Hexokinase: Difference between revisions

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Ann Taylor, Michal Harel, Alexander Berchansky, Karsten Theis

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-'''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.
+<StructureSection load='1qha' size='350' side='right' scene='' caption='Hexokinase I complex with ATP analog, glucose, glucose-phosphate and Mg+2 ion (PDB code [[1qha]])'>
+__TOC__
+== Function ==
+'''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.  See [[Glycolysis Enzymes]], [[Glycogenesis]].
--Hexokinase I/A is found in all mammalian tissues, and is considered a "housekeeping enzyme," unaffected by most physiological, hormonal, and metabolic changes. More details in [[Hexokinase Type 1]].
+* '''Hexokinase I/A''' is found in all mammalian tissues, and is considered a "housekeeping enzyme," unaffected by most physiological, hormonal, and metabolic changes. More details in [[Hexokinase Type 1]].
--Hexokinase II/B constitutes the principal regulated isoform in many cell types and is increased in many cancers.
+* '''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 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'''.
+* '''Hexokinase IV/D''' is also known as '''glucokinase'''.
-Additional details in [[The Structure and Mechanism of Hexokinase]].
+Additional details in [[The Structure and Mechanism of Hexokinase]], [[Glucokinase and Phosphorylase. Conformational changes (Spanish)]]  and [[Conformational changes in proteins]] (in Spanish).
-{{STRUCTURE_1qha|  PDB=1qha  | SIZE=400| SCENE= |right|   CAPTION=Human hexokinase 1 complex with glucose and phosphate, [[1qha]] }}
+== Structure of Hexokinase ==
+Hexokinase is composed of an N-terminal regulatory domain and a C-terminal catalytic domain. These two domains are <scene name='Bawel_sandbox1/Hexokinase/2'>joined together by an alpha helix</scene>. The molecular weights of hexokinases are around 100 kD. Each domain weighs about 50kD and contains a <scene name='Bawel_sandbox1/Glucose_binding_site/1'>glucose binding site</scene>. 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 <scene name='Bawel_sandbox1/5_beta_sheets/3'>five beta sheets and two alpha helices</scene>. 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.
+[[Image:Hexokinase_mechanism2.GIF|350px|left|thumb]]
+{{Clear}}
+== Conformational change associated with substrate binding ==
-== Structure of Hexokinase ==
+When hexokinase binds to glucose (one of its two substrates), it exhibits induced fit. This means that in the open form of the enzyme, the binding site is not fully formed. Upon binding glucose, hexokinase switches into a closed form, excluding aqueous solvent from the substrate. This is illustrated here <scene name='45/452482/Induced_fit/2'>comparing the structures of free and glucose-bound hexokinase</scene>.
-Hexokinase is composed of an N-terminal regulatory domain and a C-terminal catalytic domain. These two domains are <scene name='Bawel_sandbox1/Hexokinase/2'>joined together by an alpha helix</scene>. The molecular weights of hexokinases are around 100 kD. Each domain weighs about 50kD and contains a <scene name='Bawel_sandbox1/Glucose_binding_site/1'>glucose binding site</scene>. 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 <scene name='Bawel_sandbox1/5_beta_sheets/3'>five beta sheets and two alpha helices</scene>. 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.
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-[[Image:Hexokinase_mechanism2.GIF|350px|left|thumb]]
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+</jmol> <ref>The [[Jmol/Storymorph|Storymorph Jmol scripts]] creates the interpolated coordinates of the morph on the fly.</ref>.
