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 α-helical membrane protein sequences and folds. In conclusion, we suggest a chronology for the evolution of the five extant VKOR clades.
Highlights
In humans and other animals, vitamin K 2,3-epoxide complex subunit 1 (VKORC1) is the primary oxidoreductase enzyme that reduces vitamin K quinone (K), acquired in trace amounts by dietary uptake, to the hydroquinone (KH2 ) form, functioning as the point of entry for vitamin K into the vitaminK cycle [1,2,3]
Family (327 sequences, truncated to residues corresponding to human VKORC1: Leu13-Phe150 in order to remove highly variable N- and C-terminal sequences) and disulfide bond formation protein B (DsbB) family
Previous reports have suggested that transmembrane helices (TMHs) considerably contribute to phylogenetic noise, due to high frequency of occurrance and degeneracy among nonpolar residues in the hydrophobic membrane core and a relatively low selection pressure on residues that face into the lipid bilayer [50,51]
Summary
In humans and other animals, vitamin K 2,3-epoxide complex subunit 1 (VKORC1) is the primary oxidoreductase enzyme that reduces vitamin K quinone (K), acquired in trace amounts by dietary uptake, to the hydroquinone (KH2 ) form, functioning as the point of entry for vitamin K into the vitaminK cycle [1,2,3]. In humans and other animals, vitamin K 2,3-epoxide complex subunit 1 (VKORC1) is the primary oxidoreductase enzyme that reduces vitamin K quinone (K), acquired in trace amounts by dietary uptake, to the hydroquinone (KH2 ) form, functioning as the point of entry for vitamin K into the vitamin. In the case of pathological hypercoagulative conditions such as thrombosis and embolism, 4-hydroxycoumarin based oral anticoagulants, including warfarin as a well-known example, are administered to block the enzymatic function of VKORC1, effectively diminishing turnover of the vitamin K cycle [6]. This results in induction of a controlled hypocoagulative state to counteract the tendency towards clot formation. Evidence has been presented that a second VKOR enzyme, VKORC1-like 1 (VKORC1L1), is responsible for extrahepatic
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