Proteopedia - User contributions [en]

The Structure and Mechanism of Hexokinase

2010-03-31T16:09:55Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

==The Structure and Mechanism of Hexokinase==

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.

-Hexokinase I/A is found in all mammalian tissues, and is considered a "housekeeping enzyme," unaffected by most physiological, hormonal, and metabolic changes.

-Hexokinase II/B constitutes the principal regulated isoform in many cell types and is increased in many cancers.

-Hexokinase III/C is substrate-inhibited by glucose at physiologic concentrations. Little is known about the regulatory characteristics of this isoform.

-Hexokinase IV/D is also known as glucokinase and is described below.

'''Hexokinase Structure:''' The tertiary structure of hexokinase includes an <scene name='Kyle_Schroering_Sandbox/Secondary_structure/1'>open alpha/beta sheet</scene>. There is a large amount of variation associated with this structure. The ATP-binding domain is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme. The molecular weights of hexokinases are around 100 kD. Each consists of two similar 50kD halves, but only in hexokinase II do both halves have functional active sites.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP <ref>PMID:7048063</ref>. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

'''Glucokinase Structure:''' Glucokinase also contains <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>inactive</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>active</scene> conformation. Glucokinase consists of one chain or subunit of 448 amino acids forming a monomeric molecule consisting of 13 alpha helices and 5 beta sheets that can phosporylate glucose and other hexoses. The chain is folded into two distinct regions, a small and large domain. Glucokinase has one active binding site for glucose and one for ATP, which is the energy source for phosphorylation. This active binding site is located between the small and large domains. The carboxyl terminus is part of the alpha 13 helix, which codes for the region that forms half of the binding site for glucose. 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<ref name="king">PMID:15016359</ref>.

Glucokinase includes the <scene name='Kyle_Schroering_Sandbox/1v4s_glucose/2'>glucose binding site (active form)</scene> where glucose forms hydrogen bonds at the bottom of the deep crevice between the large domain and the small domain. E256, E290 (shown in green) of the large domain, T168, K169 (shown in red) of the small domain, and N204, D205 (shown in yellow) of a connecting region form hydrogen bonds with glucose. The <scene name='Kyle_Schroering_Sandbox/Active_form_of_glucokinase/4'>glucose binding site (inactive form)</scene> shows a different conformation. At the <scene name='Kyle_Schroering_Sandbox/1v4s_atp/3'>allosteric site (active form)</scene>, ATP forms hydrogen bonds with R63 and Y215 (shown in orange) and hydrophobically interacts with M210, Y214 (shown in blue) of the α5 helix and V452, V455 (shown in green) of the α13 helix. The <scene name='Kyle_Schroering_Sandbox/Active_atp/3'>allosteric site (inactive form)</scene> again shows structural differences. The differences in these two conformations allows glucokinase to function properly in different levels of glucose concentration.

'''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<ref name="king" />. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-31T16:08:54Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

==The Structure and Mechanism of Hexokinase==

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.

-Hexokinase I/A is found in all mammalian tissues, and is considered a "housekeeping enzyme," unaffected by most physiological, hormonal, and metabolic changes.

-Hexokinase II/B constitutes the principal regulated isoform in many cell types and is increased in many cancers.

-Hexokinase III/C is substrate-inhibited by glucose at physiologic concentrations. Little is known about the regulatory characteristics of this isoform.

-Hexokinase IV/D is also known as glucokinase and is described below.

'''Hexokinase Structure:''' The tertiary structure of hexokinase includes an <scene name='Kyle_Schroering_Sandbox/Secondary_structure/1'>open alpha/beta sheet</scene>. There is a large amount of variation associated with this structure. The ATP-binding domain is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme. The molecular weights of hexokinases are around 100 kD. Each consists of two similar 50kD halves, but only in hexokinase II do both halves have functional active sites.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP <ref>PMID:7048063</ref>. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

'''Glucokinase Structure:''' Glucokinase also contains <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>inactive</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>active</scene> conformation. Glucokinase consists of one chain or subunit of 448 amino acids forming a monomeric molecule consisting of 13 alpha helices and 5 beta sheets that can phosporylate glucose and other hexoses. The chain is folded into two distinct regions, a small and large domain. Glucokinase has one active binding site for glucose and one for ATP, which is the energy source for phosphorylation. This active binding site is located between the small and large domains. The carboxyl terminus is part of the alpha 13 helix, which codes for the region that forms half of the binding site for glucose. 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<ref name="2">PMID:15016359</ref>.

Glucokinase includes the <scene name='Kyle_Schroering_Sandbox/1v4s_glucose/2'>glucose binding site (active form)</scene> where glucose forms hydrogen bonds at the bottom of the deep crevice between the large domain and the small domain. E256, E290 (shown in green) of the large domain, T168, K169 (shown in red) of the small domain, and N204, D205 (shown in yellow) of a connecting region form hydrogen bonds with glucose. The <scene name='Kyle_Schroering_Sandbox/Active_form_of_glucokinase/4'>glucose binding site (inactive form)</scene> shows a different conformation. At the <scene name='Kyle_Schroering_Sandbox/1v4s_atp/3'>allosteric site (active form)</scene>, ATP forms hydrogen bonds with R63 and Y215 (shown in orange) and hydrophobically interacts with M210, Y214 (shown in blue) of the α5 helix and V452, V455 (shown in green) of the α13 helix. The <scene name='Kyle_Schroering_Sandbox/Active_atp/3'>allosteric site (inactive form)</scene> again shows structural differences. The differences in these two conformations allows glucokinase to function properly in different levels of glucose concentration.

'''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<ref name="2" />. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-31T16:01:35Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

==The Structure and Mechanism of Hexokinase==

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.

-Hexokinase I/A is found in all mammalian tissues, and is considered a "housekeeping enzyme," unaffected by most physiological, hormonal, and metabolic changes.

-Hexokinase II/B constitutes the principal regulated isoform in many cell types and is increased in many cancers.

-Hexokinase III/C is substrate-inhibited by glucose at physiologic concentrations. Little is known about the regulatory characteristics of this isoform.

-Hexokinase IV/D is also known as glucokinase and is described below.

'''Hexokinase Structure:''' The tertiary structure of hexokinase includes an <scene name='Kyle_Schroering_Sandbox/Secondary_structure/1'>open alpha/beta sheet</scene>. There is a large amount of variation associated with this structure. The ATP-binding domain is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme. The molecular weights of hexokinases are around 100 kD. Each consists of two similar 50kD halves, but only in hexokinase II do both halves have functional active sites.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP <ref>PMID:7048063</ref>. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

'''Glucokinase Structure:''' Glucokinase also contains <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>inactive</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>active</scene> conformation. Glucokinase consists of one chain or subunit of 448 amino acids forming a monomeric molecule consisting of 13 alpha helices and 5 beta sheets that can phosporylate glucose and other hexoses. The chain is folded into two distinct regions, a small and large domain. Glucokinase has one active binding site for glucose and one for ATP, which is the energy source for phosphorylation. This active binding site is located between the small and large domains. The carboxyl terminus is part of the alpha 13 helix, which codes for the region that forms half of the binding site for glucose. 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<ref>PMID:15016359</ref>.

Glucokinase includes the <scene name='Kyle_Schroering_Sandbox/1v4s_glucose/2'>glucose binding site (active form)</scene> where glucose forms hydrogen bonds at the bottom of the deep crevice between the large domain and the small domain. E256, E290 (shown in green) of the large domain, T168, K169 (shown in red) of the small domain, and N204, D205 (shown in yellow) of a connecting region form hydrogen bonds with glucose. The <scene name='Kyle_Schroering_Sandbox/Active_form_of_glucokinase/4'>glucose binding site (inactive form)</scene> shows a different conformation. At the <scene name='Kyle_Schroering_Sandbox/1v4s_atp/3'>allosteric site (active form)</scene>, ATP forms hydrogen bonds with R63 and Y215 (shown in orange) and hydrophobically interacts with M210, Y214 (shown in blue) of the α5 helix and V452, V455 (shown in green) of the α13 helix. The <scene name='Kyle_Schroering_Sandbox/Active_atp/3'>allosteric site (inactive form)</scene> again shows structural differences. The differences in these two conformations allows glucokinase to function properly in different levels of glucose concentration.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-31T15:59:09Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

==The Structure and Mechanism of Hexokinase==

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.

