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Due to its potential applications and attempt to overcome the industrial demand, there has been an increased interest in its heterologous production. The microbial biosynthetic pathway to produce naringenin is composed of tyrosine ammonia-lyase (TAL), 4-coumarate-CoA ligase (4CL), chalcone synthase (CHS), and chalcone isomerase (CHI). Herein, we targeted the efficient de novo production of naringenin in <jats:italic>Escherichia coli<\/jats:italic> by performing a step-by-step validation and optimization of the pathway. For that purpose, we first started by expressing two TAL genes from different sources in three different <jats:italic>E. coli<\/jats:italic> strains. The highest <jats:italic>p<\/jats:italic>-coumaric acid production (2.54\u00a0g\/L) was obtained in the tyrosine-overproducing M-PAR-121 strain carrying TAL from <jats:italic>Flavobacterium johnsoniae<\/jats:italic> (<jats:italic>FjT<\/jats:italic>AL). Afterwards, this platform strain was used to express different combinations of 4CL and CHS genes from different sources. The highest naringenin chalcone production (560.2\u00a0mg\/L) was achieved by expressing <jats:italic>Fj<\/jats:italic>TAL combined with 4CL from <jats:italic>Arabidopsis thaliana<\/jats:italic> (<jats:italic>At<\/jats:italic>4CL) and CHS from <jats:italic>Cucurbita maxima<\/jats:italic> (<jats:italic>Cm<\/jats:italic>CHS). Finally, different CHIs were tested and validated, and 765.9\u00a0mg\/L of naringenin was produced by expressing CHI from <jats:italic>Medicago sativa<\/jats:italic> (<jats:italic>Ms<\/jats:italic>CHI) combined with the other previously chosen genes. To our knowledge, this titer corresponds to the highest de novo production of naringenin reported so far in <jats:italic>E. coli<\/jats:italic>.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Key points<\/jats:title>\n            <jats:p>\n              <jats:italic>\u2022 Best enzyme and strain combination were selected for de novo naringenin production.<\/jats:italic>\n            <\/jats:p>\n            <jats:p>\n              <jats:italic>\u2022 After genetic and operational optimizations, 765.9\u00a0mg\/L of naringenin was produced.<\/jats:italic>\n            <\/jats:p>\n            <jats:p>\n              <jats:italic>\u2022 This de novo production is the highest reported so far in E. coli.<\/jats:italic>\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s00253-024-13271-7","type":"journal-article","created":{"date-parts":[[2024,8,10]],"date-time":"2024-08-10T06:02:40Z","timestamp":1723269760000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Step-by-step optimization of a heterologous pathway for de novo naringenin production in Escherichia coli"],"prefix":"10.1007","volume":"108","author":[{"given":"Daniela","family":"Gomes","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3217-2320","authenticated-orcid":false,"given":"Joana L.","family":"Rodrigues","sequence":"additional","affiliation":[]},{"given":"Ligia R.","family":"Rodrigues","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2024,8,10]]},"reference":[{"key":"13271_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/femsle\/fny162","volume":"365","author":"TS Casti\u00f1eiras","year":"2018","unstructured":"Casti\u00f1eiras TS, Williams SG, Hitchcock AG, Smith DC (2018) E. coli strain engineering for the production of advanced biopharmaceutical products. 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