title: Evolutionary root defines the structural basis of high and low level vancomycin resistance in enterococci.
abstract: D-alanyl-D-lactate (Dlac) and D-alanyl-D-serine (Dser) ligases respectively mediates high and low level vancomycin resistance among enterococci. To date, the evolutionary relationship of both ligases is largely unaddressed. Also poorly understood are the molecular differences in the magnitude of vancomycin resistance. To address the mention, we constructed the phylogenetic tree of all vancomycin resistance conferring ligases with the wild type ligases (Dala). Multiple sequence alignment and tertiary structures of the structurally unresolved proteins were constructed by homology modeling. Phylogenetic tree revealed that both Dlac and Dser are profoundly different from Dala as a result of continuous selection pressure. Separate clustering of Dlac and Dser also highlighted the structural basis of molecule in maintaining different level of resistance as exhibited by the bacteria. This notion was further augmented as the functionally key region, omega loop (ω-loop), was found relatively more structured in only Dlac. Moreover, the critically active residue, His-243/244, was also noticed to be restricted in Dlac and found replaced by non polar residues in Dser. The present study not only provides protein structural explanation of the different intensities of vancomycin resistance among enterococci, but also presents yet another example for the scope of evolutionary science in biomedicine.
authors.affiliation: Department of Molecular Pathology, Dow University of Health Sciences, Karachi, Pakistan.
authors.forename: Mushtaq
authors.initials: M
authors.lastname: Hussain
authors.forename: Nusrat
authors.initials: N
authors.lastname: Jabeen
authors.forename: Abdul
authors.initials: A
authors.lastname: Wajid
authors.forename: Rafiq
authors.initials: R
authors.lastname: Khanani
authors.forename: Syed Khaqan
authors.initials: SK
authors.lastname: Hasan
authors.forename: Sheikh Ajaz
authors.initials: SA
authors.lastname: Rasool
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D005075:Biological Evolution; D016983:Enterococcus / Q000187:drug effects / Q000235:genetics*; D008025:Ligases / Q000187:drug effects / Q000235:genetics; D008969:Molecular Sequence Data; D010802:Phylogeny; D017434:Protein Structure, Tertiary / Q000235:genetics; D016415:Sequence Alignment / Q000379:methods*; D017386:Sequence Homology, Amino Acid; D014640:Vancomycin / Q000494:pharmacology*; D020713:Vancomycin Resistance / Q000235:genetics*
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin; D008025:Ligases