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  • Sequences of hexokinases were initially

    2021-10-19

    Sequences of hexokinases were initially deduced and predicted based on cDNA clones (Andreone et al., 1989, Schwab and Wilson, 1989, Schwab and Wilson, 1991, Griffin et al., 1991, Thelen and Wilson, 1991). Analysis of genome sequence data identified, in deoxycorticosterone to the 4 expected known hexokinase enzymes (Ureta, 1982, Wilson, 1995, Wilson, 1997, Wilson, 2003, Wilson, 2004, Cárdenas et al., 1998), a total of 6 hexokinase-like genes in the human genome, and 5 in the genomes of most other vertebrates (Irwin and Tan, 2008, González-Alvarez et al., 2009). In addition to the expected genes encoding the known hexokinases (HK1, HK2, HK3, and GCK), a fifth hexokinase-like gene was found in the genome searches that is conserved throughout vertebrates. The fifth hexokinase-like gene was named hexokinase domain containing 1 (HKDC1), however, the biological function of this gene is currently unknown. SNPs near the HKDC1 gene deoxycorticosterone have been associated with attention-deficit/hyperactivity disorder (Neale et al., 2010) and the protein was found to potentially interact with iNOS2 (Foster et al., 2013). The human genome, as well as those of a few other primates, contains a sixth hexokinase-like sequence, which is a reverse-transcribed pseudogene copy of the HK2 gene (Ardehali et al., 1995, Irwin and Tan, 2008). The HK2 pseudogene was generated relatively recently during primate evolution (Ardehali et al., 1995, Irwin and Tan, 2008). Characterization of the protein sequences of the hexokinases provided an explanation for the difference in the molecular weights of the 100kD hexokinases (hexokinases I, II and III) and the 50kD glucokinase – the larger hexokinases contain two kinases domains, while the smaller glucokinase has only a single kinase domain (Andreone et al., 1989, Schwab and Wilson, 1989, Schwab and Wilson, 1991, Griffin et al., 1991, Thelen and Wilson, 1991, Cárdenas et al., 1998). This conclusion is illustrated in Fig. 1, where similarity between the different kinase domains is shown as long diagonal lines in dotplots. Glucokinase contains only a single kinase domain while hexokinase I has two. When hexokinase I is compared to glucokinase (Fig. 1A) two diagonal lines are generated since the N-terminal half of hexokinase I is similar to all of glucokinase (lower diagonal, Fig. 1A), and the C-terminal half of hexokinase I also is similar to all of glucokinase (upper diagonal in Fig. 1A). If glucokinase is compared to itself (Fig. 1B), no repetitive structure is identified, only similarity to itself along the entire sequence (diagonal from lower left to upper right), although there are short sequences that show limited similarity (short lines that are off the central diagonal, Fig. 1, also seen in the other comparisons). If hexokinase I is compared to itself (Fig. 1C) or to hexokinase II (Fig. 1D) a total of three long diagonal lines are seen due to the repetitive structures in both proteins. The central diagonal line indicates that the to proteins are similar to each other over their entire lengths, while the diagonal lines in the upper left and lower right indicate that similarity between the N-terminal and C-terminal halves of the is observed. Similar results are observed with the hexokinase III and HKDC1 (which also predicts an approximately 100kD protein) sequences (results not shown). Isolation and partial characterization of the genes encoding hexokinase II and glucokinase (Magnuson et al., 1989, Thelen and Wilson, 1991, Kogure et al., 1993) strengthened the conclusion that the larger hexokinases were generated by duplication of the kinase domain. The intron–exon structures of the two halves of the HK2 gene are similar to each other and to the glucokinase gene, where the sizes of the exons are similar and the phase of the codons interrupted by the introns are identical (Fig. 2). These observations suggesting that the two halves of HK2 were generated by a duplication of glucokinase-like sequence (Magnuson et al., 1989, Thelen and Wilson, 1991, Kogure et al., 1993). The similarity in intron–exon structure is seen not only for HK2, but also for all other members of the mammalian hexokinase gene family (Fig. 2). Hexokinase genes from non-vertebrate species also share similarities in gene structure with glucokinase (Fig. 2).