Sandbox 172: Difference between revisions
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==Introduction== | ==Introduction== | ||
Four types of hexokinase isozymes exist in the human biological system. They all serve to catalyze the exact same reaction in glycolysis even though they are encoded by different sets of genes. The hexokinase types I-III all have a high affinity for glucose and become subject to inhibition in the presence of glucose-6-phosphate- the first step reaction product in glycolysis.<ref name="two" /> Hexokinase type I is the predominant form in the muscle while hexokinase type II is the predominant form in [http://en.wikipedia.org/wiki/myocyte myocytes]. Hexokinase type IV varies from the other three hexokinase types as it is not inhibited by the production of glucose-6-phosphate and shows a lower affinity for glucose. Hexokinase type I and II have the particular ability to bind to the [http://en.wikipedia.org/wiki/outer_mitochondrial_memberane outer mitochondrial membrane], this binding happens both specifically and reversibly.<ref name="one">Garavito R., Mulichuk A., Padmanabhan K., Wilson J. The structure of mammalian hexokinase-1. Nature Structural and Molecular Biology. 1998. '''5''': 555-560.</ref> | Four types of hexokinase isozymes exist in the human biological system. They all serve to catalyze the exact same reaction in glycolysis even though they are encoded by different sets of genes. The hexokinase types I-III all have a high affinity for glucose and become subject to inhibition in the presence of glucose-6-phosphate- the first step reaction product in glycolysis.<ref name="two" /> Hexokinase type I is the predominant form in the muscle while hexokinase type II is the predominant form in [http://en.wikipedia.org/wiki/myocyte myocytes]. Hexokinase type IV varies from the other three hexokinase types as it is not inhibited by the production of glucose-6-phosphate and shows a lower affinity for glucose. Hexokinase type I and II have the particular ability to bind to the [http://en.wikipedia.org/wiki/outer_mitochondrial_memberane outer mitochondrial membrane], this binding happens both specifically and reversibly.<ref name="one">Garavito R., Mulichuk A., Padmanabhan K., Wilson J. The structure of mammalian hexokinase-1. Nature Structural and Molecular Biology. 1998. '''5''': 555-560.</ref> | ||
==Structural Overview== | ==Structural Overview== | ||
The size of hexokinase type I is approximately 100 kD.<ref>Fromm H., Zewe V. Kinetic studies of the brain hexokinase reaction. The Journal of Biological Chemistry. 1962.'''235''':1661-1667.</ref> Hexokinase type I is constructed by a N-terminal regulatory domain and a C-terminal catalytic domain joined together by an [http://en.wikipedia.org.wiki/alpha_helix alpha helix]. The glucose binding site of hexokinase type I can be found within the two sub-units that make up the isoenzyme, these are known as lobes. Factors that contribute to the binding of glucose to this active site include amino acids within the actual site and [http://en.wikipedia.orh.wiki/hydrogen_bong hydrogen bonding] that takes place on the glucose between the hydroxyl groups.<ref>Bianchi M., Bolognesi M., Deriu D., Magnani M., Murshudov G., Rizzi M., Rosano C., Sabini E., Serafini G. Binding of non-catalytic ATP to human hexokinase I highlights the structural components for enzyme-membrane association control. Structure. 1999. '''11''': 1427-1437. PMID [http://www.ncbi.nlm.nih.gov/pubmed/10574795?dopt=Abstract 10574795]</ref> | The size of hexokinase type I is approximately 100 kD.<ref>Fromm H., Zewe V. Kinetic studies of the brain hexokinase reaction. The Journal of Biological Chemistry. 1962.'''235''':1661-1667.</ref> Hexokinase type I is constructed by a N-terminal regulatory domain and a C-terminal catalytic domain joined together by an [http://en.wikipedia.org.wiki/alpha_helix alpha helix]. The glucose binding site of hexokinase type I can be found within the two sub-units that make up the isoenzyme, these are known as lobes. Factors that contribute to the binding of glucose to this active site include amino acids within the actual site and [http://en.wikipedia.orh.wiki/hydrogen_bong hydrogen bonding] that takes place on the glucose between the hydroxyl groups.<ref>Bianchi M., Bolognesi M., Deriu D., Magnani M., Murshudov G., Rizzi M., Rosano C., Sabini E., Serafini G. Binding of non-catalytic ATP to human hexokinase I highlights the structural components for enzyme-membrane association control. Structure. 1999. '''11''': 1427-1437. PMID [http://www.ncbi.nlm.nih.gov/pubmed/10574795?dopt=Abstract 10574795]</ref> | ||
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[[Image:Glucosebinding.jpg|thumb|left|The conformational change in hexokinase caused by glucose binding.]] | [[Image:Glucosebinding.jpg|thumb|left|The conformational change in hexokinase caused by glucose binding.]] | ||
===Active Site=== | ===Active Site=== | ||
In the <scene name='Sandbox_172/Mynewscene/2'>active site</scene> of hexokinase type I, Lys 621 and Asp 657 show the hydrogen-bonding distance in which a reactive O6 hydroxyl is situated in between. Here Lys 621 functions to aid the transfer of the phosphate moiety which is negatively charged; Asp 657 serves as a catalytic base or to position the glucose O6 correctly for phosphoryl transfer to take place. Though it may seem that Ser 603 may have functional significance, there has been no observed interaction of Ser 603 with glucose substrates. A torsional rotation of of the hydroxyl group brings about a much better distance for hydrogen bonding of the glucose O6. As a result of this observation, it can be assumed that Ser 603 may have some transient role during [http://en.wikipedia.org/wiki/phosphorylation phosphorylation].<ref name="one" /> | In the <scene name='Sandbox_172/Mynewscene/2'>active site</scene> of hexokinase type I, Lys 621 and Asp 657 show the hydrogen-bonding distance in which a reactive O6 hydroxyl is situated in between. Here Lys 621 functions to aid the transfer of the phosphate moiety which is negatively charged; Asp 657 serves as a catalytic base or to position the glucose O6 correctly for phosphoryl transfer to take place.<ref name="one" /> Though it may seem that Ser 603 may have functional significance, there has been no observed interaction of Ser 603 with glucose substrates. A torsional rotation of of the hydroxyl group brings about a much better distance for hydrogen bonding of the glucose O6. As a result of this observation, it can be assumed that Ser 603 may have some transient role during [http://en.wikipedia.org/wiki/phosphorylation phosphorylation].<ref name="one" /> | ||
===Regulatory Binding Site=== | ===Regulatory Binding Site=== | ||
As glucose-6-phosphate is being produced it binds to either one of the domains on hexokinase type I. On domain 1, the phosphate moiety is surrounded by Ser 88, Thr 232, and Ser 415. The presence of these three residues generate an anion binding site that is approximately 5.6 Å to the 6 hydroxyl of the glucose that is bound.<ref name="one" /> | As glucose-6-phosphate is being produced it binds to either one of the domains on hexokinase type I. On domain 1, the phosphate moiety is surrounded by Ser 88, Thr 232, and Ser 415. The presence of these three residues generate an anion binding site that is approximately 5.6 Å to the 6 hydroxyl of the glucose that is bound.<ref name="one" /> | ||
