title: Chopping and Changing: the Evolution of the Flavin-dependent Monooxygenases.
abstract: Flavin-dependent monooxygenases play a variety of key physiological roles and are also very powerful biotechnological tools. These enzymes have been classified into eight different classes (A-H) based on their sequences and biochemical features. By combining structural and sequence analysis, and phylogenetic inference, we have explored the evolutionary history of classes A, B, E, F, and G and demonstrate that their multidomain architectures reflect their phylogenetic relationships, suggesting that the main evolutionary steps in their divergence are likely to have arisen from the recruitment of different domains. Additionally, the functional divergence within in each class appears to have been the result of other mechanisms such as a complex set of single-point mutations. Our results reinforce the idea that a main constraint on the evolution of cofactor-dependent enzymes is the functional binding of the cofactor. Additionally, a remarkable feature of this family is that the sequence of the key flavin adenine dinucleotide-binding domain is split into at least two parts in all classes studied here. We propose a complex set of evolutionary events that gave rise to the origin of the different classes within this family.
authors.affiliation: IMIBIO-SL CONICET, Facultad de Química Bioquímica y Farmacia, Universidad Nacional de San Luis, Ejército de los Andes 950, San Luis D5700HHW, Argentina. Electronic address: mlmascotti@unsl.edu.ar.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Mascotti
authors.affiliation: IMIBIO-SL CONICET, Facultad de Química Bioquímica y Farmacia, Universidad Nacional de San Luis, Ejército de los Andes 950, San Luis D5700HHW, Argentina.
authors.forename: Maximiliano
authors.initials: M
authors.lastname: Juri Ayub
authors.affiliation: Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Furnham
authors.affiliation: EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Thornton
authors.affiliation: EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. Electronic address: roman@ebi.ac.uk.
authors.forename: Roman A
authors.initials: RA
authors.lastname: Laskowski
mesh_terms: D005075:Biological Evolution; D003067:Coenzymes / Q000378:metabolism; D005415:Flavins / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010802:Phylogeny; D000072417:Protein Domains / Q000502:physiology; D017421:Sequence Analysis / Q000379:methods
chemical_list: D003067:Coenzymes; D005415:Flavins; D006899:Mixed Function Oxygenases
keywords: cofactor-binding enzymes; enzyme evolution; flavin-dependent monooxygenases; multidomain architecture