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Parallel evolution of non-homologous isofunctional enzymes in methionine biosynthesis

Nature Chemical Biology volume 13, pages 858–866 (2017)Cite this article

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A Corrigendum to this article was published on 19 September 2017

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Abstract

Experimental validation of enzyme function is crucial for genome interpretation, but it remains challenging because it cannot be scaled up to accommodate the constant accumulation of genome sequences. We tackled this issue for the MetA and MetX enzyme families, phylogenetically unrelated families of acyl-L-homoserine transferases involved in L-methionine biosynthesis. Members of these families are prone to incorrect annotation because MetX and MetA enzymes are assumed to always use acetyl-CoA and succinyl-CoA, respectively. We determined the enzymatic activities of 100 enzymes from diverse species, and interpreted the results by structural classification of active sites based on protein structure modeling. We predict that >60% of the 10,000 sequences from these families currently present in databases are incorrectly annotated, and suggest that acetyl-CoA was originally the sole substrate of these isofunctional enzymes, which evolved to use exclusively succinyl-CoA in the most recent bacteria. We also uncovered a divergent subgroup of MetX enzymes in fungi that participate only in L-cysteine biosynthesis as O-succinyl-L-serine transferases.

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Figure 1: Mapping of the experimentally determined activities of MetA and MetX on a taxonomic cladogram.
Figure 2: Dividing MetX and MetA families into groups with similar active sites.
Figure 3: Biosynthetic roles of MetA and MetX enzymes.
Figure 4: Decision trees for annotation of MetX and MetA enzymes.
Figure 5: Prediction of acyltransferase activities of MetX and MetA in bacteria, archaea and fungi.

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Change history

  • 10 July 2017

    In the version of this article initially published, a sentence in the abstract, "Members of these families are prone to incorrect annotation because MetA and MetX enzymes are assumed to always use acetyl-CoA and succinyl-CoA, respectively," had the order of enzymes MetA and MetX reversed. The sentence should read, "Members of these families are prone to incorrect annotation because MetX and MetA enzymes are assumed to always use acetyl-CoA and succinyl-CoA, respectively." The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We are grateful to L. Stuani, L. Grenot, C. Gazaille, C. Richer, C. Pellé and P. Sirvain for excellent technical assistance. We thank G. Cohen, M. Bouzon-Bloch, M. Stam, A. Calteau, B. Viart and M. Sorokina for helpful discussion on the manuscript. We are indebted to P. Bowe for improvements to the manuscript. We are grateful to E. Coudert and C. Rivoire (the Swiss-Prot Group at the SIB Swiss Institute of Bioinformatics), who updated the HAMAP rules. This work was supported by Commissariat à l'énergie atomique et aux énergies alternatives (CEA), the CNRS and the University of Evry Val d'Essonne.

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Author notes

  1. Karine Bastard and Alain Perret: These authors contributed equally to this work.

Authors and Affiliations

  1. CEA, DRF, Genoscope, Evry, France

    Karine Bastard, Alain Perret, Aline Mariage, Thomas Bessonnet, Agnès Pinet-Turpault, Jean-Louis Petit, Ekaterina Darii, Pascal Bazire, Carine Vergne-Vaxelaire, Clémence Brewee, Adrien Debard, Virginie Pellouin, Marielle Besnard-Gonnet, Claudine Médigue, David Vallenet, Anne Zaparucha, Jean Weissenbach, Marcel Salanoubat & Véronique de Berardinis

  2. CNRS, UMR8030 Génomique Métabolique, Evry, France

    Karine Bastard, Alain Perret, Aline Mariage, Thomas Bessonnet, Agnès Pinet-Turpault, Jean-Louis Petit, Ekaterina Darii, Pascal Bazire, Carine Vergne-Vaxelaire, Clémence Brewee, Adrien Debard, Virginie Pellouin, Marielle Besnard-Gonnet, Claudine Médigue, David Vallenet, Anne Zaparucha, Jean Weissenbach, Marcel Salanoubat & Véronique de Berardinis

  3. Université d'Evry Val d'Essonne, Evry, France

    Karine Bastard, Alain Perret, Aline Mariage, Thomas Bessonnet, Agnès Pinet-Turpault, Jean-Louis Petit, Ekaterina Darii, Pascal Bazire, Carine Vergne-Vaxelaire, Clémence Brewee, Adrien Debard, Virginie Pellouin, Marielle Besnard-Gonnet, Claudine Médigue, David Vallenet, Anne Zaparucha, Jean Weissenbach, Marcel Salanoubat & Véronique de Berardinis

  4. Université Paris-Saclay, Evry, France

    Karine Bastard, Alain Perret, Aline Mariage, Thomas Bessonnet, Agnès Pinet-Turpault, Jean-Louis Petit, Ekaterina Darii, Pascal Bazire, Carine Vergne-Vaxelaire, Clémence Brewee, Adrien Debard, Virginie Pellouin, Marielle Besnard-Gonnet, Claudine Médigue, David Vallenet, Anne Zaparucha, Jean Weissenbach, Marcel Salanoubat & Véronique de Berardinis

  5. CEA, DRF, Centre National de Génotypage, Evry, France

    François Artiguenave

  6. Institute of Cardiometabolism and Nutrition (ICAN), Hôpital de la Pitié-Salpêtrière, Paris, France

    Antoine Danchin

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  1. Karine Bastard
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Contributions

V.d.B. conceived the project. V.d.B., K.B. and A.P. designed and supervised the project and analyzed the data. V.d.B. performed the genome analyses. A.P. designed and supervised the biochemical experiments with input from V.d.B. K.B. conceived and conducted the structural bioinformatics analysis with input from A.Z. A.P.-T., A.M., J.-L.P., C.B. and T.B. carried out the biochemical experiments. A. Debard, V.P. and M.B.-G. carried out the gene cloning, the protein expression and purifications for the whole collection of MetA and MetX enzymes. A.P. and E.D. designed and analyzed the metabolomics experiments, which were conducted by E.D., P.B. and T.B. C.V.-V. chemically synthesized reference compounds. K.B., A.P. and V.d.B. performed the taxonomic analysis, with input from D.V. and F.A. K.B. built the website with input from V.d.B. V.d.B., K.B. and A.P. wrote the manuscript with input from A. Danchin, M.S., A.Z., C.M., D.V. and J.W.

Corresponding author

Correspondence to Véronique de Berardinis.

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Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Tables 1–10 and Supplementary Figures 1–22. (PDF 5186 kb)

Supplementary Data Set 1

Primers and strains used for gene cloning. (XLSX 26 kb)

Supplementary Data Set 2

Data from PROCHECK and PROSA II analysis for homology model validation. (XLSX 422 kb)

Supplementary Data Set 3

IPR008220 (MetX) and IPR005697 (MetA) set classification via the ASMC method. (XLSX 417 kb)

Supplementary Data Set 4

Reannotation of proteins with IPR008220 (MetX) and IPR005697 (MetA) signatures. (XLSX 1732 kb)

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Bastard, K., Perret, A., Mariage, A. et al. Parallel evolution of non-homologous isofunctional enzymes in methionine biosynthesis. Nat Chem Biol 13, 858–866 (2017). https://doi.org/10.1038/nchembio.2397

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