{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T21:01:05Z","timestamp":1775509265224,"version":"3.50.1"},"reference-count":69,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T00:00:00Z","timestamp":1650412800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Research, Development and Innovation Office [\u00c9lvonal Program","award":["KKP 129814"],"award-info":[{"award-number":["KKP 129814"]}]},{"name":"National Research, Development and Innovation Office [\u00c9lvonal Program","award":["KH 125616"],"award-info":[{"award-number":["KH 125616"]}]},{"name":"Lend\u00fclet\u201d program of the Hungarian Academy of Sciences","award":["LP2009-013\/2012"],"award-info":[{"award-number":["LP2009-013\/2012"]}]},{"name":"Lend\u00fclet\u201d program of the Hungarian Academy of Sciences","award":["GINOP-2.3.2-15-2016-00026"],"award-info":[{"award-number":["GINOP-2.3.2-15-2016-00026"]}]},{"name":"The European Union\u2019s Horizon 2020 Research and Innovation Program","award":["739593"],"award-info":[{"award-number":["739593"]}]},{"name":"National Laboratory of Biotechnology Grant","award":["NKFIH-871-3\/2020"],"award-info":[{"award-number":["NKFIH-871-3\/2020"]}]},{"name":"The Hungarian Academy of Sciences Premium Postdoctoral Research Program","award":["PREMIUM-2018-294"],"award-info":[{"award-number":["PREMIUM-2018-294"]}]},{"name":"Janos Bolyai Research Fellowship from the Hungarian Academy of Sciences","award":["BO\/00728\/21\/8"],"award-info":[{"award-number":["BO\/00728\/21\/8"]}]},{"name":"New National Excellence Program of the Ministry of Human Capacities","award":["UNKP-21-5-SZTE-564"],"award-info":[{"award-number":["UNKP-21-5-SZTE-564"]}]},{"name":"National Research, Development and Innovation Office [PD","award":["128271"],"award-info":[{"award-number":["128271"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,5,26]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Motivation<\/jats:title><jats:p>Bioproduction of value-added compounds is frequently achieved by utilizing enzymes from other species. However, expression of such heterologous enzymes can be detrimental due to unexpected interactions within the host cell. Recently, an alternative strategy emerged, which relies on recruiting side activities of host enzymes to establish new biosynthetic pathways. Although such low-level \u2018underground\u2019 enzyme activities are prevalent, it remains poorly explored whether they may serve as an important reservoir for pathway engineering.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Here, we use genome-scale modeling to estimate the theoretical potential of underground reactions for engineering novel biosynthetic pathways in Escherichia coli. We found that biochemical reactions contributed by underground enzyme activities often enhance the in silico production of compounds with industrial importance, including several cases where underground activities are indispensable for production. Most of these new capabilities can be achieved by the addition of one or two underground reactions to the native network, suggesting that only a few side activities need to be enhanced during implementation. Remarkably, we find that the contribution of underground reactions to the production of value-added compounds is comparable to that of heterologous reactions, underscoring their biotechnological potential. Taken together, our genome-wide study demonstrates that exploiting underground enzyme activities could be a promising addition to the toolbox of industrial strain development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Availability and implementation<\/jats:title><jats:p>The data and scripts underlying this article are available on GitHub at https:\/\/github.com\/pappb\/Kovacs-et-al-Underground-metabolism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Supplementary information<\/jats:title><jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p><\/jats:sec>","DOI":"10.1093\/bioinformatics\/btac282","type":"journal-article","created":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T11:10:15Z","timestamp":1649934615000},"page":"3070-3077","source":"Crossref","is-referenced-by-count":12,"title":["Underground metabolism as a rich reservoir for pathway engineering"],"prefix":"10.1093","volume":"38","author":[{"given":"Szabolcs Cselg\u0151","family":"Kov\u00e1cs","sequence":"first","affiliation":[{"name":"HCEMM-BRC Metabolic Systems Biology Lab , Szeged, Hungary"},{"name":"Biological Research Centre, Institute of Biochemistry, Synthetic and Systems Biology Unit, E\u00f6tv\u00f6s Lor\u00e1nd Research Network (ELKH) , Szeged, Hungary"}]},{"given":"Bal\u00e1zs","family":"Szappanos","sequence":"additional","affiliation":[{"name":"HCEMM-BRC Metabolic Systems Biology Lab , Szeged, Hungary"},{"name":"Biological Research Centre, Institute of Biochemistry, Synthetic and Systems Biology Unit, E\u00f6tv\u00f6s Lor\u00e1nd Research Network (ELKH) , Szeged, Hungary"},{"name":"Department of Biotechnology, University of Szeged , Szeged, Hungary"}]},{"given":"Roland","family":"Teng\u00f6lics","sequence":"additional","affiliation":[{"name":"HCEMM-BRC Metabolic Systems Biology Lab , Szeged, Hungary"},{"name":"Biological Research Centre, Institute of Biochemistry, Synthetic and Systems Biology Unit, E\u00f6tv\u00f6s Lor\u00e1nd Research Network (ELKH) , Szeged, Hungary"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3469-1893","authenticated-orcid":false,"given":"Richard A","family":"Notebaart","sequence":"additional","affiliation":[{"name":"Food Microbiology, Wageningen University & Research , 6700 HB Wageningen, The Netherlands"}]},{"given":"Bal\u00e1zs","family":"Papp","sequence":"additional","affiliation":[{"name":"HCEMM-BRC Metabolic Systems Biology Lab , Szeged, Hungary"},{"name":"Biological Research Centre, Institute of Biochemistry, Synthetic and Systems Biology Unit, E\u00f6tv\u00f6s Lor\u00e1nd Research Network (ELKH) , Szeged, Hungary"}]}],"member":"286","published-online":{"date-parts":[[2022,4,20]]},"reference":[{"key":"2023041403082860100_","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/ng1482","article-title":"The \u2018evolvability\u2019 of promiscuous protein functions","volume":"37","author":"Aharoni","year":"2005","journal-title":"Nat. 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