Hexokinase
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2008-06-18T10:47:08Z
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{|align="right"
|-
|{{Protbox
| Name = Hexokinase 1
|Photo=
|Caption=
| HGNCid = 4922
| Symbol = HK1
|AltSymbols =
| Chromosome = 10
| Arm = q
| Band = 22
| LocusSupplementaryData =
|Gene=
|Gene_type=
|Protein_length=
|Molecular_weight=
|Structure=
|Type=
|Functions=
|Domains=
|Motifs=
|Alternative_products=4 known [[isoforms]] created by alternate splicing
|Catalytic_activity=[[adenosine triphosphate|ATP]] + D-[[hexose]] = [[adenosine diphosphate|ADP]] + D-[[hexose]] 6-[[phosphate]]
|Cofactors=
|Enzyme_regulation= inhibited by its product [[glucose-6-phosphate|Glc-6-P]]
|Km=
|Vmax=
|Biophysicochemical_properties=
|Diseases=[[Hexokinase deficiency]] {{OMIM|235700}}
|Pharmaceuticals=
|Biotechnology=
|Taxa=''[[H. sapiens]]''; [[Homologous series|homologs]] in many taxa, spanning several [[domains]]
|Cells=
|Location=Primary:[[Cytoplasm]]; Secondary:[[Mitochondrion]], [[Plasma membrane]]
|Mods=
|Names=
|Pathways=
|Interactions=
|Actions=
|Agonists=
|Antagonists=
|Accession_numbers=
| EntrezGene = 3098
| OMIM = 142600
| RefSeq = NM_000188
| UniProt = P19367
|PDB =
| ECnumber = 2.7.1.1
|Codes=
|Review=
|Pages=
}}
|-
|{{Protbox
| Name = hexokinase 2
| caption =
| image =
| width =
| HGNCid = 4923
| Symbol = HK2
| AltSymbols =
| EntrezGene = 3099
| OMIM = 601125
| RefSeq = NM_000189
| UniProt = P52789
| PDB =
| ECnumber = 2.7.1.1
| Chromosome = 2
| Arm = p
| Band = 13
| LocusSupplementaryData =
}}
|-
|{{Protbox
| Name = hexokinase 3 (white cell)
| caption =
| image =
| width =
| HGNCid = 4925
| Symbol = HK3
| AltSymbols =
| EntrezGene = 3101
| OMIM = 142570
| RefSeq = NM_002115
| UniProt = P52790
| PDB =
| ECnumber = 2.7.1.1
| Chromosome = 5
| Arm = q
| Band = 35.2
| LocusSupplementaryData =
}}
|}
[[Image:Hexokinase.png|thumb|Hexokinase: 1st glycolysis enzyme. Left: without glucose (shown the Glc binding pocket) (PDB code=1hkg). Right: with glucose (PDB code=2yhx) ]]
A '''hexokinase''' is an [[enzyme]] that [[phosphorylation|phosphorylates]] a six-carbon [[sugar]], a [[hexose]], to a hexose phosphate. In most tissues and organisms, [[glucose]] is the most important [[substrate (biochemistry)|substrate]] of hexokinases, and [[glucose-6-phosphate]] the most important product.
==Variation across species==
Hexokinases have been found in every organism checked, ranging from [[bacterium|bacteria]], [[yeast]], and [[plant]]s to humans and other [[vertebrate]]s. They are categorized as ''actin fold'' proteins, sharing a common [[adenosine triphosphate|ATP]] binding site core surrounded by more variable sequences that determine substrate affinities and other properties. Several hexokinase isoforms or [[isozyme]]s providing different functions can occur in a single [[species]].
==Reaction==
The intracellular reactions mediated by hexokinases can be typified as:
:Hexose-CH<sub>2</sub>OH + MgATP<sup>=</sup> → Hexose-CH<sub>2</sub>O-PO<sub>3</sub><sup>=</sup> + MgADP<sup>-</sup> + H<sup>+</sup>
where Hexose-CH<sub>2</sub>OH represents any of several hexoses (like glucose) that contain an accessible -CH<sub>2</sub>OH moiety.
==Consequences of hexose phosphorylation==
Phosphorylation of a hexose (such as glucose) often commits it to a limited number of intracellular metabolic processes (such as [[glycolysis]] or [[glycogen]] synthesis). This is aided by the fact that phosphorylation also makes it unable to move or be transported out of the cell.
==Size of different isoforms==
Most bacterial hexokinases are approximately 50kD in size. Multicellular organisms such as plants and animals often have more than one hexokinase isoform. Most are about 100kD in size, and consist of two halves (N and C terminal), which share much sequence homology. This suggests an evolutionary origin by duplication and fusion of a 50kD ancestral hexokinase similar to those of bacteria.
==Types of mammalian hexokinase==
There are four important [[mammal]]ian hexokinase isozymes ({{EC number|2.7.1.1}}) that vary somewhat in their subcellular locations, kinetic characteristics with respect to different substrates and operating conditions, and physiological function. They are designated hexokinases I, II, III, and IV or hexokinases A, B, C, and D.
