of Experimental Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, Via De Crecchio 7, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3593-5792","authenticated-orcid":false,"given":"Eduard J.","family":"Kerkhoven","sequence":"additional","affiliation":[{"name":"Department of Biology and Biological Engineering, Chalmers University of Technology, SE-412 96 Gothenburg, Sweden"},{"name":"Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, DK-2800 Kongens Lyngby, Denmark"},{"name":"SciLifeLab, Chalmers University of Technology, SE-412 96 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio J.","family":"Villar","sequence":"additional","affiliation":[{"name":"Research Group BIONUC (Biotechnology of Nutraceuticals and Bioactive Compounds), Area of Microbiology, Department of Functional Biology, University of Oviedo, 33006 Oviedo, Principality of Asturias, Spain"},{"name":"Instituto Universitario de Oncolog\u00eda del Principado de Asturias (IUOPA), 33006 Oviedo, Principality of Asturias, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA), 33006 Oviedo, Principality of Asturias, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6680-6723","authenticated-orcid":false,"given":"Felipe","family":"Lomb\u00f3","sequence":"additional","affiliation":[{"name":"Research Group BIONUC (Biotechnology of Nutraceuticals and Bioactive Compounds), Area of Microbiology, Department of Functional Biology, University of Oviedo, 33006 Oviedo, Principality of Asturias, Spain"},{"name":"Instituto Universitario de Oncolog\u00eda del Principado de Asturias (IUOPA), 33006 Oviedo, Principality of Asturias, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA), 33006 Oviedo, Principality of Asturias, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"111442","DOI":"10.1016\/j.foodres.2022.111442","article-title":"Flavonoids: Food Associations, Therapeutic Mechanisms, Metabolism and Nanoformulations","volume":"157","author":"Kaushal","year":"2022","journal-title":"Food Res. 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