-Hexokinase I/A is found in all mammalian tissues, and is considered a "housekeeping enzyme," unaffected by most physiological, hormonal, and metabolic changes.

-Hexokinase II/B constitutes the principal regulated isoform in many cell types and is increased in many cancers.

-Hexokinase III/C is substrate-inhibited by glucose at physiologic concentrations. Little is known about the regulatory characteristics of this isoform.

-Hexokinase IV/D is also known as glucokinase and is described below.

'''Hexokinase Structure:''' The tertiary structure of hexokinase includes an <scene name='Kyle_Schroering_Sandbox/Secondary_structure/1'>open alpha/beta sheet</scene>. There is a large amount of variation associated with this structure. The ATP-binding domain is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme. The molecular weights of hexokinases are around 100 kD. Each consists of two similar 50kD halves, but only in hexokinase II do both halves have functional active sites.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP <ref>PMID:7048063</ref>. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''Glucokinase Structure:''' Glucokinase also contains <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>inactive</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>active</scene> conformation. Glucokinase consists of one chain or subunit of 448 amino acids forming a monomeric molecule consisting of 13 alpha helices and 5 beta sheets that can phosporylate glucose and other hexoses. The chain is folded into two distinct regions, a small and large domain. Glucokinase has one active binding site for glucose and one for ATP, which is the energy source for phosphorylation. This active binding site is located between the small and large domains. The carboxyl terminus is part of the alpha 13 helix, which codes for the region that forms half of the binding site for glucose. 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<ref>PMID:15016359</ref>.

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

Glucokinase includes the <scene name='Kyle_Schroering_Sandbox/1v4s_glucose/2'>glucose binding site (active form)</scene> where glucose forms hydrogen bonds at the bottom of the deep crevice between the large domain and the small domain. E256, E290 (shown in green) of the large domain, T168, K169 (shown in red) of the small domain, and N204, D205 (shown in yellow) of a connecting region form hydrogen bonds with glucose. The <scene name='Kyle_Schroering_Sandbox/Active_form_of_glucokinase/4'>glucose binding site (inactive form)</scene> shows a different conformation. At the <scene name='Kyle_Schroering_Sandbox/1v4s_atp/3'>allosteric site (active form)</scene>, ATP forms hydrogen bonds with R63 and Y215 (shown in orange) and hydrophobically interacts with M210, Y214 (shown in blue) of the α5 helix and V452, V455 (shown in green) of the α13 helix. The <scene name='Kyle_Schroering_Sandbox/Active_atp/3'>allosteric site (inactive form)</scene> again shows structural differences. The differences in these two conformations allows glucokinase to function properly in different levels of glucose concentration.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-31T15:38:24Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

==The Structure and Mechanism of Hexokinase==

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.

-Hexokinase I/A is found in all mammalian tissues, and is considered a "housekeeping enzyme," unaffected by most physiological, hormonal, and metabolic changes.

-Hexokinase II/B constitutes the principal regulated isoform in many cell types and is increased in many cancers.

-Hexokinase III/C is substrate-inhibited by glucose at physiologic concentrations. Little is known about the regulatory characteristics of this isoform.

-Hexokinase IV/D is also known as glucokinase and is described below.

'''Hexokinase Structure:''' The tertiary structure of hexokinase includes an <scene name='Kyle_Schroering_Sandbox/Secondary_structure/1'>open alpha/beta sheet</scene>. There is a large amount of variation associated with this structure. The ATP-binding domain is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme. The molecular weights of hexokinases are around 100 kD. Each consists of two similar 50kD halves, but only in hexokinase II do both halves have functional active sites.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP <ref>PMID:7048063</ref>. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''Glucokinase Structure:''' Glucokinase also contains <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>inactive</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>active</scene> conformation. Glucokinase consists of one chain or subunit of 448 amino acids forming a monomeric molecule consisting of 13 alpha helices and 5 beta sheets that can phosporylate glucose and other hexoses. The chain is folded into two distinct regions, a small and large domain. Glucokinase has one active binding site for glucose and one for ATP, which is the energy source for phosphorylation. This active binding site is located between the small and large domains. The carboxyl terminus is part of the alpha 13 helix, which codes for the region that forms half of the binding site for glucose. 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<ref>PMID:15016359</ref>.

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

Glucokinase includes the <scene name='Kyle_Schroering_Sandbox/1v4s_glucose/1'>glucose binding site (active form)</scene> where glucose forms hydrogen bonds at the bottom of the deep crevice between the large domain and the small domain. E256, E290 (shown in green) of the large domain, T168, K169 (shown in red) of the small domain, and N204, D205 (shown in yellow) of a connecting region form hydrogen bonds with glucose. The <scene name='Kyle_Schroering_Sandbox/Active_form_of_glucokinase/2'>glucose binding site (inactive form)</scene> shows a different conformation. At the <scene name='Kyle_Schroering_Sandbox/1v4s_atp/2'>allosteric site (active form)</scene>, ATP forms hydrogen bonds with R63 and Y215 (shown in orange) and hydrophobically interacts with M210, Y214 (shown in blue) of the α5 helix and V452, V455 (shown in green) of the α13 helix. The <scene name='Kyle_Schroering_Sandbox/Active_atp/2'>allosteric site (inactive form)</scene> again shows structural differences. The differences in these two conformations allows glucokinase to function properly in different levels of glucose concentration.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-31T15:31:14Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

==The Structure and Mechanism of Hexokinase==

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.

-Hexokinase I/A is found in all mammalian tissues, and is considered a "housekeeping enzyme," unaffected by most physiological, hormonal, and metabolic changes.

-Hexokinase II/B constitutes the principal regulated isoform in many cell types and is increased in many cancers.

-Hexokinase III/C is substrate-inhibited by glucose at physiologic concentrations. Little is known about the regulatory characteristics of this isoform.

-Hexokinase IV/D is also known as glucokinase and is described below.

'''Hexokinase Structure:''' The tertiary structure of hexokinase includes an <scene name='Kyle_Schroering_Sandbox/Secondary_structure/1'>open alpha/beta sheet</scene>. There is a large amount of variation associated with this structure. The ATP-binding domain is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP <ref>PMID:7048063</ref>. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''Glucokinase Structure:''' Glucokinase also contains <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>inactive</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>active</scene> conformation. Glucokinase consists of one chain or subunit of 448 amino acids forming a monomeric molecule consisting of 13 alpha helices and 5 beta sheets that can phosporylate glucose and other hexoses. The chain is folded into two distinct regions, a small and large domain. Glucokinase has one active binding site for glucose and one for ATP, which is the energy source for phosphorylation. This active binding site is located between the small and large domains. The carboxyl terminus is part of the alpha 13 helix, which codes for the region that forms half of the binding site for glucose. 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<ref>PMID:15016359</ref>.

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

Glucokinase includes the <scene name='Kyle_Schroering_Sandbox/1v4s_glucose/1'>glucose binding site (active form)</scene> where glucose forms hydrogen bonds at the bottom of the deep crevice between the large domain and the small domain. E256, E290 (shown in green) of the large domain, T168, K169 (shown in red) of the small domain, and N204, D205 (shown in yellow) of a connecting region form hydrogen bonds with glucose. The <scene name='Kyle_Schroering_Sandbox/Active_form_of_glucokinase/2'>glucose binding site (inactive form)</scene> shows a different conformation. At the <scene name='Kyle_Schroering_Sandbox/1v4s_atp/2'>allosteric site (active form)</scene>, ATP forms hydrogen bonds with R63 and Y215 (shown in orange) and hydrophobically interacts with M210, Y214 (shown in blue) of the α5 helix and V452, V455 (shown in green) of the α13 helix. The <scene name='Kyle_Schroering_Sandbox/Active_atp/2'>allosteric site (inactive form)</scene> again shows structural differences. The differences in these two conformations allows glucokinase to function properly in different levels of glucose concentration.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-31T15:30:26Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

==The Structure and Mechanism of Hexokinase==

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.