===Hexokinases I, II, and III===
Hexokinases I, II, and III are referred to as "low-K<sub>m</sub>" isozymes because of a high affinity for glucose even at low concentrations (below 1 mM). Hexokinases I and II follow [[Michaelis-Menten kinetics]] at physiologic concentrations of substrates. All three are strongly [[Enzyme inhibitor|inhibited]] by their product, [[glucose-6-phosphate]]. [[Molecular weight]]s are around 100 kD. Each consists of two similar 50kD halves, but only in hexokinase II do both halves have functional active sites.
* Hexokinase I (hexokinase A) is found in all mammalian tissues, and is considered a "housekeeping enzyme," unaffected by most physiological, hormonal, and metabolic changes.
* Hexokinase III (or C) is inhibited by excessive glucose (substrate inhibition).
===Hexokinase IV ("glucokinase")===
Mammalian hexokinase IV, also referred to as [[glucokinase]], has unique characteristics and functions compared to other hexokinases.
* The location of the [[phosphorylation]] on a subcellular level occurs when [[glucokinase]] translocates between the [[cytoplasm]] and [[Cell nucleus|nucleus]] of [[liver]] cells. Glucokinase can only phosphorylate glucose if the concentration of this substrate is high enough; its Km for glucose is 100 times higher than that of hexokinases I, II, and III.
* It is monomeric, about 50kD, displays positive cooperativity with glucose, and is not [[allosterically]] inhibited by its product, glucose-6-phosphate.
It is present in the [[liver]], [[pancreas]], [[hypothalamus]], [[small intestine]], and perhaps certain other [[neuroendocrine]] cells, and plays an important regulatory role in [[carbohydrate metabolism]].
* In the [[beta cell]]s of the pancreatic [[islets of Langerhans|islet]]s, it serves as a glucose sensor to control [[insulin]] release, and similarly controls [[glucagon]] release in the [[alpha cell]]s.
* In [[hepatocyte]]s of the liver, glucokinase responds to changes of ambient glucose levels by increasing or reducing glycogen synthesis.
==Hexokinase in glycolysis==
The use of glucose as an energy source in cells is via the [[metabolic pathway]] known as [[glycolysis]]. The first step of this sequence of reactions is the [[phosphorylation]] of glucose by hexokinase to prepare it for later breakdown in order to provide energy.
{{Enzymatic Reaction
|foward_enzyme=[[Hexokinase]]
|reverse_enzyme=
|substrate=<small>D</small>-[[Glucose]]
|product=α-<small>D</small>-[[Glucose-6-phosphate]]
|reaction_direction_(foward/reversible/reverse)=foward
|minor_foward_substrate(s)=[[adenosine triphosphate|ATP]]
|minor_foward_product(s)=[[adenosine diphosphate|ADP]]
|minor_reverse_substrate(s)=
|minor_reverse_product(s)=
|substrate_image=Glucose_wpmp.png
|product_image=Glucose-6-phosphate_wpmp.png
}}
{{KEGG compound|C00031}} {{KEGG enzyme|2.7.1.1}} {{KEGG compound|C00668}} {{KEGG reaction|R01786}}
The major reason for the immediate phosphorylation of glucose by a hexokinase is to prevent diffusion out of the cell. The phosphorylation adds a charged [[phosphate]] group so the [[glucose 6-phosphate]] cannot easily cross the cell membrane.
==Association to mitochondria==
Hexokinases I, II, and III can associate physically to the outer surface of the external membrane of [[mitochondria]] through specific binding to a porin (or Voltage Dependent Anion Channel). This association confers hexokinase direct access to mitochondrially-generated ATP, which is one of the two substrates of hexokinase. Mitochondrial hexokinase is highly elevated in rapidly-growing malignant tumor cells, with levels up to 200 times higher than normal tissues. Mitochondrially-bound hexokinase has been demonstrated to be the driving force<ref>{{cite journal |author=Bustamante E, Pedersen P |title=High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase |journal=Proc Natl Acad Sci U S A |volume=74 |issue=9 |pages=3735–9 |year=1977 |pmid=198801 |url=http://www.pnas.org/cgi/reprint/74/9/3735 |doi=10.1073/pnas.74.9.3735}}</ref> for the extremely high glycolytic rates that take place aerobically in tumor cells (the so-called Warburg effect described by [[Otto Warburg]] in 1930).
== See also ==
*[[glucokinase]]
*[[glycolysis]]
*[[glycogen]]
*[[insulin]]
* [[Glucose 6-phosphatase]]
==References==
<references/>
{{glycolysis}}
{{Kinases}}
{{Glycolysis enzymes}}
[[Category:EC 2.7.1]]
[[es:Hexoquinasa]]
[[de:Glucokinase]]
[[fr:Hexokinase]]
[[he:הקסוקינאז]]
[[it:Esochinasi]]
[[ru:Гексокиназа]]
[[zh:六碳醣激酶]]