title: Exploring the biological and chemical complexity of the ligases.
abstract: Using a novel method to map and cluster chemical reactions, we have re-examined the chemistry of the ligases [Enzyme Commission (EC) Class 6] and their associated protein families in detail. The type of bond formed by the ligase can be automatically extracted from the equation of the reaction, replicating the EC subclass division. However, this subclass division hides considerable complexities, especially for the C-N forming ligases, which fall into at least three distinct types. The lower levels of the EC classification for ligases are somewhat arbitrary in their definition and add little to understanding their chemistry or evolution. By comparing the multi-domain architecture of the enzymes and using sequence similarity networks, we examined the links between overall reaction and evolution of the ligases. These show that, whilst many enzymes that perform the same overall chemistry group together, both convergent (similar function, different ancestral lineage) and divergent (different function, common ancestor) evolution of function are observed. However, a common theme is that a single conserved domain (often the nucleoside triphosphate binding domain) is combined with ancillary domains that provide the variation in substrate binding and function.
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. Electronic address: gemma.holliday@ucsf.edu.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Holliday
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Syed Asad
authors.initials: SA
authors.lastname: Rahman
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Furnham
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Thornton
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002384:Catalysis; D016000:Cluster Analysis; D019143:Evolution, Molecular; D006801:Humans; D008025:Ligases / Q000737:chemistry* / Q000145:classification / Q000502:physiology*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D008025:Ligases
keywords: enzyme evolution; enzyme function; ligase; overall reaction similarity