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PreprintCited by 24Microbial Metabolic Engineering and BioproductionBacterial Genetics and BiotechnologyRedox biology and oxidative stress

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Metabolite Damage and Damage-Control in a Minimal Genome

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Haas, Drago, Thamm, Antje M., Sun, Jiayi, Huang, Lili, Sun, Lijie, Beaudoin, Guillaume A.W., Wise, Kim S., Lerma-Ortiz, Claudia, Bruner, Steven D., Breuer, Marian, Luthey-Schulten, Zaida, Lin, Jiusheng, Wilson, Mark A., Brown, Greg, Yakunin, Alexander F., Kurilyak, Inna, Folz, Jacob, Fiehn, Oliver, Glass, John I., Hanson, Andrew D., Henry, Christopher S., de Crécy-Lagard, Valérie·2021·mBio
DOI 10.1101/2021.12.01.470718PMC PMC9426524

Preprint — published as 10.1128/mbio.01630-22

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Abstract

Analysis of the genes retained in the minimized Mycoplasma JCVI-Syn3A genome established that systems that repair or preempt metabolite damage are essential to life. Several genes with known metabolite damage repair or preemption functions were identified and experimentally validated, including 5-formyltetrahydrofolate cyclo-ligase, CoA disulfide reductase, and certain hydrolases. Furthermore, we discovered that an enigmatic YqeK hydrolase domain fused to NadD has a novel proofreading function in NAD synthesis and could double as a MutT-like sanitizing enzyme for the nucleotide pool. Finally, we combined metabolomics and cheminformatics approaches to extend the core metabolic map of JCVI-Syn3A to include promiscuous enzymatic reactions and spontaneous side reactions. This extension revealed that several key metabolite damage-control systems remain to be identified in JCVI-Syn3A, such as that for methylglyoxal.

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  • Gene 0066 was identified as dUMP phosphatase primarily acting on dUMP and dTMP, also acting on dGMP and dAMP less than dUMP.

    “Gene 0066 was identified as dUMP phosphatase primarily acting on dUMP and dTMP, which agrees with previous experimental results from the literature (Neale et al., 1983).”

    From Fundamental behaviors emerge from simulations of a living minimal cell (2022) · cites this paper as Haas et al., 2021

    The Results and Discussion (p. 6) suggest that gene 0066 is a major deoxyribonucleoside monophosphatase acting on dUMP, dTMP, dGMP, and dAMP, among other substrates. They do not establish that it acts primarily on dUMP and dTMP or less on dGMP and dAMP; the paper instead describes gene 0077 as dUMP-specific. The same section notes that nucleotide-phosphatase activity for 0066 was not observed in the in vitro substrate screen. (LLM, conf=0.88)

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Metadata

Authors
Haas, D., Thamm, A. M., Sun, J., Huang, L., Sun, L., Beaudoin, G. A. W., Wise, K. S., Lerma-Ortiz, C., Bruner, S. D., Breuer, M., Luthey-Schulten, Z., Lin, J., Wilson, M. A., Brown, G., Yakunin, A. F., Kurilyak, I., Folz, J., Fiehn, O., Glass, J. I., Hanson, A. D., Henry, C. S., & de Crécy-Lagard, V.
Affiliations
  • University of Florida (US)
  • J. Craig Venter Institute (US)
  • Maastricht University (NL)
  • University of Illinois Urbana-Champaign (US)
  • University of Nebraska–Lincoln (US)
  • Bangor University (GB)
  • University of California, Davis (US)
  • Argonne National Laboratory (US)
Corresponding author
Henry, Christopher S.
ORCID
Venue
mBio
Publisher
openRxiv
Published
2021-12-01
Volume
13
Issue
4
Pages
e0163022-e0163022
ISSN
2150-7511 (ISSN-L)
DOI
10.1101/2021.12.01.470718
PMC
PMC9426524
OpenAlex
W4285005438
Cited by
24
References
80
Citations by year
2026: 6 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 4
FWCI
1.47
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • mBio (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion, other-oa)
  • Lincoln (University of Nebraska) (submittedVersion, cc-by)
  • Research Publications (Maastricht University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • Bangor University Research Portal (Bangor University) (submittedVersion, other-oa)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
Funders
National Science Foundation (1611952, 1611711, 1840301, 1611846, 1840320, 1818344)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
damage control, minimal genome, genome reduction, metabolomics, cheminformatics, metabolic networks, repair mechanisms
MeSH terms
Oxidoreductases, Genome, Bacterial, Metabolomics

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