-Hexokinase I/A is found in all mammalian tissues, and is considered a "housekeeping enzyme," unaffected by most physiological, hormonal, and metabolic changes.
-Hexokinase II/B constitutes the principal regulated isoform in many cell types and is increased in many cancers.
-Hexokinase III/C is substrate-inhibited by glucose at physiologic concentrations. Little is known about the regulatory characteristics of this isoform.
-Hexokinase IV/D is also known as glucokinase and is described below.

'''Hexokinase Structure:''' The tertiary structure of hexokinase includes an <scene name='Kyle_Schroering_Sandbox/Secondary_structure/1'>open alpha/beta sheet</scene>. There is a large amount of variation associated with this structure. The ATP-binding domain is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP <ref>PMID:7048063</ref>. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''Glucokinase Structure:''' Glucokinase also contains <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>inactive</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>active</scene> conformation. Glucokinase consists of one chain or subunit of 448 amino acids forming a monomeric molecule consisting of 13 alpha helices and 5 beta sheets that can phosporylate glucose and other hexoses. The chain is folded into two distinct regions, a small and large domain. Glucokinase has one active binding site for glucose and one for ATP, which is the energy source for phosphorylation. This active binding site is located between the small and large domains. The carboxyl terminus is part of the alpha 13 helix, which codes for the region that forms half of the binding site for glucose. 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<ref>PMID:15016359</ref>.

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

Glucokinase includes the <scene name='Kyle_Schroering_Sandbox/1v4s_glucose/1'>glucose binding site (active form)</scene> where glucose forms hydrogen bonds at the bottom of the deep crevice between the large domain and the small domain. E256, E290 (shown in green) of the large domain, T168, K169 (shown in red) of the small domain, and N204, D205 (shown in yellow) of a connecting region form hydrogen bonds with glucose. The <scene name='Kyle_Schroering_Sandbox/Active_form_of_glucokinase/2'>glucose binding site (inactive form)</scene> shows a different conformation. At the <scene name='Kyle_Schroering_Sandbox/1v4s_atp/2'>allosteric site (active form)</scene>, ATP forms hydrogen bonds with R63 and Y215 (shown in orange) and hydrophobically interacts with M210, Y214 (shown in blue) of the α5 helix and V452, V455 (shown in green) of the α13 helix. The <scene name='Kyle_Schroering_Sandbox/Active_atp/2'>allosteric site (inactive form)</scene> again shows structural differences. The differences in these two conformations allows glucokinase to function properly in different levels of glucose concentration.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-31T15:28:57Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

==The Structure and Mechanism of Hexokinase==

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.

* Hexokinase I/A is found in all mammalian tissues, and is considered a "housekeeping enzyme," unaffected by most physiological, hormonal, and metabolic changes.

* Hexokinase II/B constitutes the principal regulated isoform in many cell types and is increased in many cancers.

* Hexokinase III/C is substrate-inhibited by glucose at physiologic concentrations. Little is known about the regulatory characteristics of this isoform.

* Hexokinase IV/D is also known as glucokinase and is described below.

'''Hexokinase Structure:''' The tertiary structure of hexokinase includes an <scene name='Kyle_Schroering_Sandbox/Secondary_structure/1'>open alpha/beta sheet</scene>. There is a large amount of variation associated with this structure. The ATP-binding domain is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP <ref>PMID:7048063</ref>. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''Glucokinase Structure:''' Glucokinase also contains <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>inactive</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>active</scene> conformation. Glucokinase consists of one chain or subunit of 448 amino acids forming a monomeric molecule consisting of 13 alpha helices and 5 beta sheets that can phosporylate glucose and other hexoses. The chain is folded into two distinct regions, a small and large domain. Glucokinase has one active binding site for glucose and one for ATP, which is the energy source for phosphorylation. This active binding site is located between the small and large domains. The carboxyl terminus is part of the alpha 13 helix, which codes for the region that forms half of the binding site for glucose. 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<ref>PMID:15016359</ref>.

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

Glucokinase includes the <scene name='Kyle_Schroering_Sandbox/1v4s_glucose/1'>glucose binding site (active form)</scene> where glucose forms hydrogen bonds at the bottom of the deep crevice between the large domain and the small domain. E256, E290 (shown in green) of the large domain, T168, K169 (shown in red) of the small domain, and N204, D205 (shown in yellow) of a connecting region form hydrogen bonds with glucose. The <scene name='Kyle_Schroering_Sandbox/Active_form_of_glucokinase/2'>glucose binding site (inactive form)</scene> shows a different conformation. At the <scene name='Kyle_Schroering_Sandbox/1v4s_atp/2'>allosteric site (active form)</scene>, ATP forms hydrogen bonds with R63 and Y215 (shown in orange) and hydrophobically interacts with M210, Y214 (shown in blue) of the α5 helix and V452, V455 (shown in green) of the α13 helix. The <scene name='Kyle_Schroering_Sandbox/Active_atp/2'>allosteric site (inactive form)</scene> again shows structural differences. The differences in these two conformations allows glucokinase to function properly in different levels of glucose concentration.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-23T09:51:14Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

==The Structure and Mechanism of Hexokinase==

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.

'''Hexokinase Structure:''' The tertiary structure of hexokinase includes an <scene name='Kyle_Schroering_Sandbox/Secondary_structure/1'>open alpha/beta sheet</scene>. There is a large amount of variation associated with this structure. The ATP-binding domain is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP <ref>PMID:7048063</ref>. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''Glucokinase Structure:''' Glucokinase also contains <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>inactive</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>active</scene> conformation. Glucokinase consists of one chain or subunit of 448 amino acids forming a monomeric molecule consisting of 13 alpha helices and 5 beta sheets that can phosporylate glucose and other hexoses. The chain is folded into two distinct regions, a small and large domain. Glucokinase has one active binding site for glucose and one for ATP, which is the energy source for phosphorylation. This active binding site is located between the small and large domains. The carboxyl terminus is part of the alpha 13 helix, which codes for the region that forms half of the binding site for glucose. 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<ref>PMID:15016359</ref>.

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

Glucokinase includes the <scene name='Kyle_Schroering_Sandbox/1v4s_glucose/1'>glucose binding site (active form)</scene> where glucose forms hydrogen bonds at the bottom of the deep crevice between the large domain and the small domain. E256, E290 (shown in green) of the large domain, T168, K169 (shown in red) of the small domain, and N204, D205 (shown in yellow) of a connecting region form hydrogen bonds with glucose. The <scene name='Kyle_Schroering_Sandbox/Active_form_of_glucokinase/2'>glucose binding site (inactive form)</scene> shows a different conformation. At the <scene name='Kyle_Schroering_Sandbox/1v4s_atp/2'>allosteric site (active form)</scene>, ATP forms hydrogen bonds with R63 and Y215 (shown in orange) and hydrophobically interacts with M210, Y214 (shown in blue) of the α5 helix and V452, V455 (shown in green) of the α13 helix. The <scene name='Kyle_Schroering_Sandbox/Active_atp/2'>allosteric site (inactive form)</scene> again shows structural differences. The differences in these two conformations allows glucokinase to function properly in different levels of glucose concentration.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-23T07:31:51Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

==The Structure and Mechanism of Hexokinase==

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.

'''Hexokinase Structure:''' The tertiary structure of hexokinase includes an <scene name='Kyle_Schroering_Sandbox/Secondary_structure/1'>open alpha/beta sheet</scene>. There is a large amount of variation associated with this structure. The ATP-binding domain is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP <ref>PMID:7048063</ref>. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''Glucokinase Structure:''' Glucokinase also contains <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>inactive</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>active</scene> conformation. Glucokinase consists of one chain or subunit of 448 amino acids forming a monomeric molecule consisting of 13 alpha helices and 5 beta sheets that can phosporylate glucose and other hexoses. The chain is folded into two distinct regions, a small and large domain. Glucokinase has one active binding site for glucose and one for ATP, which is the energy source for phosphorylation. This active binding site is located between the small and large domains. The carboxyl terminus is part of the alpha 13 helix, which codes for the region that forms half of the binding site for glucose. 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<ref>PMID:15016359</ref>.

