Abstract
Among all cellular life on earth, with the exception of yeasts, fungi, and some prokaryotes, VKOR family homologs are ubiquitously encoded in nuclear genomes, suggesting ancient and important biological roles for these enzymes. Despite single gene and whole genome duplications on the largest evolutionary timescales, and the fact that most gene duplications eventually result in loss of one copy, it is surprising that all jawed vertebrates (gnathostomes) have retained two paralogous VKOR genes. Both VKOR paralogs function as entry points for nutritionally acquired and recycled K vitamers in the vitamin K cycle. Here we present phylogenetic evidence that the human paralogs likely arose earlier than gnathostomes, possibly in the ancestor of crown chordates. We ask why gnathostomes have maintained these paralogs throughout evolution and present a current summary of what we know. In particular, we look to published studies about tissue- and developmental stage-specific expression, enzymatic function, phylogeny, biological roles and associated pathways that together suggest subfunctionalization as a major influence in evolutionary fixation of both paralogs. Additionally, we investigate on what evolutionary timescale the paralogs arose and under what circumstances in order to gain insight into the biological raison d’être for both VKOR paralogs in gnathostomes.
Highlights
Genomes of higher vertebrates possess two paralog genes, VKORC1 and VKORC1L1, Genomes of higher vertebrates possess two paralog genes, VKORC1 and VKORC1L1 that encode enzymes unique in catalyzing de-epoxidation of vitamin K 2,3-epoxide (K>O), a product, that encode enzymes unique in catalyzing de-epoxidation of vitamin K 2,3-epoxide of post-translational modification of vitamin K-dependent (VKD) proteins [2,3]
Inspection of vertebrate VKORC1 and VKORC1L1 full-length protein sequences in the NCBI Proteins database revealed that most vertebrate VKORC1 orthologs are about 161–163 residues (Figure 3, yellow bars; range 160–163 residues), whereas VKORC1L1 sequences are predominantly
Closed circulatory systems of ever increasing volume and requiring increased cardiac capacity evolved leading to ever increasing circulatory pressure [108]. Parallel to these evolutionary developments in early metazoans, there arose the need for a robust hemostatic system and clotting capability to stem off bleeding through injury [109]. With all of this in mind, we propose that the regulatory mechanisms for VKOR paralog gene expression needed to keep pace with evolutionarily increasing circulatory volume and pressure, and so both VKOR paralogs were maintained in vertebrates due to selection pressure for distinct regulation of expression in non-coding regions of the genes
Summary
Genomes of higher vertebrates possess two paralog genes, VKORC1 and VKORC1L1 (see Note 1 [1]), Genomes of higher vertebrates possess two paralog genes, VKORC1 and VKORC1L1 that encode enzymes unique in catalyzing de-epoxidation of vitamin K 2,3-epoxide (K>O), a product (see Note 1 [1]), that encode enzymes unique in catalyzing de-epoxidation of vitamin K 2,3-epoxide of post-translational modification of vitamin K-dependent (VKD) proteins [2,3]. Calcification [9,10,11,12,13]; cellular growth, survival, and signaling [14,15]; metabolic homeostasis [16,17]; While the respective VKORC1 and VKORC1L1 protein primary sequences share „50% identity and and fertility [18]. While the respective VKORC1 and VKORC1L1 protein primary sequences share highly homologous function (Figure 1), it is surprising that both genes have been maintained with high. We point out structural and differences between both paralog enzymes and explore phylogenetic relationships in order to construct functional similarities and differences between both paralog enzymes and explore phylogenetic arelationships hypothesis that addresses the question “Why dothat vertebrates have vitamin“Why. K 2,3-epoxide reductase in order to construct a hypothesis addresses thetwo question do vertebrates have (VKOR).
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