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dc.contributor.authorAlderson, Rosanna Grace
dc.contributor.authorBarker, Daniel
dc.contributor.authorMitchell, John B. O.
dc.identifier.citationAlderson , R G , Barker , D & Mitchell , J B O 2014 , ' One origin for metallo-β-lactamase activity, or two? An investigation assessing a diverse set of reconstructed ancestral sequences based on a sample of phylogenetic trees ' , Journal of Molecular Evolution , vol. 79 , no. 3-4 , pp. 117-129 .
dc.identifier.otherPURE: 145494212
dc.identifier.otherPURE UUID: 8a3b1ec9-59e7-4e3d-a996-da4205cb7c71
dc.identifier.otherBibtex: urn:6cfe696d9a2ba25080c339759672006d
dc.identifier.otherScopus: 84919769155
dc.identifier.otherORCID: /0000-0002-0379-6097/work/34033389
dc.identifier.otherWOS: 000343292500005
dc.descriptionThis work was supported by BBSRC (grant BB/F016778/1)en
dc.description.abstractBacteria use metallo-β-lactamase enzymes to hydrolyse lactam rings found in many antibiotics, rendering them ineffective. Metallo-β-lactamase activity is thought to be polyphyletic, having arisen on more than one occasion within a single functionally diverse homologous superfamily. Since discovery of multiple origins of enzymatic activity conferring antibiotic resistance has broad implications for the continued clinical use of antibiotics, we test the hypothesis of polyphyly further; if lactamase function has arisen twice independently, the most recent common ancestor (MRCA) is not expected to possess lactam-hydrolysing activity. Two major problems present themselves. Firstly, even with a perfectly known phylogeny, ancestral sequence reconstruction is error prone. Secondly, the phylogeny is not known, and in fact reconstructing a single, unambiguous phylogeny for the superfamily has proven impossible. To obtain a more statistical view of the strength of evidence for or against MRCA lactamase function, we reconstructed a sample of 98 MRCAs of the metallo-β-lactamases, each based on a different tree in a bootstrap sample of reconstructed phylogenies. InterPro sequence signatures and homology modelling were then used to assess our sample of MRCAs for lactamase functionality. Only 5 % of these models conform to our criteria for metallo-β-lactamase functionality, suggesting that the ancestor was unlikely to have been a metallo-β-lactamase. On the other hand, given that ancestral proteins may have had metallo-β-lactamase functionality with variation in sequence and structural properties compared with extant enzymes, our criteria are conservative, estimating a lower bound of evidence for metallo-β-lactamase functionality but not an upper bound.
dc.relation.ispartofJournal of Molecular Evolutionen
dc.rights© The Author(s) 2014. This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.en
dc.subjectAntibiotic resistanceen
dc.subjectMost recent common ancestoren
dc.subjectAncestral sequence reconstructionen
dc.subjectQH301 Biologyen
dc.subjectQD Chemistryen
dc.titleOne origin for metallo-β-lactamase activity, or two? An investigation assessing a diverse set of reconstructed ancestral sequences based on a sample of phylogenetic treesen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews. School of Chemistryen
dc.contributor.institutionUniversity of St Andrews. School of Biologyen
dc.contributor.institutionUniversity of St Andrews. Biomedical Sciences Research Complexen
dc.contributor.institutionUniversity of St Andrews. EaSTCHEMen
dc.description.statusPeer revieweden

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