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

Glucokinase includes the <scene name='Kyle_Schroering_Sandbox/1v4s_glucose/1'>glucose binding site (active form)</scene> where glucose forms hydrogen bonds at the bottom of the deep crevice between the large domain and the small domain. E256, E290 (shown in green) of the large domain, T168, K169 (shown in red) of the small domain, and N204, D205 (shown in yellow) of a connecting region form hydrogen bonds with glucose. The <scene name='Kyle_Schroering_Sandbox/Active_form_of_glucokinase/2'>glucose binding site (inactive form)</scene> shows a different conformation. At the <scene name='Kyle_Schroering_Sandbox/1v4s_atp/1'>allosteric site (active form)</scene>, ATP forms hydrogen bonds with R63 and Y215 (shown in orange) and hydrophobically interacts with M210, Y214 (shown in blue) of the α5 helix and V452, V455 (shown in green) of the α13 helix. The <scene name='Kyle_Schroering_Sandbox/Active_atp/2'>allosteric site (inactive form)</scene> again shows structural differences. The differences in these two conformations allows glucokinase to function properly in different levels of glucose concentration.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-23T07:16:11Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

==The Structure and Mechanism of Hexokinase==

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.

'''Hexokinase Structure:''' The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. The ATP-binding domain is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP <ref>PMID:7048063</ref>. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''Glucokinase Structure:''' Glucokinase also contains <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>inactive</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>active</scene> conformation. Glucokinase consists of one chain or subunit of 448 amino acids forming a monomeric molecule consisting of 13 alpha helices and 5 beta sheets that can phosporylate glucose and other hexoses. The chain is folded into two distinct regions, a small and large domain. Glucokinase has one active binding site for glucose and one for ATP, which is the energy source for phosphorylation. This active binding site is located between the small and large domains. The carboxyl terminus is part of the alpha 13 helix, which codes for the region that forms half of the binding site for glucose. 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<ref>PMID:15016359</ref>.

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

Glucokinase includes the <scene name='Kyle_Schroering_Sandbox/1v4s_glucose/1'>glucose binding site (active form)</scene> where glucose forms hydrogen bonds at the bottom of the deep crevice between the large domain and the small domain. E256, E290 (shown in green) of the large domain, T168, K169 (shown in red) of the small domain, and N204, D205 (shown in yellow) of a connecting region form hydrogen bonds with glucose. The <scene name='Kyle_Schroering_Sandbox/Active_form_of_glucokinase/2'>glucose binding site (inactive form)</scene> shows a different conformation. At the <scene name='Kyle_Schroering_Sandbox/1v4s_atp/1'>allosteric site (active form)</scene>, ATP forms hydrogen bonds with R63 and Y215 (shown in orange) and hydrophobically interacts with M210, Y214 (shown in blue) of the α5 helix and V452, V455 (shown in green) of the α13 helix. The <scene name='Kyle_Schroering_Sandbox/Active_atp/2'>allosteric site (inactive form)</scene> again shows structural differences. The differences in these two conformations allows glucokinase to function properly in different levels of glucose concentration.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-01T22:23:39Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

==The Structure and Mechanism of Hexokinase==

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.

'''Hexokinase Structure:''' The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. The ATP-binding domain is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP <ref>PMID:7048063</ref>. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''Glucokinase Structure:''' Glucokinase also contains <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>inactive</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>active</scene> conformation. Glucokinase consists of one chain or subunit of 448 amino acids forming a monomeric molecule consisting of 13 alpha helices and 5 beta sheets that can phosporylate glucose and other hexoses. The chain is folded into two distinct regions, a small and large domain. Glucokinase has one active binding site for glucose and one for ATP, which is the energy source for phosphorylation. This active binding site is located between the small and large domains. The carboxyl terminus is part of the alpha 13 helix, which codes for the region that forms half of the binding site for glucose. 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<ref>PMID:15016359</ref>.

Glucokinase includes the <scene name='Kyle_Schroering_Sandbox/1v4s_glucose/1'>glucose binding site (active form)</scene> where glucose forms hydrogen bonds at the bottom of the deep crevice between the large domain and the small domain. E256, E290 (shown in green) of the large domain, T168, K169 (shown in red) of the small domain, and N204, D205 (shown in yellow) of a connecting region form hydrogen bonds with glucose. The <scene name='Kyle_Schroering_Sandbox/Active_form_of_glucokinase/2'>glucose binding site (inactive form)</scene> shows a different conformation. At the <scene name='Kyle_Schroering_Sandbox/1v4s_atp/1'>allosteric site (active form)</scene>, ATP forms hydrogen bonds with R63 and Y215 (shown in orange) and hydrophobically interacts with M210, Y214 (shown in blue) of the α5 helix and V452, V455 (shown in green) of the α13 helix. The <scene name='Kyle_Schroering_Sandbox/Active_atp/2'>allosteric site (inactive form)</scene> again shows structural differences. The differences in these two conformations allows glucokinase to function properly in different levels of glucose concentration.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-01T21:57:24Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

==The Structure and Mechanism of Hexokinase==

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.

'''Hexokinase Structure:''' The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. The ATP-binding domain is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP <ref>PMID:7048063</ref>. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''Glucokinase Structure:''' Glucokinase also contains <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>inactive</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>active</scene> conformation. Glucokinase consists of one chain or subunit of 448 amino acids forming a monomeric molecule consisting of 13 alpha helices and 5 beta sheets that can phosporylate glucose and other hexoses. The chain is folded into two distinct regions, a small and large domain. Glucokinase has one active binding site for glucose and one for ATP, which is the energy source for phosphorylation. This active binding site is located between the small and large domains. The carboxyl terminus is part of the alpha 13 helix, which codes for the region that forms half of the binding site for glucose. 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<ref>PMID:15016359</ref>.

The active form of glucokinase includes the <scene name='Kyle_Schroering_Sandbox/Active_form_of_glucokinase/2'>glucose binding site</scene> where glucose forms hydrogen bonds at the bottom of the deep crevice between the large domain and the small domain. E256, E290 of the large domain (shown in green), T168, K169 of the small domain, and N204, D205 (shown in yellow) of a connecting region form hydrogen bonds with glucose. At the <scene name='Kyle_Schroering_Sandbox/Active_atp/2'>allosteric site</scene>, ATP forms hydrogen bonds with R63 and Y215 (shown in orange) and hydrophobically interacts with M210, Y214 (shown in blue) of the α5 helix and V452, V455 (shown in green) of the α13 helix.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-01T21:41:28Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

==The Structure and Mechanism of Hexokinase==

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.

'''Hexokinase Structure:''' The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. The ATP-binding domain is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP <ref>PMID:7048063</ref>. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''Glucokinase Structure:''' Glucokinase also contains <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>inactive</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>active</scene> conformation. Glucokinase consists of one chain or subunit of 448 amino acids forming a monomeric molecule consisting of 13 alpha helices and 5 beta sheets that can phosporylate glucose and other hexoses. The chain is folded into two distinct regions, a small and large domain. Glucokinase has one active binding site for glucose and one for ATP, which is the energy source for phosphorylation. This active binding site is located between the small and large domains. The carboxyl terminus is part of the alpha 13 helix, which codes for the region that forms half of the binding site for glucose. 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<ref>PMID:15016359</ref>.

The active form of glucokinase includes the <scene name='Kyle_Schroering_Sandbox/Active_form_of_glucokinase/2'>glucose binding site</scene> where glucose forms hydrogen bonds at the bottom of the deep crevice between the large domain and the small domain. E256, E290 of the large domain (shown in green), T168, K169 of the small domain, and N204, D205 (shown in yellow) of a connecting region form hydrogen bonds with glucose.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-01T21:40:07Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

==The Structure and Mechanism of Hexokinase==

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.

