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{{STRUCTURE_1hkc | PDB=1hkc | SCENE= }} | {{STRUCTURE_1hkc | PDB=1hkc | SCENE= }} | ||
== Hexokinase | == Structure of Hexokinase == | ||
Hexokinase type I is composed of an N-terminal regulatory domain and a C-terminal catalytic domain. These two domains are joined together by an alpha helix. The molecular weights of hexokinases are around 100 kD. Each domain weighs about 50kD and contains a glucose binding site. But, only in hexokinase II do both halves have functional active sites. 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. | Hexokinase type I is composed of an N-terminal regulatory domain and a C-terminal catalytic domain. These two domains are joined together by an alpha helix. The molecular weights of hexokinases are around 100 kD. Each domain weighs about 50kD and contains a glucose binding site. But, only in hexokinase II do both halves have functional active sites. 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. | ||
[[Image:Hexokinase_mechanism2.GIF|350px|left|thumb]] | [[Image:Hexokinase_mechanism2.GIF|350px|left|thumb]] | ||
== Mechanism of Hexokinase | == 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. Hexokinase catalyzes this phosphoryl group transfer. To start this reaction, ATP forms a complex with magnesium (II) ion and glucose binds to kexokinase. The magnesium-ATP complex then binds with the hexokinase-glucose complex and forms an intermediate (Zeng, et al. present a picture showing the interctions of brain hexokinase with ATP). The hydroxyl group on the terminal phosphoryl group of the ATP molecule nucleophilically attacks the carbon 6 on glucose. This produces glucose-6-phosphate still bound to hexokinase and ADP still in complex with magnesium ion [5]. Glucose-6-phosphate and the magnesium-ADP complex leave hexokinase. Glucose-6-phosphate and ADP are the products of this reaction. Hexokinase undergoes an induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP. It also experiences potent allosteric inhibition under physiological concentrations by its immediate products, glucose-6-phosphate [4]. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled. | |||
== Kinetics and Inhibition of Hexokinase == | |||
Hexokinase activates glycoloysis by phosphorylating glucose. Since the phosphorylation of glucose to glucose-6-phosphate is the rate limiting step of glucose metabolism, hexokinase has a very important job in regulating healthy glucose levels in the human body [7]. Hexokinase has high affinity, thus a low Km, for glucose. Tisssues where hexokinase is present use glucose at low blood serum levels. G6P inhibits hexokinase by binding to the N-terminal domain(this is simple feedback inhibition). If the cell is not using the G6P that it is making, then it stops making it. In this way, hexokinase can also slow down glycolysis. Hexokinase I is thought to be the "pacemaker of glycolysis in brain tissue and red blood cells [4]. | |||