A conserved SH3-like fold in diverse putative proteins tetramerizes into an oxidoreductase providing an antimicrobial resistance phenotype

Lemay-St-Denis, Claudèle; Alejaldre, Lorea; Jemouai, Zakaria; Lafontaine, Kiana; St-Aubin, Maxime; Hitache, Katia; Valikhani, Donya; Weerasinghe, Nuwani W; Létourneau, Myriam; Thibodeaux, Christopher J; Doucet, Nicolas ORCID: https://orcid.org/0000-0002-1952-9380; Baron, Christian; Copp, Janine N et Pelletier, Joelle N. (2023). A conserved SH3-like fold in diverse putative proteins tetramerizes into an oxidoreductase providing an antimicrobial resistance phenotype Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences , vol. 378 , nº 1871:202. pp. 1-14. DOI: 10.1098/rstb.2022.0040.

Prévisualisation

PDF - Version publiée Disponible sous licence Creative Commons Attribution. Télécharger (2MB) | Prévisualisation

Résumé

We present a potential mechanism for emergence of catalytic activity that is essential for survival, from a non-catalytic protein fold. The type B dihydrofolate reductase (DfrB) family of enzymes were first identified in pathogenic bacteria because their dihydrofolate reductase activity is sufficient to provide trimethoprim (TMP) resistance. DfrB enzymes are described as poorly evolved as a result of their unusual structural and kinetic features. No characterized protein shares sequence homology with DfrB enzymes; how they evolved to emerge in the modern resistome is unknown. In this work, we identify DfrB homologues from a database of putative and uncharacterized proteins. These proteins include an SH3-like fold homologous to the DfrB enzymes, embedded in a variety of additional structural domains. By means of functional, structural and biophysical characterization, we demonstrate that these distant homologues and their extracted SH3-like fold can display dihydrofolate reductase activity and confer TMP resistance. We provide evidence of tetrameric assembly and catalytic mechanism analogous to that of DfrB enzymes. These results contribute, to our knowledge, the first insights into a potential evolutionary path taken by this SH3-like fold to emerge in the modern resistome following introduction of TMP. This article is part of the theme issue 'Reactivity and mechanism in chemical and synthetic biology'.

Type de document:	Article
Mots-clés libres:	R67 DHFR; SH3-like fold; antibiotic resistance; enzyme evolution; evolutionary biochemistry.
Centre:	Centre INRS-Institut Armand Frappier
Date de dépôt:	11 déc. 2023 14:18
Dernière modification:	11 déc. 2023 14:21
URI:	https://espace.inrs.ca/id/eprint/13412

Gestion Actions (Identification requise)

Modifier la notice