'''Hexokinase Structure:''' The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. The ATP-binding domain is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP <ref>PMID:7048063</ref>. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''Glucokinase Structure:''' Glucokinase also contains <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>inactive</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>active</scene> conformation. Glucokinase consists of one chain or subunit of 448 amino acids forming a monomeric molecule consisting of 13 alpha helices and 5 beta sheets that can phosporylate glucose and other hexoses. The chain is folded into two distinct regions, a small and large domain. Glucokinase has one active binding site for glucose and one for ATP, which is the energy source for phosphorylation. This active binding site is located between the small and large domains. The carboxyl terminus is part of the alpha 13 helix, which codes for the region that forms half of the binding site for glucose. 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<ref>PMID:15016359</ref>.

The <scene name='Kyle_Schroering_Sandbox/Active_form_of_glucokinase/2'>active form of glucokinase</scene> includes the glucose binding site where glucose forms hydrogen bonds at the bottom of the deep crevice between the large domain and the small domain. E256, E290 of the large domain (shown in green), T168, K169 of the small domain, and N204, D205 (shown in yellow) of a connecting region form hydrogen bonds with glucose.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-01T21:01:30Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Structure of Glucokinase' />

==The Structure and Mechanism of Hexokinase==

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.

'''Hexokinase Structure:''' Hexokinase contains 17 alpha helices and 11 beta sheets. The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.

The hexokinase molecule has two distinct conformations, open and closed, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. The existance of a salt link between Arg 539 and Asp 895 of the open conformation of the C-terminal half breaks in the closed conformation. Arg 539 is essential for catalysis interacting with a phosphory group of ATP. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accommodate ATP <ref>PMID: 6115422 </ref>. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP <ref>PMID:7048063</ref>. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

Five loops exist that exhibit conformational change that cannot be represented by rigid body movements. The specific residues involved in the conformational change include Lys 621 which binds to glucose and a second loop (residues 618-624) that interact with glucose. Both of these loops relax together to new conformations in the absence of glucose. Loop 532-537 which bind G6P, also relaxes in the absence of the inhibitor. Thr 536 hydrogen bonds with the 6-phosphoryl group of the inhibitor in the glucose/G6P dimer, and may be a factor in the tight binding of G6P by hexokinase. Three rigid-body transformations, which convert the glucose/Pi conformer into the glucose/G6P conformer, prompt the belief in existence of hinges in the polypeptide chain of hexokinase. One hinge spans from residues 462 to 469 of the transition helix between the N and C terminal halves. These residues are hydrophobic, being exposed to solvent and free of side-chain hydrogen bonds to other elements of the protein. Three additional hinges allow the relative movement of the small and large domains of the C-terminal half. The existance of a salt link between Arg 539 and Asp 895 of the open conformation of the C-terminal half breaks in the closed conformation. Arg 539 is essential for catalysis interacting with a phosphoryl group of ATP.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels. Glucokinase also contains <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>inactive</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>active</scene> conformation.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-01T20:53:44Z

Kyle Schroering: Undo revision 1051068 by Kyle Schroering (Talk)

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Hexokinase' />

==The Structure and Mechanism of Hexokinase==

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.

'''Hexokinase Structure:''' Hexokinase contains 17 alpha helices and 11 beta sheets. The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.

The hexokinase molecule has two distinct conformations, open and closed, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. The existance of a salt link between Arg 539 and Asp 895 of the open conformation of the C-terminal half breaks in the closed conformation. Arg 539 is essential for catalysis interacting with a phosphory group of ATP. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accommodate ATP <ref>PMID: 6115422 </ref>. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP <ref>PMID:7048063</ref>. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

Five loops exist that exhibit conformational change that cannot be represented by rigid body movements. The specific residues involved in the conformational change include Lys 621 which binds to glucose and a second loop (residues 618-624) that interact with glucose. Both of these loops relax together to new conformations in the absence of glucose. Loop 532-537 which bind G6P, also relaxes in the absence of the inhibitor. Thr 536 hydrogen bonds with the 6-phosphoryl group of the inhibitor in the glucose/G6P dimer, and may be a factor in the tight binding of G6P by hexokinase. Three rigid-body transformations, which convert the glucose/Pi conformer into the glucose/G6P conformer, prompt the belief in existence of hinges in the polypeptide chain of hexokinase. One hinge spans from residues 462 to 469 of the transition helix between the N and C terminal halves. These residues are hydrophobic, being exposed to solvent and free of side-chain hydrogen bonds to other elements of the protein. Three additional hinges allow the relative movement of the small and large domains of the C-terminal half. The existance of a salt link between Arg 539 and Asp 895 of the open conformation of the C-terminal half breaks in the closed conformation. Arg 539 is essential for catalysis interacting with a phosphoryl group of ATP.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels. Glucokinase also contains <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>active</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>inactive</scene> conformation.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-01T20:36:29Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Hexokinase' />

==The Structure and Mechanism of Hexokinase==

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.

'''Hexokinase Structure:''' Hexokinase contains 17 alpha helices and 11 beta sheets. The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.

The hexokinase molecule has two distinct conformations, open and closed, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. The existance of a salt link between Arg 539 and Asp 895 of the open conformation of the C-terminal half breaks in the closed conformation. Arg 539 is essential for catalysis interacting with a phosphory group of ATP. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accommodate ATP <ref>PMID: 6115422 </ref>. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP <ref>PMID:7048063</ref>. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

Five loops exist that exhibit conformational change that cannot be represented by rigid body movements. The specific residues involved in the conformational change include Lys 621 which binds to glucose and a second loop (residues 618-624) that interact with glucose. Both of these loops relax together to new conformations in the absence of glucose. Loop 532-537 which bind G6P, also relaxes in the absence of the inhibitor. Thr 536 hydrogen bonds with the 6-phosphoryl group of the inhibitor in the glucose/G6P dimer, and may be a factor in the tight binding of G6P by hexokinase. Three rigid-body transformations, which convert the glucose/Pi conformer into the glucose/G6P conformer, prompt the belief in existence of hinges in the polypeptide chain of hexokinase. One hinge spans from residues 462 to 469 of the transition helix between the N and C terminal halves. These residues are hydrophobic, being exposed to solvent and free of side-chain hydrogen bonds to other elements of the protein. Three additional hinges allow the relative movement of the small and large domains of the C-terminal half. The existance of a salt link between Arg 539 and Asp 895 of the open conformation of the C-terminal half breaks in the closed conformation. Arg 539 is essential for catalysis interacting with a phosphoryl group of ATP <ref>PMID:7048063</ref>.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels. Glucokinase also contains <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>active</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>inactive</scene> conformation.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-01T19:50:22Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Hexokinase' />

==The Structure and Mechanism of Hexokinase==

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.

'''Hexokinase Structure:''' Hexokinase contains 17 alpha helices and 11 beta sheets. The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.

The hexokinase molecule has two distinct conformations, <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>open</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>closed</scene>, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. The existance of a salt link between Arg 539 and Asp 895 of the open conformation of the C-terminal half breaks in the closed conformation. Arg 539 is essential for catalysis interacting with a phosphory group of ATP. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accommodate ATP <ref>PMID: 6115422 </ref>. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP <ref>PMID:7048063</ref>. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

Five loops exist that exhibit conformational change that cannot be represented by rigid body movements. The specific residues involved in the conformational change include Lys 621 which binds to glucose and a second loop (residues 618-624) that interact with glucose. Both of these loops relax together to new conformations in the absence of glucose. Loop 532-537 which bind G6P, also relaxes in the absence of the inhibitor. Thr 536 hydrogen bonds with the 6-phosphoryl group of the inhibitor in the glucose/G6P dimer, and may be a factor in the tight binding of G6P by hexokinase. Three rigid-body transformations, which convert the glucose/Pi conformer into the glucose/G6P conformer, prompt the belief in existence of hinges in the polypeptide chain of hexokinase. One hinge spans from residues 462 to 469 of the transition helix between the N and C terminal halves. These residues are hydrophobic, being exposed to solvent and free of side-chain hydrogen bonds to other elements of the protein. Three additional hinges allow the relative movement of the small and large domains of the C-terminal half. The existance of a salt link between Arg 539 and Asp 895 of the open conformation of the C-terminal half breaks in the closed conformation. Arg 539 is essential for catalysis interacting with a phosphoryl group of ATP <ref>PMID:7048063</ref>.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-01T19:47:53Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Hexokinase' />

==The Structure and Mechanism of Hexokinase==

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.

