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    • The glucokinase protein sequence is most closely

    2021-11-18

    The glucokinase protein sequence is most closely related to the C-terminal domain of 100kD hexokinases, thus for glucokinase to evolve from a larger hexokinase ancestor it must have lost its N-terminal kinase domain. The genetic mechanism by which this occurred is currently unknown. Here we propose a possible model for the generation of a glucokinase gene (Fig. 4B). The C-terminal kinase domain of the 100kD hexokinases is encoded by exons 10 through 18. Glucokinase, however, is unlikely to have been generated simply for the 3′ half of a 100kD hexokinase genes. Exon 10, the 5′ end of the second half of the two kinase-domain containing hexokinases, encodes sequences from both exon 2 and 10 of the ancestral single kinase domain-containing gene (Fig. 4A). The hybrid exon 10 was generated due to recombination generating the 100kD hexokinases (see Fig. 4A, exon 10 has sequences from exon 2a and 10b) and thus encodes sequences from the C-terminus of the hexokinase domain followed by sequences from near the N-terminus of the domain. The N-terminal sequence of glucokinase shows no similarity to the C-terminal sequences of kinases domains (see Fig. 1A), thus does not appear to have evolved from an exon 10-like sequence. Instead, exon 2 (and exon 1) of glucokinase appears to be more similar, in sequence and structure, to exon 2 (and exon 1) of the 100kD hexokinase genes. This suggests that the 5′ end of the glucokinase gene is derived from the 5′ end (exons 1 and 2) of a 100kD hexokinase gene (and would also provide a promoter for expression), while the 3′ end of glucokinase is derived from the 3′ end (exons 11–18, named 3b–10b in Fig. 4B) of the larger gene (since the glucokinase protein sequence is most closely related to the C-terminal hexokinase domain) (Fig. 4B). This model would imply an internal ZLN005 synthesis of exons 3–10 (named 3a to 10a/2b in Fig. 4B). Whether this loss was initially due to the deletion of these exons, or a change in splicing pattern to skip these exons is unknown, however none of the extant glucokinase genes examined possesses genomic sequences bearing similarity to the lost exons (results not shown). Enzymes encoded by members of the hexokinase gene family differ in their regulatory and enzymatic properties (Ureta, 1982, Wilson, 1995, Wilson, 1997, Wilson, 2003, Wilson, 2004, Cárdenas et al., 1998), presumably due to changes in their amino acid sequences. Although hexokinases I, II, and III each have a pair of hexokinase domains, only hexokinase II retains hexokinase activity for both of these domains (Tsai and Wilson, 1996). Only the C-terminal kinase domains of hexokinase I and II have been demonstrated to have kinase activity (White and Wilson, 1989, Tsai and Wilson, 1997). Loss of the hexokinase activity may account for the more rapid evolution of the N-terminal domains of the hexokinase I and III protein sequences, and thus explain, at least in part, the observed greater divergence in sequence of the N-terminal, compared to C-terminal, domains of the 100kD hexokinases (Fothergill-Gilmore and Michels, 1993, Cárdenas et al., 1998). The more rapid evolution of the N-terminal regions of hexokinase I and III suggests that a smaller portion of these sequences are constrained by evolution, however, the observation that these sequence are retained in hexokinases from diverse vertebrates suggest that these sequences likely still have functional roles. Experimental studies have shown that while the N-terminal kinase domains of hexokinase I and III have lost kinase activity, they retain regulatory activity by being able to bind glucose-6-phosphate (Tsai and Wilson, 1997). It is unknown whether HKDC1 has any hexokinase activity, as its amino acid sequence contains all of the known functional active residues (Irwin and Tan, 2008). Extensive searches of diverse tissues in many vertebrate species have not suggested the presence of any additional hexokinase activities that could not be accounted for by the known hexokinase isozymes (Ureta, 1982, Wilson, 1995, Wilson, 1997, Wilson, 2003, Wilson, 2004, Cárdenas et al., 1998). These observations suggest that HKDC1 does not phosphorylate glucose, and likely has a different enzymatic or regulatory function.