InterPro domain: IPR001312

Hexokinase ( 2.7.1.1 ) [ 1 , 2 ] is an important glycolytic enzyme that catalyzesthe phosphorylation of keto- and aldohexoses (e.g. glucose, mannose andfructose) using MgATP as the phosphoryl donor.

In vertebrates there are four major isoenzymes, commonly referred as types I,II, III and IV. Type IV hexokinase, which is often incorrectly designatedglucokinase [ 3 ], is only expressed in liver and pancreatic beta-cells andplays an important role in modulating insulin secretion; it is a protein of amolecular mass of about 50 Kd. Hexokinases of types I to III, which have lowKm values for glucose, have a molecular mass of about 100 Kd. Structurallythey consist of a very small N-terminal hydrophobic membrane-binding domainfollowed by two highly similar domains of 450 residues. The first domain haslost its catalytic activity and has evolved into a regulatory domain.

In yeast there are three different isoenzymes: hexokinase PI (gene HXK1), PII(gene HXKB), and glucokinase (gene GLK1). All three proteins have a molecularmass of about 50 Kd.

The hexokinase domain has an alpha/beta fold and is distinctly folded in twosubdomains of unequal size: the large and small subdomains.The large subdomain comprises a six-stranded mixed beta-sheet and a number ofadditional alpha-helices. On one side, the sheet packs against the smallsubdomain, and on the other side it is shielded by several alpha-helices. Thedominant feature of the small subdomain is a five stranded mixed beta-sheet.The sheet is flanked by two helices on one side and by one helix on the other.The subdomain also has an additional beta-sheet formed by two antiparallelstrands [ 4 , 5 ].

All these enzymes contain one (or two in the case of types I to III isozymes)strongly conserved region which has been shown [ 6 ] to be involved in substrate binding.

1. Hexokinases and glucokinases. Biochem. Soc. Trans. 18, 180-3
2. Mammalian hexokinase 1: evolutionary conservation and structure to function analysis. Genomics 11, 1014-24
3. Hexokinase and 'glucokinase' in liver metabolism. Trends Biochem. Sci. 16, 281-2
4. The high resolution crystal structure of yeast hexokinase PII with the correct primary sequence provides new insights into its mechanism of action. J. Biol. Chem. 275, 20814-21
5. The mechanism of regulation of hexokinase: new insights from the crystal structure of recombinant human brain hexokinase complexed with glucose and glucose-6-phosphate. Structure 6, 39-50
6. Rat brain hexokinase: location of the substrate hexose binding site in a structural domain at the C-terminus of the enzyme. Arch. Biochem. Biophys. 254, 385-96