'''Hexokinase Structure:''' Hexokinase contains 17 alpha helices and 11 beta sheets. The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.

The hexokinase molecule has two distinct conformations, <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>open</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>closed</scene>, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. The existance of a salt link between Arg 539 and Asp 895 of the open conformation of the C-terminal half breaks in the closed conformation. Arg 539 is essential for catalysis interacting with a phosphory group of ATP. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accommodate ATP. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

Five loops exist that exhibit conformational change that cannot be represented by rigid body movements. The specific residues involved in the conformational change include Lys 621 which binds to glucose and a second loop (residues 618-624) that interact with glucose. Both of these loops relax together to new conformations in the absence of glucose. Loop 532-537 which bind G6P, also relaxes in the absence of the inhibitor. Thr 536 hydrogen bonds with the 6-phosphoryl group of the inhibitor in the glucose/G6P dimer, and may be a factor in the tight binding of G6P by hexokinase. Three rigid-body transformations, which convert the glucose/Pi conformer into the glucose/G6P conformer, prompt the belief in existence of hinges in the polypeptide chain of hexokinase. One hinge spans from residues 462 to 469 of the transition helix between the N and C terminal halves. These residues are hydrophobic, being exposed to solvent and free of side-chain hydrogen bonds to other elements of the protein. Three additional hinges allow the relative movement of the small and large domains of the C-terminal half. The existance of a salt link between Arg 539 and Asp 895 of the open conformation of the C-terminal half breaks in the closed conformation. Arg 539 is essential for catalysis interacting with a phosphoryl group of ATP <ref>PMID:7048063</ref>.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-01T19:32:30Z

Kyle Schroering:

<applet load='1v4t' size='300' color='white' frame='true' align='right' caption='Hexokinase' />

==The Structure and Mechanism of Hexokinase==

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.

'''Hexokinase Structure:''' Hexokinase contains 17 alpha helices and 11 beta sheets. The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.

The hexokinase molecule has two distinct conformations, <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>open</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>closed</scene>, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. The existance of a salt link between Arg 539 and Asp 895 of the open conformation of the C-terminal half breaks in the closed conformation. Arg 539 is essential for catalysis interacting with a phosphory group of ATP. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accommodate ATP. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

Five loops exist that exhibit conformational change that cannot be represented by rigid body movements. The specific residues involved in the conformational change include Lys 621 which binds to glucose and a second loop (residues 618-624) that interact with glucose. Both of these loops relax together to new conformations in the absence of glucose. Loop 532-537 which bind G6P, also relaxes in the absence of the inhibitor. Thr 536 hydrogen bonds with the 6-phosphoryl group of the inhibitor in the glucose/G6P dimer, and may be a factor in the tight binding of G6P by hexokinase. Three rigid-body transformations, which convert the glucose/Pi conformer into the glucose/G6P conformer, prompt the belief in existence of hinges in the polypeptide chain of hexokinase. One hinge spans from residues 462 to 469 of the transition helix between the N and C terminal halves. These residues are hydrophobic, being exposed to solvent and free of side-chain hydrogen bonds to other elements of the protein. Three additional hinges allow the relative movement of the small and large domains of the C-terminal half. The existance of a salt link between Arg 539 and Asp 895 of the open conformation of the C-terminal half breaks in the closed conformation. Arg 539 is essential for catalysis interacting with a phosphoryl group of ATP.

==Glucokinase, an Isoenzyme of Hexokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level

<references/>

The Structure and Mechanism of Hexokinase

2010-03-01T09:33:09Z

Kyle Schroering:

==The Structure and Mechanism of Hexokinases (Specifically the Isoenzyme Glucokinase)==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P).

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level.

'''General Hexokinase Structure:''' Hexokinase contains 17 alpha helices and 11 beta sheets. The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.

The hexokinase molecule has two distinct conformations, <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>open</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>closed</scene>, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. The existance of a salt link between Arg 539 and Asp 895 of the open conformation of the C-terminal half breaks in the closed conformation. Arg 539 is essential for catalysis interacting with a phosphory group of ATP. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accommodate ATP. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

'''Glucokinase vs. Other Hexokinases:''' Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. The magnesium ion is required as the reactive form of ATP is the complex with magnesium (II) ion. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

Five loops exist that exhibit conformational change that cannot be represented by rigid body movements. The specific residues involved in the conformational change include Lys 621 which binds to glucose and a second loop (residues 618-624) that interact with glucose. Both of these loops relax together to new conformations in the absence of glucose. Loop 532-537 which bind G6P, also relaxes in the absence of the inhibitor. Thr 536 hydrogen bonds with the 6-phosphoryl group of the inhibitor in the glucose/G6P dimer, and may be a factor in the tight binding of G6P by hexokinase. Three rigid-body transformations, which convert the glucose/Pi conformer into the glucose/G6P conformer, prompt the belief in existence of hinges in the polypeptide chain of hexokinase. One hinge spans from residues 462 to 469 of the transition helix between the N and C terminal halves. These residues are hydrophobic, being exposed to solvent and free of side-chain hydrogen bonds to other elements of the protein. Three additional hinges allow the relative movement of the small and large domains of the C-terminal half. The existance of a salt link between Arg 539 and Asp 895 of the open conformation of the C-terminal half breaks in the closed conformation. Arg 539 is essential for catalysis interacting with a phosphoryl group of ATP.

<references/>

{{STRUCTURE_1glk| PDB=1glk | SCENE=Kyle_Schroering_Sandbox/Glucokinase/1 }}

The Structure and Mechanism of Hexokinase

2010-03-01T09:07:59Z

Kyle Schroering:

==The Structure and Mechanism of the Hexokinase isoenzyme Glucokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P). Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level.

'''General Hexokinase Structure:''' Hexokinase contains 17 alpha helices and 11 beta sheets. The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.

The hexokinase molecule has two distinct conformations, <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>open</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>closed</scene>, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. The existance of a salt link between Arg 539 and Asp 895 of the open conformation of the C-terminal half breaks in the closed conformation. Arg 539 is essential for catalysis interacting with a phosphory group of ATP. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accommodate ATP. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

'''Glucokinase vs. Other Hexokinases:''' The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gama-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose (magnesium ion is required as the reactive form of ATP is the chelated complex with magnesium (II) ion). This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP. Hexokinase is the enzyme that catalyzes this phosphoryl-group-transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

Lys 621 binds binds to glucose and a second loop (618-624) interacts with it . Both of these loops relax together to new conformations in the absence of glucose. Loop 532-537 which bind G6P, also relaxes in the absence of the inhibitor . Thr 536 hydrogen bonds with the 6-phosphoryl group of the inhibitor in the glucose/G6P dimer, and may be a factor in the tight binding of G6P by hexokinase.

<references/>

{{STRUCTURE_1glk| PDB=1glk | SCENE=Kyle_Schroering_Sandbox/Glucokinase/1 }}

The Structure and Mechanism of Hexokinase

2010-03-01T09:07:02Z

Kyle Schroering:

==The Structure and Mechanism of the Hexokinase isoenzyme Glucokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P). Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level.

