Native metabolomics identifies pteridines as CutA ligands and modulators of copper binding

CutA, a conserved protein across all domains of life, has been suggested to be involved in copper tolerance in bacteria, though recent studies have questioned this association, leaving its biological role unknown. To clarify its function, we studied <i>cutA</i> knockout mutants from two phylogenetically distant species, <i>Synechococcus elongatus PCC 7942</i> and <i><i>Escherichia coli</i></i>, using phenotyping combined with metabolomics. To investigate the interaction of CutA with potential substrates and cofactors, we performed a series of native metabolomics experiments with CutA and cell extracts from which we identified the lumazine 2'-deoxyxanthopterin B2, a previously uncharacterized pteridine, to bind CutA in both species. Based on these results, we identified a set of other pteridines, including the essential cofactor tetrahydrobiopterin, as ligands of CutA. In the presence of pterins, we observed an increased affinity of CutA for copper ions. In addition, <i><i>E. coli</i></i> CutA mutants exhibited decreased copper resistance. These findings, alongside the known role of pteridines as redox shuttles, suggest a previously unrecognized role for CutA in coordinating cellular copper homeostasis and redox balance via pteridine metabolism.

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Journal
Proceedings of the National Academy of Sciences
Published
2025-11-25
DOI
https://doi.org/10.1073/pnas.2509468122
Primary Topic
Trace Elements in Health
Type
article
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0.00

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article

Native metabolomics identifies pteridines as CutA ligands and modulators of copper binding

Daniel Petras, Ansel Hsiao, Khaled A. Selim, Johanna Rapp et al.
Proceedings of the National Academy of Sciences
Trace Elements in Health
article

Native metabolomics identifies pteridines as CutA ligands and modulators of copper binding

Daniel Petras, Ansel Hsiao, Khaled A. Selim, Johanna Rapp, Chambers C. Hughes, Hannes Link, Berenike Wagner, Karl Forchhammer, Marcus D. Hartmann, Christian Geibel, Amelie Stadelmann, Karoline Steuer-Lodd, Nouneh Boodaghian, Reinhard Albrecht, T Schramm, Eva Nußbaum, Heinz-Paul Grenzendorfer
article en

Abstract

CutA, a conserved protein across all domains of life, has been suggested to be involved in copper tolerance in bacteria, though recent studies have questioned this association, leaving its biological role unknown. To clarify its function, we studied <i>cutA</i> knockout mutants from two phylogenetically distant species, <i>Synechococcus elongatus PCC 7942</i> and <i><i>Escherichia coli</i></i>, using phenotyping combined with metabolomics. To investigate the interaction of CutA with potential substrates and cofactors, we performed a series of native metabolomics experiments with CutA and cell extracts from which we identified the lumazine 2'-deoxyxanthopterin B2, a previously uncharacterized pteridine, to bind CutA in both species. Based on these results, we identified a set of other pteridines, including the essential cofactor tetrahydrobiopterin, as ligands of CutA. In the presence of pterins, we observed an increased affinity of CutA for copper ions. In addition, <i><i>E. coli</i></i> CutA mutants exhibited decreased copper resistance. These findings, alongside the known role of pteridines as redox shuttles, suggest a previously unrecognized role for CutA in coordinating cellular copper homeostasis and redox balance via pteridine metabolism.

Proceedings of the National Academy of SciencesVol. 122(48)
University of California, Riverside (US), Max Planck Institute for Developmental Biology (DE), German Center for Infection Research (DE), Czech Academy of Sciences, Institute of Microbiology (CZ), Innovation Cluster (Canada) (CA), Human Computer Interaction (Switzerland) (CH), Plant (United States) (US), Heinrich Heine University Düsseldorf (DE), University of Tübingen (DE)
National Science Foundation, Science Foundation Ireland, Deutsche Forschungsgemeinschaft, National Institute of General Medical Sciences
Openalex Percentile: Top 57%
Trace Elements in Health
DOIOpen Access PDFOpenAlex
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