Hexokinase

Description :

A hexokinase is an enzyme that phosphorylates a six-carbon sugar, a hexose, to a hexose phosphate. In most tissues and organisms, glucose is the most important substrate of hexokinases, and glucose-6-phosphate the most important product. Hexokinases have been found in every organism checked, ranging from bacteria, yeast, and plants to humans and other vertebrates. They are categorized as actin fold proteins, sharing a common ATP binding site core surrounded by more variable sequences that determine substrate affinities and other properties. Several hexokinase isoforms or isozymes providing different functions can occur in a single species.

(i) The display image of hexokinase (below) has been set to ball and stick.

Phosphorylation of a hexose such as glucose often commits it to a limited number of intracellular metabolic processes (such as glycolysis or glycogen synthesis). Phosphorylation also makes it unable to move or be transported out of the cell. Most bacterial hexokinases are approximately 50kD in size. Multicellular organisms such as plants and animals often have more than one hexokinase. Most are about 100kD in size, and consist of two halves (N and C terminal), which share much sequence homology. This suggests an evolutionary origin by duplication and fusion of a 50kD ancestral hexokinase similar to those of bacteria.

Figure of Hexokinase on the left is a kind of PDB image. This image is downloaded from Protein Database Bank (PDB) at its specific website that is www.pdb.org.
The structure has been set into ball and stick using Accelrys ViewerLite 5.0.

(ii) The display image (below) has been set to stick.

There are four important mammalian hexokinase isozymes (EC 2.7.1.1) that vary somewhat in their locations, kinetic characteristics with respect to different substrates and operating conditions, and physiological functions. They are designated hexokinases I, II, III, and IV or hexokinases A, B, C, and D.

Hexokinases I, II, and III are referred to as "low-Km" isozymes because of a high affinity for glucose even at low concentrations (below 1 mM). Hexokinases I and II (or A and B) follow Michaelis-Menten kinetics at physiologic concentrations of substrates. All three are strongly inhibited by their product, glucose-6-phosphate. Molecular weights are around 100 kD. Each consists of two similar 50kD halves, but only in hexokinase II do both halves have functional active sites. Hexokinase I (hexokinase A) is found in all mammalian tissues, and is considered a "housekeeping enzyme," unaffected by most physiological, hormonal, and metabolic changes. Hexokinase III (or C) is inhibited by excessive glucose (substrate inhibition).

Mammalian hexokinase IV (or D), also referred to as glucokinase, has unique characteristics and functions compared to other hexokinases. The location of the phosphorylation on a subcellular level occurs when glucokinase translocates between the cytoplasm and nucleus of liver cells. Glucokinase can only phosphorylate glucose if the concentration of this substrate is high enough; its Km for glucose is 100 times higher than that of hexokinases I, II, and III. It is monomeric, about 50kD, displays positive cooperativity with glucose, and is not allosterically inhibited by its product, glucose-6-phosphate. It is present in the liver, pancreas, hypothalamus, small intestine, and perhaps certain other neuroendocrine cells, and plays an important regulatory role in carbohydrate metabolism. In the beta cells of the pancreatic islets, it serves as a glucose sensor to control insulin release, and similarly controls glucagon release in the alpha cells. In hepatocytes of the liver, glucokinase responds to changes of ambient glucose levels by increasing or reducing glycogen synthesis.

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