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Nutrients 2015, 7(8), 6224-6249; doi:10.3390/nu7085281

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

1
Im Hermeshain 6, 60388 Frankfurt am Main, Germany
2
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, 60388 Frankfurt am Main, Germany
3
Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, 53105 Bonn, Germany
*
Author to whom correspondence should be addressed.
Received: 18 May 2015 / Revised: 25 June 2015 / Accepted: 9 July 2015 / Published: 29 July 2015
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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. 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
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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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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