{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T22:40:58Z","timestamp":1781304058598,"version":"3.54.1"},"reference-count":40,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2022,4,30]],"date-time":"2022-04-30T00:00:00Z","timestamp":1651276800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003627","name":"Rural Development Administration","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003627","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Biotech &amp;amp; Bioengineering"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pikromycin is an important precursor of drugs, for example, erythromycin. Hence, systems metabolic engineering for the enhanced pikromycin production can contribute to the development of pikromycin\u2010related drugs. In this study, metabolic genes in <jats:italic>Streptomyces venezuelae<\/jats:italic> were systematically engineered for enhanced pikromycin production. For this, a genome\u2010scale metabolic model of <jats:italic>S. venezuelae<\/jats:italic> was reconstructed and simulated, which led to the selection of 11 metabolic gene targets. These metabolic genes, including four overexpression targets and seven knockdown targets, were individually engineered first. Next, two overexpression targets and two knockdown targets were selected based on the 11 strains' production performances to engineer two to four of these genes together for the potential synergistic effects on the pikromycin production. As a result, the NM1 strain with AQF52_RS24510 (methenyltetrahydrofolate cyclohydrolase\/methylenetetrahydrofolate dehydrogenase) overexpression and AQF52_RS30320 (sulfite reductase) knockdown showed the best production performance among all the 22 strains constructed in this study. Fed\u2010batch fermentation of the NM1 strain produced 295.25\u2009mg\/L of pikromycin, by far the best production titer using the native producer <jats:italic>S. venezuelae<\/jats:italic>, to the best of our knowledge. The systems metabolic engineering strategy demonstrated herein can also be applied to the overproduction of other secondary metabolites using <jats:italic>S. venezuelae<\/jats:italic>.<\/jats:p>","DOI":"10.1002\/bit.28114","type":"journal-article","created":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T21:49:20Z","timestamp":1650491360000},"page":"2250-2260","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Systems metabolic engineering of <i>Streptomyces venezuelae<\/i> for the enhanced production of pikromycin"],"prefix":"10.1002","volume":"119","author":[{"given":"Min Kyung","family":"Cho","sequence":"first","affiliation":[{"name":"Department of Chemical and Biological Engineering Korea University Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byung Tae","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering (BK21 four) Korea Advanced Institute of Science and Technology (KAIST) Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7224-642X","authenticated-orcid":false,"given":"Hyun Uk","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering (BK21 four) Korea Advanced Institute of Science and Technology (KAIST) Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6406-3930","authenticated-orcid":false,"given":"Min\u2010Kyu","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering Korea University Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,4,30]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00903778"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1511027112"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.synbio.2016.01.003"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acssynbio.7b00423"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.00115-10"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/sb500351f"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/JB.184.20.5746-5752.2002"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)54377-5"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2011.07567.x"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0151149"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12010-021-03627-4"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-019-1730-3"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/abbs\/gmv007"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.27150"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.3.530"},{"key":"e_1_2_9_17_1","volume-title":"Practical Streptomyces genetics","author":"Kieser T.","year":"2000"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12272-015-0638-z"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1039\/c6np00019c"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2008.10.082"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/metabo11050304"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/biot.201800180"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0446-y"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10529-008-9735-0"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15053-x"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.000722"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00449-013-1007-2"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-08833-7"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/acssynbio.6b00202"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/bioengineering8080103"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1128\/jb.178.19.5660-5667.1996"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1821905116"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12257-020-0080-z"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiotec.2015.12.028"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12934-021-01561-y"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.00985-13"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12257-014-0407-8"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1006\/mben.2000.0167"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10295-018-2024-6"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1093\/femsle\/fnw241"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M005619200"}],"container-title":["Biotechnology and Bioengineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bit.28114","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/bit.28114","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bit.28114","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T20:37:37Z","timestamp":1760042257000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/bit.28114"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,30]]},"references-count":40,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2022,8]]}},"alternative-id":["10.1002\/bit.28114"],"URL":"https:\/\/doi.org\/10.1002\/bit.28114","archive":["Portico"],"relation":{},"ISSN":["0006-3592","1097-0290"],"issn-type":[{"value":"0006-3592","type":"print"},{"value":"1097-0290","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,30]]},"assertion":[{"value":"2022-03-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-04-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-04-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}