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Phylogeny of the Vitamin K 2,3-Epoxide Reductase (VKOR) Family and Evolutionary Relationship to the Disulfide Bond Formation Protein B (DsbB) Family

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Im Hermeshain 6, 60388 Frankfurt am Main, Germany
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Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, 60388 Frankfurt am Main, Germany
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Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, 53105 Bonn, Germany
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Author to whom correspondence should be addressed.
Nutrients 2015, 7(8), 6224-6249; https://doi.org/10.3390/nu7085281
Received: 18 May 2015 / Revised: 25 June 2015 / Accepted: 9 July 2015 / Published: 29 July 2015
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. View Full-Text
Keywords: cyclic permutation; DsbB; homology modeling; phylogeny; sequence conservation; vitamin K; vitamin K 2,3-epoxide; VKOR; VKORC1; VKORC1L1 cyclic permutation; DsbB; homology modeling; phylogeny; sequence conservation; vitamin K; vitamin K 2,3-epoxide; VKOR; VKORC1; VKORC1L1
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Bevans, C.G.; Krettler, C.; Reinhart, C.; Watzka, M.; Oldenburg, J. Phylogeny of the Vitamin K 2,3-Epoxide Reductase (VKOR) Family and Evolutionary Relationship to the Disulfide Bond Formation Protein B (DsbB) Family. Nutrients 2015, 7, 6224-6249.

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