CoChat
Sign Up
Cited by 6Metalloenzymes and iron-sulfur proteinsGenomics and Phylogenetic StudiesEnzyme Structure and Function

The DOI matches its Crossref record; 2 of the 2 references it cites were found in a registry or an index.

Evolutionary plasticity and functional repurposing of the essential metabolic enzyme MoeA

Open access
Megrian, Daniela, Martinez, Mariano, Alzari, Pedro M., Wehenkel, Anne Marie·2025·Communications Biology
DOI 10.1038/s42003-025-07476-3PMC PMC11733289

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

MoeA, also known as gephyrin in higher eukaryotes, is an enzyme essential for molybdenum cofactor (Moco) biosynthesis and involved in GABA and GlyR receptor clustering at the synapse in animals. We recently discovered that Actinobacteria have a repurposed version of MoeA (Glp) linked to bacterial cell division. Since MoeA exists in all domains of life, our study explores how it gained multifunctionality over time. We use phylogenetic inference and protein structure analyses to study its diversity and evolutionary history. Glp-expressing Bacteria have at least two copies of the gene, and analysis of their putative active sites suggests that Glp lost its enzymatic role. In Archaea, we find an ancestral duplication, with one paralog that may bind tungsten instead of molybdenum. Early eukaryotes acquired MoeA from Bacteria, MogA fused with MoeA in the opisthokont ancestors, and it finally gained roles in anchoring inhibitory neurotransmitters. Our findings highlight MoeA’s functional versatility and repurposing.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s42003-025-07476-3

