Academic journal article Genetics

Genes Encoding Vitamin-K Epoxide Reductase Are Present in Drosophila and Trypanosomatid Protists

Academic journal article Genetics

Genes Encoding Vitamin-K Epoxide Reductase Are Present in Drosophila and Trypanosomatid Protists

Article excerpt

ABSTRACT

Vitamin-K epoxide reductase is encoded by the VKORC1 gene in mammals and other vertebrates, which also have a paralog, VKORC1L1. Single homologs are present in basal deuterostome and insect genomes, including Drosophila, and three trypanosomatid protists. VKOR is therefore an ancient gene/protein that can be studied in the Drosophila model system.

VITAMIN K is an important nutrient for animals. It annois a cofactor in carboxylation of glutamine residues of proteins by vitamin-K-dependent gamma-glutamyl carboxylase. While this reaction is probably important for many protein modifications, it is particularly important in vertebrates for activation of several blood-clotting proteins and hence for blood coagulation. The resultant vitamin-K 2,3-epoxide is recycled to the reduced active form by vitamin-K epoxide reductase (VKOR). Inhibition of VKOR by the drug warfarin can be beneficial at low concentrations to humans with blood clots but causes lethal bleeding in rats at high concentrations (see SADLER 2004). The gene encoding one subunit of this enzyme complex, VKORC1, was recently identified in mammals by ROST et al. (2004) and LI et al. (2004). Both articles note that there is a homologous protein encoded by a gene in the African malaria mosquito Anopheles gambiae genome, but apparently not in Drosophila melanogaster. ROST et al. (2004) noted that this was unusual because D. melanogaster encodes a homolog of vitamin-K-dependent gamma-glutamyl carboxylase (LI et al. 2000), an enzyme activity also known from molluscs, which they proposed might therefore predate VKOR activity (despite the existence of the Anopheles insect VKORC1 homolog). This observation is also unusual in that these two, admittedly highly divergent, flies encode mostly the same repertoire of conserved genes (ZDOBNOV et al. 2002). I therefore examined the Drosophila genome sequences, using TBLASTN searches with the vertebrate and Anopheles proteins, and the VKORC1 homolog is readily apparent, but not annotated in Release 3.1 (MISRA et al. 2003). It is now partly annotated in the Third Party Annotation (TPA) database at NCBI through the work of HILD et al. (2003), who undertook an independent annotation of the D. melanogaster genome, although the annotation (HDC06808) fuses this gene and a downstream gene. I also undertook a phylogenetic analysis of this gene/protein in animals, revealing its presence in all available insect genomes, as well as in the sea urchin Strongylocentrotus purpuratus and urochordate Ciona genomes. Finally, I root these phylogenetic analyses using three trypanosomatid homologs that are the only confident available outgroup.

TBLASTN searches of the Release 3.1 assembly of the D. melanogaster genome revealed a compact three-coding-exon gene of 570 bp encoding a VKORC1 homolog at cytological position 53C15 on chromosome arm 2R in the 4-kb region between Actin-related protein 53D (Arp53D or CG5409) and CG15920, which I propose to name vitamin-K epoxide reductase (vkor). This gene structure with two introns in the coding region (phases 2 and 1) is present throughout the animals, the only modifications being loss of the second intron in A. gambiae and loss of both introns in Ciona savignyi. The gene annotation in Hild et al. (2003; HDC06808) splices from within the third exon to a downstream exon just before CG15920-this downstream exon is likely to represent yet another unannotated gene, because there is an exsophila pressed sequence tag (EST) from it. The homolog was also identified in the draft genome sequence of D. pseudoobscura, although raw trace information was required to extend the assembled contig sequence that contains the gene. The homolog in the honey bee Apis mellifera draft genome sequence v1.1 was readily identified in Contig5445, as was the silk moth Bombyx mori homolog in three short contigs of the Japanese assembly (MITA et al. 2004). The homolog in the sea urchin S. purpuratus was assembled manually from the raw sequence traces (as is true for much of this genome, two quite divergent haplotypes are present, so the manually assembled sequence might represent a chimera of the two alleles), while the urochordate sea squirt C. …

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