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Ancient loss of catalytic selenocysteine spurred convergent adaptation in a mammalian oxidoreductase

View ORCID ProfileJasmin Rees, Gaurab Sarangi, Qing Cheng, Martin Floor, Aida M Andrés, Baldomero Oliva Miguel, Jordi Villà-Freixa, View ORCID ProfileElias SJ Arnér, View ORCID ProfileSergi Castellano
doi: https://doi.org/10.1101/2023.01.03.522577
Jasmin Rees
1Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
2Division of Biosciences, University College London, London, United Kingdom
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  • ORCID record for Jasmin Rees
Gaurab Sarangi
3Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
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Qing Cheng
4Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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Martin Floor
5Department of Biosciences, Faculty of Sciences and Technology, Universitat de Vic - Universitat Central de Catalunya, Vic, Spain
6Barcelona Supercomputing Center (BSC), Barcelona, Spain
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Aida M Andrés
2Division of Biosciences, University College London, London, United Kingdom
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Baldomero Oliva Miguel
7Department of Health and Experimental Sciences, Universitat Pompeu Fabra, Barcelona, Spain
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Jordi Villà-Freixa
5Department of Biosciences, Faculty of Sciences and Technology, Universitat de Vic - Universitat Central de Catalunya, Vic, Spain
8Institut de Recerca i Innovació en Ciències de la Vida i de la Salut a la Catalunya Central (IRIS-CC), Vic, Spain
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Elias SJ Arnér
4Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
9Department of Selenoprotein Research, National Institute of Oncology, Budapest, Hungary
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Sergi Castellano
1Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
10UCL Genomics, University College London, London, United Kingdom
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  • For correspondence: s.castellano@ucl.ac.uk
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Abstract

Selenocysteine (Sec), the 21st amino acid specified by the genetic code, is a rare selenium-containing residue found in the catalytic site of selenoprotein oxidoreductases. Sec is analogous to the common cysteine (Cys) amino acid but its selenium atom offers physicalchemical properties not provided by the corresponding sulfur atom in Cys. Catalytic sites with Sec in selenoproteins of vertebrates are under strong purifying selection but one enzyme, Glutathione Peroxidase 6 (GPX6), independently exchanged Sec for Cys less than one hundred million years ago in several mammalian lineages. We reconstructed and assayed these ancient enzymes before and after Sec was lost and up to today, and found them to have lost their classic ability to reduce hydroperoxides using glutathione (GSH). This loss of function, however, was accompanied by bursts of amino acid changes in the catalytic domain, with protein sites concertedly changing under positive selection across distant lineages abandoning Sec in GPX6. This demonstrates that when sulfur in Cys impairs catalysis a narrow evolutionary path is followed, with epistasis and pleiotropy leading to convergent evolution and triggering enzymatic properties likely beyond those in classic GPXs. These findings are an unusual example of adaptive convergence towards unexplored oxidoreductase functions during mammalian evolution.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 04, 2023.
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Ancient loss of catalytic selenocysteine spurred convergent adaptation in a mammalian oxidoreductase
Jasmin Rees, Gaurab Sarangi, Qing Cheng, Martin Floor, Aida M Andrés, Baldomero Oliva Miguel, Jordi Villà-Freixa, Elias SJ Arnér, Sergi Castellano
bioRxiv 2023.01.03.522577; doi: https://doi.org/10.1101/2023.01.03.522577
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Ancient loss of catalytic selenocysteine spurred convergent adaptation in a mammalian oxidoreductase
Jasmin Rees, Gaurab Sarangi, Qing Cheng, Martin Floor, Aida M Andrés, Baldomero Oliva Miguel, Jordi Villà-Freixa, Elias SJ Arnér, Sergi Castellano
bioRxiv 2023.01.03.522577; doi: https://doi.org/10.1101/2023.01.03.522577

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