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 44

  1. Mayr, S. J., Mendel, R. R. & Schwarz, G. Molybdenum cofactor biology, evolution and deficiency. Biochim. Biophys. Acta Mol. Cell Res. 1868, 118883 (2021). · DOI
  2. Peng, T., Xu, Y. & Zhang, Y. Comparative genomics of molybdenum utilization in prokaryotes and eukaryotes. BMC Genomics 19, 691 (2018). · DOI
  3. Zhong, Q., Kobe, B. & Kappler, U. Molybdenum Enzymes and How They Support Virulence in Pathogenic Bacteria. Front. Microbiol. 11, https://doi.org/10.3389/fmicb.2020.615860 (2020). · DOI
  4. Schwarz, G. Molybdenum cofactor biosynthesis and deficiency. Cell. Mol. Life Sci. 62, 2792–2810 (2005). · DOI
  5. Mendel, R. R. & Leimkühler, S. The biosynthesis of the molybdenum cofactors. J. Biol. Inorg. Chem. 20, 337–347 (2015). · DOI
  6. Tyagarajan, S. K. & Fritschy, J. M. Gephyrin: A master regulator of neuronal function? Nat. Rev. Neurosci. 15, 141–156 (2014). · DOI
  7. Martinez, M. et al. Eukaryotic-like gephyrin and cognate membrane receptor coordinate corynebacterial cell division and polar elongation. Nat. Microbiol. 8, 1896–1910 (2023). · DOI
  8. Kirsch, J., Langosch, D., Littauer, U. Z., Schmitt, B. & Betz, H. The 93-KDa Glycine Receptor-Associated Protein Binds to Tubulin. J. Biol. Chem. 266, 22242–22245 (1991). · DOI
  9. Stallmeyer, B. et al. The Neurotransmitter Receptor-Anchoring Protein Gephyrin Reconstitutes Molybdenum Cofactor Biosynthesis in Bacteria, Plants, and Mammalian Cells. Proc. Natl Acad. Sci. USA 96,1333–1338 (1999). · DOI
  10. Schwarz, G. et al. The Molybdenum Cofactor Biosynthetic Protein Cnx1 Complements Molybdate-Repairable Mutants, Transfers Molybdenum to the Metal Binding Pterin, and Is Associated with the Cytoskeleton. Plant Cell 12, https://academic.oup.com/plcell/article/12/12/2455/6009386 (2000). · DOI
  11. Choii, G. & Ko, J. Gephyrin: a central GABAergic synapse organizer. Exper. Mol. Med. 47, https://doi.org/10.1038/EMM.2015.5 (2015). · DOI
  12. Zhang, Y., Rump, S. & Gladyshev, V. N. Comparative genomics and evolution of molybdenum utilization. Coordination Chem. Rev. 255, 1206–1217 (2011). · DOI
  13. Kaufholdt, D. et al. The molybdenum cofactor biosynthesis complex interacts with actin filaments via molybdenum insertase Cnx1 as anchor protein in Arabidopsis thaliana. Plant Sci. 244, 8–18 (2016). · DOI
  14. Sola, M. et al. Structural basis of dynamic glycine receptor clustering by gephyrin. EMBO J. 23, 2510–2519 (2004). · DOI
  15. Burki, F., Roger, A. J., Brown, M. W. & Simpson, A. G. B. The New Tree of Eukaryotes. Trends Ecol. Evol. 35, 43–55 (2020). · DOI · Paper page
  16. Bevers, L. E. et al. Function of MoaB proteins in the biosynthesis of the molybdenum and tungsten cofactors. Biochemistry 47, 949–956 (2008). · DOI
  17. Hagen, W. R. Cellular uptake of molybdenum and tungsten. Coordination Chem. Rev. 255, 1117–1128 (2011). · DOI
  18. Castelle, C. J. & Banfield, J. F. Major New Microbial Groups Expand Diversity and Alter our Understanding of the Tree of Life. Cell 172, 1181–1197 (2018). · DOI · Paper page
  19. McIlroy, S. J. et al. Culture-independent analyses reveal novel anaerolineaceae as abundant primary fermenters in anaerobic digesters treating waste activated sludge. Front. Microbiol. 8, 1134 (2017). · DOI
  20. Sekiguchi, Y. et al. Anaerolinea thermophila gen. nov., sp. nov. and Caldilinea aerophila gen. nov., sp. nov., novel filamentous thermophiles that represent a previously uncultured lineage of the domain bacteria at the subphylum level. Int. J. Syst. Evol. Microbiol. 53, 1843–1851 (2003). · DOI
  21. Looft, T., Levine, U. Y. & Stanton, T. B. Cloacibacillus porcorum sp. nov., a mucin-degrading bacterium from the swine intestinal tract and emended description of the genus Cloacibacillus. Int. J. Syst. Evol. Microbiol. 63, 1960–1966 (2013). · DOI
  22. Etchebehere, C., Zorzopulos, J., Soubes, M. & Muxi, L. Coprothermobacter Platensis S p m Now, a New Anaerobic Proteolytic Thermophilic Bacterium Isolated from an Anaerobic Mesophilic Sludge. J. Syst. Bacteriol. 48, 1297–1304 (1998). · DOI
  23. Guangsheng, C., Plugge, C. M., Roelofsen, W., Houwen, F. P. & Stams, A. J. M. Selenomonas Acidaminovorans Sp. Nov., a Versatile Thermophilic Proton-Reducing Anaerobe Able to Grow by Decarboxylation of Succinate to Propionate. Arch. Microblol. 157, 169–175 (1992). · DOI
  24. Zeikus, J. G., Dawson, M. A., Thompson, T. E., Ingvorsen, K. & Hatchikian, E. C. Microbial Ecology of Volcanic Sulphidogenesis: Isolation and Characterization of Thevmodesulfobacteviurn Commune Gen. Nov. and Sp. Nov. J. Gen. Microbiol. 129, 1159–1169 (1983). · DOI