'''General Hexokinase Structure:''' Hexokinase contains 17 alpha helices and 11 beta sheets. The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.
The hexokinase molecule has two distinct conformations, <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>open</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>closed</scene>, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. The existance of a salt link between Arg 539 and Asp 895 of the open conformation of the C-terminal half breaks in the closed conformation. Arg 539 is essential for catalysis interacting with a phosphory group of ATP. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accommodate ATP. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

'''Glucokinase vs. Other Hexokinases:''' The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gama-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose (magnesium ion is required as the reactive form of ATP is the chelated complex with magnesium (II) ion). This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP. Hexokinase is the enzyme that catalyzes this phosphoryl-group-transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.
Lys 621 binds binds to glucose and a second loop (618-624) interacts with it . Both of these loops relax together to new conformations in the absence of glucose. Loop 532-537 which bind G6P, also relaxes in the absence of the inhibitor . Thr 536 hydrogen bonds with the 6-phosphoryl group of the inhibitor in the glucose/G6P dimer, and may be a factor in the tight binding of G6P by hexokinase.

<references/>

{{STRUCTURE_1glk| PDB=1glk | SCENE=Kyle_Schroering_Sandbox/Glucokinase/1 }}

The Structure and Mechanism of Hexokinase

2010-03-01T09:04:56Z

Kyle Schroering:

==The Structure and Mechanism of the Hexokinase isoenzyme Glucokinase==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme. All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P). Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level.

'''General Hexokinase Structure:''' Hexokinase contains 17 alpha helices and 11 beta sheets. The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.
The hexokinase molecule has two distinct conformations, <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>open</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>closed</scene>, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. The existance of a salt link between Arg 539 and Asp 895 of the open conformation of the C-terminal half breaks in the closed conformation. Arg 539 is essential for catalysis interacting with a phosphory group of ATP. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accommodate ATP. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

'''Glucokinase vs. Other Hexokinases:''' The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''Mechanism of Hexokinase:'''
In the first reaction of glycolysis, the gama-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose (magnesium ion is required as the reactive form of ATP is the chelated complex with magnesium (II) ion). This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP. Hexokinase is the enzyme that catalyzes this phosphoryl-group-transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.
Lys 621 binds binds to glucose and a second loop (618-624) interacts with it . Both of these loops relax together to new conformations in the absence of glucose. Loop 532-537 which bind Glc-6-P, also relaxes in the absence of the inhibitor . Thr 536 hydrogen bonds with the 6-phosphoryl group of the inhibitor in the glucose/Glc-6-p dimer, and may be a factor in the tight binding of Glc-6-P by hexokinase.

<references/>

{{STRUCTURE_1glk| PDB=1glk | SCENE=Kyle_Schroering_Sandbox/Glucokinase/1 }}

The Structure and Mechanism of Hexokinase

2010-03-01T08:52:47Z

Kyle Schroering:

==The Structure and Mechanism of Glucokinase (Hexokinase D)==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P). Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level.

'''General Hexokinase Structure:''' The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alpha/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.
The hexokinase molecule has two distinct conformations, <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>open</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>closed</scene>, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accommodate ATP. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

'''Glucokinase vs. Other Hexokinases:''' The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''Mechanism of Glucokinase:'''
In the first reaction of glycolysis, the gama-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose (magnesium ion is required as the reactive form of ATP is the chelated complex with magnesium (II) ion). This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucose-6-phosphate and ADP. Hexokinase is the enzyme that catalyzes this phosphoryl-group-transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It is also allosterically inhibited by physiological concentrations of its immediate product, glucose-6-phosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled.

<references/>

{{STRUCTURE_1glk| PDB=1glk | SCENE=Kyle_Schroering_Sandbox/Glucokinase/1 }}

The Structure and Mechanism of Hexokinase

2010-03-01T08:45:24Z

Kyle Schroering:

==The Structure and Mechanism of Glucokinase (Hexokinase D)==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate (G6P). Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level.

'''General Hexokinase Structure:''' The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alpha/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet. The crevice indicates the ATP-binding domain of this glycolytic enzyme.
The hexokinase molecule has two distinct conformations, <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>open</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>closed</scene>, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accomodate ATP. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

'''Glucokinase vs. Other Hexokinases:''' The difference of glucokinase from the other hexokinases is that glucokinase has a lower affinity, thus a higher Km, for glucose. Essentially, this means that it operates only when serum glucose levels are high. High glucose is the signal to store glucose. Other tissues need to use glucose at lower serum levels and thus use the higher affinity (lower Km) hexokinase. Also, G6P inhibits hexokinase. This is simple "product inhibition". If the cell is not using up the G6P that it is making, then it should stop making it. G6P does not inhibit glucokinase. This allows it to remain active in storing as much glucose as possible in the presence of high glucose levels.

'''Mechanism of Glucokinase:'''

<references/>

{{STRUCTURE_1glk| PDB=1glk | SCENE=Kyle_Schroering_Sandbox/Glucokinase/1 }}

The Structure and Mechanism of Hexokinase

2010-03-01T08:21:44Z

Kyle Schroering:

==The Structure and Mechanism of Glucokinase (Hexokinase D)==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate. Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level. Glucokinase can also phosporylate other proteins, specifically hexoses. Glucokinase is inhibited by glucokinase regulatory protein, which becomes active in low glucose environments.

'''General Hexokinase Structure:''' This monomeric enzyme contains 17 alpha helices and 11 beta sheets The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet.The crevice indicates the ATP-binding domain of this glycolytic enzyme.
The hexokinase molecule has two distinct conformations, <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>open</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>closed</scene>, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accomodate ATP. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

<references/>

{{STRUCTURE_1glk| PDB=1glk | SCENE=Kyle_Schroering_Sandbox/Glucokinase/1 }}

The Structure and Mechanism of Hexokinase

2010-03-01T08:20:54Z

Kyle Schroering:

<applet load='1glk' size='300' frame='true' align='right' caption='Insert caption here' />==The Structure and Mechanism of Glucokinase (Hexokinase D)==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate. Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level. Glucokinase can also phosporylate other proteins, specifically hexoses. Glucokinase is inhibited by glucokinase regulatory protein, which becomes active in low glucose environments.

'''General Hexokinase Structure:''' This monomeric enzyme contains 17 alpha helices and 11 beta sheets The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet.The crevice indicates the ATP-binding domain of this glycolytic enzyme.
The hexokinase molecule has two distinct conformations, <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>open</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>closed</scene>, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accomodate ATP. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

<references/>

{{STRUCTURE_1glk| PDB=1glk | SCENE=Kyle_Schroering_Sandbox/Glucokinase/1 }}

The Structure and Mechanism of Hexokinase

2010-03-01T08:20:03Z

Kyle Schroering:

==The Structure and Mechanism of Glucokinase (Hexokinase D)==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate. Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level. Glucokinase can also phosporylate other proteins, specifically hexoses. Glucokinase is inhibited by glucokinase regulatory protein, which becomes active in low glucose environments.

'''General Hexokinase Structure:''' This monomeric enzyme contains 17 alpha helices and 11 beta sheets The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet.The crevice indicates the ATP-binding domain of this glycolytic enzyme.
The hexokinase molecule has two distinct conformations, <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>open</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>closed</scene>, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accomodate ATP. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

<references/>

{{STRUCTURE_1glk| PDB=1glk | SCENE=Kyle_Schroering_Sandbox/Glucokinase/1 }}

The Structure and Mechanism of Hexokinase

2010-03-01T08:18:20Z

Kyle Schroering:

==The Structure and Mechanism of Glucokinase (Hexokinase D)==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate. Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level. Glucokinase can also phosporylate other proteins, specifically hexoses. Glucokinase is inhibited by glucokinase regulatory protein, which becomes active in low glucose environments.

'''General Hexokinase Structure:''' This monomeric enzyme contains 17 alpha helices and 11 beta sheets The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet.The crevice indicates the ATP-binding domain of this glycolytic enzyme.
The hexokinase molecule has two distinct conformations, <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>open</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>closed</scene>, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accomodate ATP. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

<references/>

{{STRUCTURE_1glk | PDB=1glk | SCENE=Kyle_Schroering_Sandbox/Glucokinase/1 }}

The Structure and Mechanism of Hexokinase

2010-03-01T08:17:03Z

Kyle Schroering:

==The Structure and Mechanism of Glucokinase (Hexokinase D)==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate. Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level. Glucokinase can also phosporylate other proteins, specifically hexoses. Glucokinase is inhibited by glucokinase regulatory protein, which becomes active in low glucose environments.

