{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T12:46:54Z","timestamp":1777121214370,"version":"3.51.4"},"posted":{"date-parts":[[2026,4,21]]},"group-title":"Physiology","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Formaldehyde is a highly toxic metabolite that can cause extensive damage to DNA and proteins, and strategies to mitigate formaldehyde toxicity are poorly understood. Methylotrophic bacteria, such as\n                  <jats:italic>Methylobacterium extorquens<\/jats:italic>\n                  , thrive on one-carbon compounds as sole sources of carbon and energy. These organisms are excellent models for discovering formaldehyde stress response systems because formaldehyde is an obligate intermediate in their central carbon metabolism. Here, we characterize an evolved\n                  <jats:italic>def<\/jats:italic>\n                  allele (\n                  <jats:italic>\n                    def\n                    <jats:sup>evo<\/jats:sup>\n                  <\/jats:italic>\n                  ) that increases formaldehyde resistance in\n                  <jats:italic>M. extorquens<\/jats:italic>\n                  . The\n                  <jats:italic>def<\/jats:italic>\n                  gene encodes peptide deformylase (PDF, EC:3.5.1.88), an enzyme that contributes to protein processing by removing the formyl group from\n                  <jats:italic>N-<\/jats:italic>\n                  formylmethionine (fMet) on nascent peptides. The\n                  <jats:italic>\n                    def\n                    <jats:sup>evo<\/jats:sup>\n                  <\/jats:italic>\n                  allele has a single missense mutation that decreases PDF activity both\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  . Transcriptomic analysis of the\n                  <jats:italic>\n                    def\n                    <jats:sup>evo<\/jats:sup>\n                  <\/jats:italic>\n                  strain indicates there are pleiotropic effects of this mutation and a differential response to formaldehyde stress. We investigate possible mechanisms for the\n                  <jats:italic>\n                    def\n                    <jats:sup>evo<\/jats:sup>\n                  <\/jats:italic>\n                  mutant\u2019s increased resistance to formaldehyde, including mitigation of formaldehyde-induced protein stress and altered membrane physiology. We find that the\n                  <jats:italic>\n                    def\n                    <jats:sup>evo<\/jats:sup>\n                  <\/jats:italic>\n                  allele selectively alleviates exogenous, but not endogenous, formaldehyde stress and identify a tradeoff in heat shock resistance. This study reports the first observation of lowered PDF activity benefiting a cellular physiological phenotype. Our work indicates that altered protein metabolism can mitigate the toxic effects of formaldehyde and furthers our understanding of the strategies that can protect cells from formaldehyde-induced damage.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>\n                    Formaldehyde is a toxic chemical that can damage essential molecules inside of cells, yet all organisms inevitably produce it during normal metabolism. Despite its ubiquity, our understanding of strategies for how cells navigate formaldehyde toxicity is incomplete. This study focuses on\n                    <jats:italic>Methylobacterium extorquens<\/jats:italic>\n                    , which naturally generates high levels of formaldehyde as part of its growth on simple carbon compounds. We show herein that a single genetic change, which slows down how newly made proteins are processed during translation, can unexpectedly improve the bacterium\u2019s ability to resist formaldehyde stress. Further, we show that this single change has numerous effects on the cell, many of which may contribute to formaldehyde resistance.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.16.718930","type":"posted-content","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T15:00:34Z","timestamp":1776783634000},"source":"Crossref","is-referenced-by-count":0,"title":["Decreasing peptide deformylase activity is a beneficial strategy for increasing formaldehyde resistance in\n                  <i>Methylobacterium extorquens<\/i>"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7694-0715","authenticated-orcid":false,"given":"Chandler N.","family":"Hellenbrand","sequence":"first","affiliation":[{"name":"Department of Plant and Microbial Biology, University of Minnesota, Twin Cities, MN, USA"},{"name":"Department of Bacteriology, University of Wisconsin \u2013 Madison, Madison, WI, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tyler","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Plant and Microbial Biology, University of Minnesota, Twin Cities, MN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9527-7189","authenticated-orcid":false,"given":"Elias I.","family":"Kemna","sequence":"additional","affiliation":[{"name":"Department of Plant and Microbial Biology, University of Minnesota, Twin Cities, MN, USA"},{"name":"Department of Bacteriology, University of Wisconsin \u2013 Madison, Madison, WI, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric L.","family":"Bruger","sequence":"additional","affiliation":[{"name":"Department of Plant and Microbial Biology, University of Minnesota, Twin Cities, MN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7922-6798","authenticated-orcid":false,"given":"Zachary T.","family":"Hying","sequence":"additional","affiliation":[{"name":"Department of Plant and Microbial Biology, University of Minnesota, Twin Cities, MN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9012-2260","authenticated-orcid":false,"given":"Jannell V.","family":"Bazurto","sequence":"additional","affiliation":[{"name":"Department of Plant and Microbial Biology, University of Minnesota, Twin Cities, MN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026042505202029000_2026.04.16.718930v1.1","first-page":"1","article-title":"How formaldehyde reacts with amino acids","volume":"2","year":"2019","journal-title":"1. 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