Formaldehyde-Responsive Proteins TtmR and EfgA Reveal a Trade-off between Formaldehyde Resistance and Efficient Transition to Methylotrophy in Methylorubrum extorquens

Jannell V. Bazurto, Eric L. Bruger, Jessica A. Lee, Leah B. Lambert, Christopher J. Marx

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


For bacteria to thrive they must be well-adapted to their environmental niche, which may involve specialized metabolism, timely adaptation to shifting environments, and/or the ability to mitigate numerous stressors. These attributes are highly dependent on cellular machinery that can sense both the external and intracellular environment. Methylorubrum extorquens is an extensively studied facultative methylotroph, an organism that can use single-carbon compounds as their sole source of carbon and energy. In methylotrophic metabolism, carbon flows through formaldehyde as a central metabolite; thus, formaldehyde is both an obligate metabolite and a metabolic stressor. Via the one-carbon dissimilation pathway, free formaldehyde is rapidly incorporated by formaldehyde activating enzyme (Fae), which is constitutively expressed at high levels. In the presence of elevated formaldehyde levels, a recently identified formaldehyde-sensing protein, EfgA, induces growth arrest. Herein, we describe TtmR, a formaldehyde-responsive transcription factor that, like EfgA, modulates formaldehyde resistance. TtmR is a member of the MarR family of transcription factors and impacts the expression of 75 genes distributed throughout the genome, many of which are transcription factors and/or involved in stress response, including efgA Notably, when M. extorquens is adapting its metabolic network during the transition to methylotrophy, efgA and ttmR mutants experience an imbalance in formaldehyde production and a notable growth delay. Although methylotrophy necessitates that M. extorquens maintain a relatively high level of formaldehyde tolerance, this work reveals a tradeoff between formaldehyde resistance and the efficient transition to methylotrophic growth and suggests that TtmR and EfgA play a pivotal role in maintaining this balance. Importance: All organisms produce formaldehyde as a byproduct of enzymatic reactions and as a degradation product of metabolites. The ubiquity of formaldehyde in cellular biology suggests all organisms have evolved mechanisms of mitigating formaldehyde toxicity. However, formaldehyde-sensing is poorly described and prevention of formaldehyde-induced damage is primarily understood in the context of detoxification. Here we use an organism that is regularly exposed to elevated intracellular formaldehyde concentrations through high-flux one-carbon utilization pathways to gain insight into the role of formaldehyde-responsive proteins that modulate formaldehyde resistance. Using a combination of genetic and transcriptomic analyses, we identify dozens of genes putatively involved in formaldehyde resistance, determined the relationship between two different formaldehyde response systems and identified an inherent tradeoff between formaldehyde resistance and optimal transition to methylotrophic metabolism.

Original languageEnglish (US)
Article numbere00589
JournalJournal of bacteriology
Issue number9
Early online dateFeb 22 2021
StatePublished - May 2021

Bibliographical note

Funding Information:
We thank Juan E. Abrahante of the University of Minnesota Informatics Institute (UMII) for assistance with the pipeline for transcriptome sequencing (RNA-seq) data analysis and Siavash Riazi for assistance with modifying R scripts. We thank members of the Marx laboratory, Bazurto laboratory, and Lon Chubiz for critical reading of the manuscript. We thank Chandler Hellenbrand for assistance in conducting experiments. The flow cytometry was carried out at the IBEST Optical Imaging Core at the University of Idaho (IBEST is supported in part by NIH COBRE grant P30GM103324).

Funding Information:
This work was supported by funding from an Army Research Office MURI subaward to C.J.M. (W911NF-12-1-0390), a CMCI pilot grant to C.J.M. (parent NIH award P20GM104420), an INBRE Undergraduate Research Fellowship to L.B.L. (parent NIH award P20GM103408), and a Beacon Center for Evolution in Action pilot grants to J.V.B. and E.L.B. (NSF cooperative agreement DBI-0939454).

Publisher Copyright:
© 2021 American Society for Microbiology. All Rights Reserved.


  • Adaptation
  • Enhanced formaldehyde growth protein a (efga)
  • Formaldehyde
  • Marr transcription factor
  • Methylotrophy
  • Stress response
  • Trade-offs

PubMed: MeSH publication types

  • Journal Article


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