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Furthermore, formaldehyde assimilatory pathways play a fundamental role in many methylotrophs, which are microorganisms able to build biomass and obtain energy from single- and multicarbon compounds with no carbon\u2013carbon bonds. Here, we describe how formaldehyde is formed in the environment, the mechanisms of its toxicity to the cells, and the cell\u2019s strategies to circumvent it. While their importance is unquestionable for cell survival in formaldehyde rich environments, we present examples of how the modification of native formaldehyde dissimilation pathways in nonmethylotrophic bacteria can be applied to redirect carbon flux toward heterologous, synthetic formaldehyde assimilation pathways introduced into their metabolism. Attempts to engineer methylotrophy into nonmethylotrophic hosts have gained interest in the past decade, with only limited successes leading to the creation of autonomous synthetic methylotrophy. Here, we discuss how native formaldehyde assimilation pathways can additionally be employed as a premise to achieving synthetic methylotrophy. Lastly, we discuss how emerging knowledge on regulation of formaldehyde metabolism can contribute to creating synthetic regulatory circuits applied in metabolic engineering strategies.<\/jats:p>","DOI":"10.3390\/microorganisms10020220","type":"journal-article","created":{"date-parts":[[2022,1,20]],"date-time":"2022-01-20T22:51:06Z","timestamp":1642719066000},"page":"220","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":81,"title":["Unravelling Formaldehyde Metabolism in Bacteria: Road towards Synthetic Methylotrophy"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2661-6930","authenticated-orcid":false,"given":"Vivien Jessica","family":"Klein","sequence":"first","affiliation":[{"name":"Department of Biotechnology and Food Science, Norwegian University of Science and Technology, 7491 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7097-6656","authenticated-orcid":false,"given":"Marta","family":"Irla","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Food Science, Norwegian University of Science and Technology, 7491 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6391-9039","authenticated-orcid":false,"given":"Marina","family":"Gil L\u00f3pez","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Food Science, Norwegian University of Science and Technology, 7491 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trygve","family":"Brautaset","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Food Science, Norwegian University of Science and Technology, 7491 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana","family":"Fernandes Brito","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Food Science, Norwegian University of Science and Technology, 7491 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1002\/tcr.20056","article-title":"Assimilation, Dissimilation, and Detoxification of Formaldehyde, a Central Metabolic Intermediate of Methylotrophic Metabolism","volume":"5","author":"Yurimoto","year":"2005","journal-title":"Chem. 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