 == 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 hexokinase. 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). <scene name='Bawel_sandbox1/Asp_532_and_thr_680/2'>Asp 532 and Thr 680</scene> are thought to be involved in binding the magnesium ion in the magnesium-ATP complex [4]. The hydroxyl group on the terminal phosphoryl group of the ATP molecule nucleophilically attacks 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 ==
@@ Line 32: / Line 67: @@
 ==3D structures of hexokinase==
+[[Hexokinase 3D structures]]
-[[3o08]], [[3o1b]], [[3o1w]], [[3o4w]], [[3o6w]], [[3o80]] – KlHK – ''Kluyveromyces lactis''<br />
+</StructureSection>
-[[2e2n]] – StHK – ''Sulfolobus tokodaii''<br />
-[[2e2o]] - StHK + glucose<br />
-[[2e2p]] – StHK + ADP<br />
-[[2e2q]] - StHK + ADP + xylose + Mg<br />
-[[3o5b]], [[3o8m]] – KlHK + glucose<br />
-[[1bdg]] – HK + glucose – ''Schistosoma mansoni''
-===Hexokinase I===
-[[3b8a]] – yHK I + glucose – yeast<br />
-[[1hkg]] – yHK I<br />
-[[1dgk]] – hHK I (mutant) + ADP + glucose – human<br />
-[[1cza]] - hHK I (mutant) + ADP + glucose-6-phosphate + glucose<br />
-[[1bg3]] - HK I + glucose-6-phosphate + glucose - rat<br />
-[[1qha]] – hHK I + AMP-PNP<br />
-[[1hkc]] - hHK I + phosphate + glucose<br />
-[[1hkb]] - hHK I + glucose-6-phosphate + glucose<br />
-===Hexokinase II===
-[[1ig8]], [[2yhx]] – yHK II<br />
-[[2nzt]] – hHK II
-===Hexokinase III===
-[[3hm8]] – hHK III C terminal
-===Hexokinase IV (Glucokinase GK)===
-[[3qic]] – hHK IV residues 12-465 (mutant) <br />
-[[1v4t]] – hGK <br />
-[[3mcp]] – GK – ''Parabacterioides distasonis''<br />
-[[2qm1]] – GK – ''Enterococcus faecalis''<br />
-[[3vgk]] – SgGK – ''Streptomyces griseus''<br />
-[[1q18]] – EcGK – ''Escherichia coli''<br />
-[[4eun]] – GK – ''Janibacter''<br />
-[[3vov]] – GK – ''Thermus thermophilus''
-''Hexokinase IV binary complex''
-[[1sz2]] - EcGK + glucose<br />
-[[3vgm]] - SgGK + glucose<br />
-[[3idh]] - hHK IV residues 12-465 + glucose<br />
-[[3h1v]], [[3imx]], [[3a0i]], [[3goi]],[[1v4s]], [[3s41]], [[3vev]], [[3vf6]], [[4dch]], [[4dhy]] - hHK IV residues 12-465 + synthetic activator<br />
-[[3fr0]] - hHK IV residues 12-465 + activator<br />
-''Hexokinase IV ternary complex''
-[[3id8]], [[3fgu]] - hHK IV residues 12-465 + AMP-PNP + glucose<br />
-[[3f9m]] - hHK IV residues 12-465 + activator + glucose<br />
-[[2q2r]] - GK + glucose + ADP – ''Trypanosoma cruzi''<br />
-[[3vgl]] - SgGK + glucose + AMP-PNP<BR />
-[[3vey]] - hGK + glucose + ATPgS
-===ADP-dependent GK===
-[[1gc5]] – AGK + ADP – ''Thermococcus litoralis''<br />
-[[1l2l]] – AGK – ''Pyrococcus horikoshii''<br />
-[[1ua4]] - AGK – ''Pyrococcus furiosus''
 ==Additional Resources==
 For additional information, see: [[Carbohydrate Metabolism]]
 ==References==
@@ Line 114: / Line 90: @@
 .↑ Aleshin A, Malfois M, Liu X, Kim C, Fromm H, Honzatko R, Koch M, Svergun D. Nonaggregating Mutant of Recombinant Human Hexokinase I Exhibits Wild-Type Kinetics and Rod-like Conformations in Solution. Biochem. 1999 Apr 29;38:8359-8366.
+<references/>
 Seth Bawel and Kyle_Schroering created this page in Che 361 at Wabash College.
 [[Category:Topic Page]]