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A lot of effort has been devoted toward the discovery of PQQ high-producing microbial species and characterization of biosynthesis, but it is still challenging to achieve a high PQQ yield. In this study, a combined strategy of random mutagenesis and adaptive laboratory evolution (ALE) with fermentation optimization was applied to improve PQQ production in\n                      <jats:italic>Hyphomicrobium denitrificans<\/jats:italic>\n                      H4-45. A mutant strain AE-9 was obtained after nearly 400 generations of UV-LiCl mutagenesis, followed by an ALE process, which was conducted with a consecutive increase of oxidative stress generated by kanamycin, sodium sulfide, and potassium tellurite. In the flask culture condition, the PQQ production in mutant strain AE-9 had an 80.4% increase, and the cell density increased by 14.9% when compared with that of the initial strain H4-45. Moreover, batch and fed-batch fermentation processes were optimized to further improve PQQ production by pH control strategy, methanol and H\n                      <jats:sub>2<\/jats:sub>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      feed flow, and segmented fermentation process. Finally, the highest PQQ production and productivity of the mutant strain AE-9 reached 307\u00a0mg\/L and 4.26\u00a0mg\/L\/h in a 3.7-L bioreactor, respectively. Whole genome sequencing analysis showed that genetic mutations in the\n                      <jats:italic>ftfL<\/jats:italic>\n                      gene and\n                      <jats:italic>thiC<\/jats:italic>\n                      gene might contribute to improving PQQ production by enhancing methanol consumption and cell growth in the AE-9 strain. Our study provided a systematic strategy to obtain a PQQ high-producing mutant strain and achieve high production of PQQ in fermentation. These practical methods could be applicable to improve the production of other antioxidant compounds with uncleared regulation mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:italic>\u2022 Improvement of PQQ production by UV-LiCl mutagenesis combined with adaptive laboratory evolution (ALE) and fermentation optimization.<\/jats:italic>\n                    <\/jats:p>\n                    <jats:p>\n                      <jats:italic>\u2022 A consecutive increase of oxidative stress could be used as the antagonistic factor for ALE to enhance PQQ production.<\/jats:italic>\n                    <\/jats:p>\n                    <jats:p>\n                      <jats:italic>\u2022 Mutations in the ftfL gene and thiC gene indicated that PQQ production might be increased by enhancing methanol consumption and cell growth.<\/jats:italic>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00253-024-13053-1","type":"journal-article","created":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T03:01:55Z","timestamp":1707793315000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Oxidative stress resistance prompts pyrroloquinoline quinone biosynthesis in Hyphomicrobium denitrificans H4-45"],"prefix":"10.1007","volume":"108","author":[{"given":"Jiale","family":"Liang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjie","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4725-6962","authenticated-orcid":false,"given":"Wenjie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinle","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,13]]},"reference":[{"issue":"11","key":"13053_CR1","doi-asserted-by":"publisher","first-page":"6127","DOI":"10.1016\/j.sjbs.2021.06.063","volume":"28","author":"S Alkahtani","year":"2021","unstructured":"Alkahtani S, Alarifi S, Alkahtane AA, Albasher G, Al-Zharani M, Alhoshani NM, Al-Johani NS, Aljarba NH, Saquib Hasnain M (2021) Pyrroloquinoline quinone alleviates oxidative damage induced by high glucose in HepG2 cells. 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