'''General Hexokinase Structure:''' This monomeric enzyme contains 17 alpha helices and 11 beta sheets The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet.The crevice indicates the ATP-binding domain of this glycolytic enzyme.
The hexokinase molecule has two distinct conformations, <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>open</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>closed</scene>, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accomodate ATP. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

<references/>

{{STRUCTURE_1glk | PDB=1glk | SCENE=Kyle_Schroering_Sandbox/Glucokinase/1}}

The Structure and Mechanism of Hexokinase

2010-03-01T08:10:58Z

Kyle Schroering:

==The Structure and Mechanism of Glucokinase (Hexokinase D)==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate. Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level. Glucokinase can also phosporylate other proteins, specifically hexoses. Glucokinase is inhibited by glucokinase regulatory protein, which becomes active in low glucose environments.

'''General Hexokinase Structure:''' This monomeric enzyme contains 17 alpha helices and 11 beta sheets The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet.The crevice indicates the ATP-binding domain of this glycolytic enzyme.
The hexokinase molecule has two distinct conformations, <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>open</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>closed</scene>, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accomodate ATP. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

<references/>

{{STRUCTURE_3cin | PDB=3cin | SCENE= }}

The Structure and Mechanism of Hexokinase

2010-03-01T08:09:14Z

Kyle Schroering:

==The Structure and Mechanism of Glucokinase (Hexokinase D)==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate. Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level. Glucokinase can also phosporylate other proteins, specifically hexoses. Glucokinase is inhibited by glucokinase regulatory protein, which becomes active in low glucose environments.

'''General Hexokinase Structure:''' This monomeric enzyme contains 17 alpha helices and 11 beta sheets The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet.The crevice indicates the ATP-binding domain of this glycolytic enzyme.
The hexokinase molecule has two distinct conformations, <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>open</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>closed</scene>, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accomodate ATP. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

<references/>

{{STRUCTURE_1glk | PDB=1glk | SCENE= }}

The Structure and Mechanism of Hexokinase

2010-03-01T08:07:26Z

Kyle Schroering:

==The Structure and Mechanism of Glucokinase (Hexokinase D)==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate. Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level. Glucokinase can also phosporylate other proteins, specifically hexoses. Glucokinase is inhibited by glucokinase regulatory protein, which becomes active in low glucose environments.

'''General Hexokinase Structure:''' This monomeric enzyme contains 17 alpha helices and 11 beta sheets The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet.The crevice indicates the ATP-binding domain of this glycolytic enzyme.
The hexokinase molecule has two distinct conformations, <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>open</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>closed</scene>, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accomodate ATP. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein. 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.

{{STRUCTURE_1glk | PDB=1glk | SCENE= }}

The Structure and Mechanism of Hexokinase

2010-03-01T07:58:37Z

Kyle Schroering:

==The Structure and Mechanism of Glucokinase (Hexokinase D)==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate. Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level. Glucokinase can also phosporylate other proteins, specifically hexoses. Glucokinase is inhibited by glucokinase regulatory protein, which becomes active in low glucose environments.

'''General Hexokinase Structure:''' This monomeric enzyme contains The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet.The crevice indicates the ATP-binding domain of this glycolytic enzyme.
The hexokinase molecule has two distinct conformations, <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>open</scene> and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>closed</scene>, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accomodate ATP. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein.

{{STRUCTURE_1glk | PDB=1glk | SCENE= }}

The Structure and Mechanism of Hexokinase

2010-03-01T07:57:28Z

Kyle Schroering:

==The Structure and Mechanism of Glucokinase (Hexokinase D)==

Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut and brain. It serves to regulate glucose levels in these organs. Glucokinase uses phosphorylation to increase the metabolism of glucose. Glucokinase is a hexokinase isoenzyme All hexokinases are capable of prompting the first step of glycogen synthesis and glycolysis, the phosphorylation of glucose to glucose-6-phosphate. Glucokinase is unique from other hexokinase in kinetic properties and is coded by a different gene. The reduced affinity for glucose allows the activity of glucokinase to differ under physiological conditions according to the amount of glucose present.

'''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<ref>PMID:15016359 </ref>. 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<ref>PMID:11237213</ref>. Glucokinase is the first step in this reaction. Insulin then allows other cells in the body to take up glucose, actively lowering the glucose level. Glucokinase can also phosporylate other proteins, specifically hexoses. Glucokinase is inhibited by glucokinase regulatory protein, which becomes active in low glucose environments.

'''General Hexokinase Structure:''' This monomeric enzyme contains The tertiary structure of hexokinase includes an open alpha/beta sheet. There is a large amount of variation associated with this structure. It is composed of five beta sheets and three alpha helices. In this open alph/beta sheet four of the beta sheets are parallel and one is in the anitparallel directions. The alpha helices and beta loops connect the beta sheets to produce this open alpha/beta sheet.The crevice indicates the ATP-binding domain of this glycolytic enzyme.
The hexokinase molecule has two distinct conformations, <scene name='Kyle_Schroering_Sandbox/Open_conformation/1'>open</scene>and <scene name='Kyle_Schroering_Sandbox/Closed_conformation/1'>closed</scene>, and the conformational fluctuation between the two states involves relative motion of the two domains or two halves of the protein. In the open conformation, the molecule has a low affinity for both the glucose molecule and the ATP molecule. The binding of one of the molecules, say glucose, shifts the equilibrium to the closed conformation of the protein, which has a higher affinity for ATP because now the ATP binding site has the correct conformation to accomodate ATP. By the same reasoning, if ATP were to bind first, that would also shift the equilibrium to the closed conformation and hence increase the affinity for glucose. Therefore the binding of glucose and ATP are coupled and this kind of conformational coupling makes hexokinase an allosteric protein.

{{STRUCTURE_3cin | PDB=3cin | SCENE= }}

The Structure and Mechanism of Hexokinase

2010-03-01T07:32:41Z

Kyle Schroering:

The Structure and Mechanism of Hexokinase

2010-03-01T06:06:01Z

Kyle Schroering:

The Structure and Mechanism of Hexokinase

2010-03-01T05:36:38Z

Kyle Schroering:

The Structure and Mechanism of Hexokinase

2010-03-01T05:29:05Z

Kyle Schroering:

The Structure and Mechanism of Hexokinase

2010-03-01T05:27:42Z

Kyle Schroering:

The Structure and Mechanism of Hexokinase

2010-03-01T05:17:28Z

Kyle Schroering: New page: ==The Structure and Mechanism of Glucokinase (Hexokinase D)== Glucokinase (hexokinase D) is a monomeric cytoplasmic enzyme found in the liver and pancreas but can also be found in the gut...

Kyle Schroering Sandbox 1

2010-02-19T14:54:18Z

Kyle Schroering:

==The Mechanism of Trypsin==

Trypsin structure contains an aspartate residue (189) in its catalytic pocket that is used to attract and stabilize the positively charged lysine and/or arginine. Therefore, the aspartate residue is responsible for the specificity of the enzyme. Trypsin cleaves protein on the carboxyl end of lysine and arginine except when they are bound to proline. Once in the small intestine, the enzyme enteropeptidase activates it into trypsin by proteolytic cleavage. The cleavage occurs within the polypeptide chain rather than at the terminal amino acids located at the ends of polypeptides.

[[2age]]<ref>PMID:16636277</ref>.

{{STRUCTURE_2age | PDB=2age | SCENE= }}

<references/>

Kyle Schroering Sandbox 1

2010-02-19T14:51:37Z

Kyle Schroering:

Kyle Schroering Sandbox 1

2010-02-19T14:48:38Z

Kyle Schroering:

Kyle Schroering Sandbox 1

2010-02-19T14:46:23Z

Kyle Schroering: New page: ==The Mechanism of Trypsin== {{STRUCTURE_2age | PDB=2age | SCENE= }}

==The Mechanism of Trypsin==

{{STRUCTURE_2age | PDB=2age | SCENE= }}