Glucokinase can be modulated to form an inactive and active complex. The inactive conformation forms when the alpha 13 helix has been modulated away from the rest of the molecule forming a large space. This space is too large to bind glucose so it is said to be in the inactive form. The alternative is when the alpha 13 helix is modulated to form a smaller space thus activating the protein [4]. Glucokinase includes the where glucose forms hydrogen bonds at the bottom of the deep crevice between the large domain and the small domain.
E, E shown in green of the large domain, T, K shown in red of the small domain, and N, D shown in yellow of a connecting region form hydrogen bonds with glucose. The shows a different conformation. The again shows structural differences. The differences in these two conformations allows glucokinase to function properly in different levels of glucose concentration. Proposed Mechanism for Glucokinase: As described above, glucokinase has a distinct conformation change from the active and inactive form.
Experiments have also shown an intermediate open form based on analysis of the movement between the active and inactive form. The switch in conformations between the active form and the intermediate is a kinetically faster step than the change between the intermediate and the inactive form. The inactive form of gluckokinase is the thermodynamically favored unless there is glucose present. Glucokinase does not change conformation until the glucose molecule binds.
The conformation change may be triggered by the interaction between Asp and the glucose molecule. Once glucokinase is in the active form, the enzymatic reaction is carried out with the presence of ATP. The experiments suggest that glucokinase is found in hepatocyte nuclei and are found inactive at low plasma glucose levels, but found active when higher glucose levels are present. GKRP would then would likely be an allosteric inhibitor of glucokinase that specifically binds to the inactive form of glucokinase.
The crystal structures of the glucokinase-GKRP complex are being determined to clearly identify the interactions between glucokinase and glucokinase regulatory protein. Role in Organ Systems: In the liver glucokinase increases the synthesis of glycogen and is the first step in glycolysis, the main producer of ATP in the body.
Glucokinase is responsible for phospohorylating the majority of glucose in the liver and pancreas. Glucokinase only binds to and phosphorylates glucose when levels are higher than normal blood glucose level, allowing it to maintain constant glucose levels [4]. By phosphorylating glucose, glucokinase creates glucose 6-phosphate. Glucose 6-phosphate can then be used by the liver through the glycolytic pathway.
Along with this process in the liver, glucokinase also facilitates glycogen synthesis. Through this the majority of the body's glucose is stored. Glucose 6-phosphate is also one of the starting materials of the TCA cycle which is responsible for the majority of ATP production in the body.
In the pancreas, a rise in glucose levels increases the activity of glucokinase causing an increase in glucose 6-phosphate. This causes the triggering of the beta cells to secret insulin [5]. They can be found in bacteria, plants and vertebrates, including humans. More than one isoform or isozyme can occur in one species, providing different functions. Hexokinases are actin fold proteins and share a common ATP binding site core surrounded by more variable sequences.
When a hexose is phosphorylated it is often limited to several intracellular metabolic processes. The phosphorylated hexoses are charges so they can not be transported out of a cell as easily. Hexokinase Structure Mammalian hexokinase isozymes have four important forms. These isozymes have different subcellular locations and movements, as well as physiological functions.
The first three are called low-K isozymes due to their high affinity for glucose. They are inhibited by their product glucosephosphate. Hexokinase I is present in all mammalian tissues and is not affected by most changes, whether physiological, hormonal or metabolic. Hexokinase II is the principal regulated isoform in many cell types, and is in the muscle and heart, as well as in the mitochondria outer membrane.
Comparisons of the amino acid sequence of a few peptides from hexokinase C are presented to support the gene duplication hypothesis. Also, partial sequence comparisons of vertebrate hexokinases with the sequences of two hexokinase isozymes from yeast show strong similarities suggesting a rather slow amino acid substitution rate of homologous genes. Abstract Recent advances in the knowledge of the structural and functional aspects of the enzymes catalyzing sugar phosphorylation by ATP are reviewed.
Gov't Review.
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