Explain hexokinase induced fit .
it 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 manycancers
-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 anopen 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. 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. 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.
Active SitesThe active site residues for Hexokinase are Asp205, Lys169, Asn204, Glu256,and Thr168.These residues are located in the deep cleft at the interface between the two lobes. This active site is capable of bonding two ligands, glucose, and glucose-6-phosphate. Hexokinase undergoes an induced fit conformational change when glucose binds. This conformational change prevents the hydrolysis of ATP, and is allosterically inhibited by physiological concentrations of glucose-6-phosphate the product. Hexokinase has two conformational states. The open state occurs prior to glucose binding. ATP is bound to the large lobe, but is far away from the glucose binding site, and in a different position than it assumes in the active site. When the glucose binds to Hexokinase a large conformational change occurs. This change closes the two lobes around the glucose substrate. This conformational state is referred to as the closed state.
it 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 manycancers
-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 anopen 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. 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. 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.
Active SitesThe active site residues for Hexokinase are Asp205, Lys169, Asn204, Glu256,and Thr168.These residues are located in the deep cleft at the interface between the two lobes. This active site is capable of bonding two ligands, glucose, and glucose-6-phosphate. Hexokinase undergoes an induced fit conformational change when glucose binds. This conformational change prevents the hydrolysis of ATP, and is allosterically inhibited by physiological concentrations of glucose-6-phosphate the product. Hexokinase has two conformational states. The open state occurs prior to glucose binding. ATP is bound to the large lobe, but is far away from the glucose binding site, and in a different position than it assumes in the active site. When the glucose binds to Hexokinase a large conformational change occurs. This change closes the two lobes around the glucose substrate. This conformational state is referred to as the closed state.
