title: Phylogeny of the Vitamin K 2,3-Epoxide Reductase (VKOR) Family and Evolutionary Relationship to the Disulfide Bond Formation Protein B (DsbB) Family.
abstract: In humans and other vertebrate animals, vitamin K 2,3-epoxide reductase (VKOR) family enzymes are the gatekeepers between nutritionally acquired K vitamins and the vitamin K cycle responsible for posttranslational modifications that confer biological activity upon vitamin K-dependent proteins with crucial roles in hemostasis, bone development and homeostasis, hormonal carbohydrate regulation and fertility. We report a phylogenetic analysis of the VKOR family that identifies five major clades. Combined phylogenetic and site-specific conservation analyses point to clade-specific similarities and differences in structure and function. We discovered a single-site determinant uniquely identifying VKOR homologs belonging to human pathogenic, obligate intracellular prokaryotes and protists. Building on previous work by Sevier et al. (Protein Science 14:1630), we analyzed structural data from both VKOR and prokaryotic disulfide bond formation protein B (DsbB) families and hypothesize an ancient evolutionary relationship between the two families where one family arose from the other through a gene duplication/deletion event. This has resulted in circular permutation of primary sequence threading through the four-helical bundle protein folds of both families. This is the first report of circular permutation relating distant a-helical membrane protein sequences and folds. In conclusion, we suggest a chronology for the evolution of the five extant VKOR clades.
authors.affiliation: Im Hermeshain 6, 60388 Frankfurt am Main, Germany. bevans@jhu.edu.
authors.forename: Carville G
authors.initials: CG
authors.lastname: Bevans
authors.affiliation: Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, 60388 Frankfurt am Main, Germany. christoph.krettler@biophys.mpg.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Krettler
authors.affiliation: Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, 60388 Frankfurt am Main, Germany. christoph.reinhart@biophys.mpg.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Reinhart
authors.affiliation: Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, 53105 Bonn, Germany. matthias.watzka@ukb.uni-bonn.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Watzka
authors.affiliation: Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, 53105 Bonn, Germany. johannes.oldenburg@ukb.uni-bonn.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001105:Archaea; D001419:Bacteria; D005075:Biological Evolution; D004220:Disulfides; D006801:Humans; D008969:Molecular Sequence Data; D010802:Phylogeny; D017433:Protein Structure, Secondary; D011961:Receptors, Fc / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D014812:Vitamin K / Q000378:metabolism*; D064417:Vitamin K Epoxide Reductases / Q000737:chemistry / Q000235:genetics*
chemical_list: D004220:Disulfides; C045281:IgA receptor; D011961:Receptors, Fc; D014812:Vitamin K; D064417:Vitamin K Epoxide Reductases
keywords: DsbB; VKOR; VKORC1; VKORC1L1; cyclic permutation; homology modeling; phylogeny; sequence conservation; vitamin K; vitamin K 2,3-epoxide