  25. López-García, P. & Moreira, D. Selective forces for the origin of the eukaryotic nucleus. BioEssays 28, 525–533 (2006). · DOI
  26. Adam, P. S., Borrel, G., Brochier-Armanet, C. & Gribaldo, S. The growing tree of Archaea: New perspectives on their diversity, evolution and ecology. ISME J. 11, 2407–2425 (2017). · DOI
  27. Borrok, M. J., Zhu, Y., Forest, K. T. & Kiessling, L. L. Structure-based design of a periplasmic binding protein antagonist that prevents domain closure. ACS Chem. Biol. 4, 447–456 (2009). · DOI
  28. Leimkühler, S. The biosynthesis of the molybdenum cofactors in Escherichia coli. Environ. Microbiol. 22 2007–2026 (2020). · DOI
  29. Wolf, Y. I. & Koonin, E. V. Genome reduction as the dominant mode of evolution. BioEssays 35, 829–837 (2013). · DOI
  30. Megrian, D., Taib, N., Jaffe, A. L., Banfield, J. F. & Gribaldo, S. Ancient origin and constrained evolution of the division and cell wall (dcw) gene cluster across the Tree of Bacteria. Nat. Microbiol. 7, 2114–2127 (2022). · DOI
  31. Maia, L. B., Moura, I. & Moura, J. J. G. Molybdenum and Tungsten-Containing Enzymes: An Overview. In Molybdenum and Tungsten Enzymes: Biochemistry (ed. Hille, R.) (Royal Society of Chemistry, 2017). · DOI
  32. Mota, C. S. et al. Effects of molybdate and tungstate on expression levels and biochemical characteristics of formate dehydrogenases produced by Desulfovibrio alaskensis NCIMB 13491. J. Bacteriol. 193, 2917–2923 (2011). · DOI
  33. Pende, N. et al. SepF is the FtsZ anchor in archaea, with features of an ancestral cell division system. Nat. Commun. 12, 3214 (2021). · DOI
  34. Sayers, E. W. et al. Database resources of the national center for biotechnology information. Nucleic Acids Res. 50, D20–D26 (2022). · DOI · Paper page
  35. Johnson, L. S., Eddy, S. R. & Portugaly, E. Hidden Markov model speed heuristic and iterative HMM search procedure. BMC Bioinformatics 11, 431 (2010). · DOI
  36. Marchler-Bauer, A. & Bryant, S. H. CD-Search: Protein domain annotations on the fly. Nucleic Acids Res. 32, W327–W331 (2004). · DOI
  37. Letunic, I. & Bork, P. Interactive Tree of Life (iTOL) v4: Recent updates and new developments. Nucleic Acids Res. 47, 256–259 (2019). · DOI
  38. Katoh, K. & Standley, D. M. MAFFT multiple sequence alignment software version 7: Improvements in performance and usability. Mol. Biol. Evol. 30, 772–780 (2013). · DOI · Paper page
  39. Capella-Gutiérrez, S., Silla-Martínez, J. M. & Gabaldón, T. trimAl: A tool for automated alignment trimming in large-scale phylogenetic analyses. Bioinformatics 25, 1972–1973 (2009). · DOI
  40. Nguyen, L. T., Schmidt, H. A., Von Haeseler, A. & Minh, B. Q. IQ-TREE: A fast and effective stochastic algorithm for estimating maximum-likelihood phylogenies. Mol. Biol. Evol. 32, 268–274 (2015). · DOI · Paper page
  41. Pettersen, E. F. et al. UCSF ChimeraX: Structure visualization for researchers, educators, and developers. Protein Sci. 30, 70–82 (2021). · DOI
  42. Pei, J. & Grishin, N. V. AL2CO: Calculation of Positional Conservation in a Protein Sequence Alignment. Bioinformatics 17, 700–712 (2001). · DOI
  43. Cock, P. J. A. et al. Biopython: Freely available Python tools for computational molecular biology and bioinformatics. Bioinformatics 25, 1422–1423 (2009). · DOI · Paper page
  44. Liu, H. et al. A taxon-rich and genome-scale phylogeny of Opisthokonta. PLoS Biol. 22, e3002794 (2024). · DOI

Metadata

Authors
Megrian, D., Martinez, M., Alzari, P. M., & Wehenkel, A. M.
Affiliations
Centre National de la Recherche Scientifique (FR)
Corresponding author
  • Megrian, Daniela
  • Wehenkel, Anne Marie
ORCID
Venue
Communications Biology
Publisher
Springer Science and Business Media LLC
Published
2025-01-14
Volume
8
Issue
1
Pages
49-49
ISSN
2399-3642 (ISSN-L)
DOI
10.1038/s42003-025-07476-3
PMC
PMC11733289
OpenAlex
W4406362311
Cited by
6
References
2
Citations by year
2026: 4 · 2025: 2
FWCI
0.83
Type
journal article
Language
en
Open access
Licence
Locations
  • Communications Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Agence Nationale de la Recherche (ANR-21-CE11-0003, ANR-18-CE11-0017)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Metalloenzymes and iron-sulfur proteins
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords
multi-objective evolutionary algorithms, gephyrin, molybdenum cofactor biosynthesis, evolutionary plasticity, actinobacteria, bacterial cell division, MOGA, gene duplication, archaeal evolution, eukaryotic evolution, protein evolution

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review