ArticlePhilosophical transactions of the Royal Society of London. Series B, Biological sciences2023
A conserved SH3-like fold in diverse putative proteins tetramerizes into an oxidoreductase providing an antimicrobial resistance phenotype.
Article in Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 11 citations in OpenAlex.
- From Binding to Catalysis: Emergence of a Rudimentary Enzyme Conferring Intrinsic Antibiotic Resistance.Molecular biology and evolution · 2025Article
- Crystal structure of the plasmid-encoded R67 dihydrofolate reductase complexed with Congo red an amyloid binding dye.Scientific reports · 2025Article
- Photoaffinity probe-enabled discovery of sennoside A reductase inJournal of pharmaceutical analysis · 2025Article
- Metabolite microextraction on surface-enhanced Raman scattering nanofibres and DNpj biosensing · 2025Article
- Bacteria of the order Burkholderiales are original environmental hosts of type II trimethoprim resistance genes (dfrB).The ISME journal · 2024Article
- 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 · 2023Article
- Reactivity and mechanism in chemical and synthetic biology.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Article
- Discovery of Highly Trimethoprim-Resistant DfrB Dihydrofolate Reductases in Diverse Environmental Settings Suggests an Evolutionary Advantage Unrelated to Antibiotic Resistance.Antibiotics (Basel, Switzerland) · 2022Article
Corrections and comments
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Authors and funding
14 authors at 6 institutions in 6 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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'.
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