View source for Hexokinase

{{enzyme
| Name = Hexokinase
| EC_number = 2.7.1.1
| CAS_number = 9001-51-8
| IUBMB_EC_number = 2/7/1/1
| GO_code = 0004396
| image = Hexokinase_3O08.png
| width =
| caption  =Crystal structures of hexokinase 1 from ''[[Kluyveromyces lactis]]''.<ref name="Kuettner_2010">{{PDB|3O08}}; {{cite journal |vauthors=Kuettner EB, Kettner K, Keim A, Svergun DI, Volke D | title = Crystal structure of dimeric KlHxk1 in crystal form I | doi=10.2210/pdb3o08/pdb | year = 2010}}</ref>
}}
{{infobox protein
| Name = [[HK1|hexokinase 1]]
| caption =
| image =
| width =
| HGNCid = 4922
| Symbol = [[HK1]]
| AltSymbols =
| EntrezGene = 3098
| OMIM = 142600
| RefSeq = NM_000188
| UniProt = P19367
| PDB =
| ECnumber =
| Chromosome = 10
| Arm = q
| Band = 22
| LocusSupplementaryData =
}}
{{infobox protein
| Name = [[HK2|hexokinase 2]]
| caption =
| image =
| width =
| HGNCid = 4923
| Symbol = [[HK2]]
| AltSymbols =
| EntrezGene = 3099
| OMIM = 601125
| RefSeq = NM_000189
| UniProt = P52789
| PDB =
| ECnumber =
| Chromosome = 2
| Arm = p
| Band = 13
| LocusSupplementaryData =
}}
{{infobox protein
| Name = [[HK3|hexokinase 3 (white cell)]]
| caption =
| image =
| width =
| HGNCid = 4925
| Symbol = [[HK3]]
| AltSymbols =
| EntrezGene = 3101
| OMIM = 142570
| RefSeq = NM_002115
| UniProt = P52790
| PDB =
| ECnumber =
| Chromosome = 5
| Arm = q
| Band = 35.2
| LocusSupplementaryData =
}}
{{Infobox protein family
| Symbol = Hexokinase_1
| Name = Hexokinase_1
| image = PDB 1v4t EBI.jpg
| width = 
| caption = crystal structure of human glucokinase
| Pfam = PF00349
| Pfam_clan = CL0108 
| InterPro = IPR022672
| SMART = 
| PROSITE = PDOC00370
| MEROPS = 
| SCOP = 1cza
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
{{Infobox protein family
| Symbol = Hexokinase_2
| Name = Hexokinase_2
| image = PDB 1bg3 EBI.jpg
| width = 
| caption = rat brain hexokinase type i complex with glucose and inhibitor glucose-6-phosphate
| Pfam = PF03727
| Pfam_clan = CL0108 
| InterPro = IPR022673
| SMART = 
| PROSITE = PDOC00370
| MEROPS = 
| SCOP = 1cza
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
A '''hexokinase''' is an [[enzyme]] that [[phosphorylation|phosphorylates]] hexoses (six-carbon [[sugar]]s), forming hexose phosphate. In most organisms, [[glucose]] is the most important [[substrate (biochemistry)|substrate]] of hexokinases, and [[glucose-6-phosphate]] is the most important product. Hexokinase possesses the ability to transfer an inorganic phosphate group from ATP to a substrate.

Hexokinases should not be confused with [[glucokinase]], which is a specific isoform of hexokinase.  While other hexokinases are capable of phosphorylating several hexoses, glucokinase acts with a 50-fold lower substrate affinity and its only hexose substrate is glucose.

==Variation==
Genes that encode hexokinase have been discovered in every domain of life, and exist among a variety of species that range from [[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 that is surrounded by more variable sequences which determine substrate affinities and other properties.

Several hexokinase isoforms or [[isozyme]]s that provide 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{{su|p=2&minus;}} → Hexose-CH<sub>2</sub>O-PO{{su|b=3|p=2&minus;}} + MgADP{{su|p=&minus;}} + 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.
[[File:Hexokinase-glucose.png|Action of Hexokinase on Glucose]]

==Consequences of hexose phosphorylation==
Phosphorylation of a hexose such as glucose often limits it to a number of intracellular metabolic processes, such as [[glycolysis]] or [[glycogen]] synthesis. This is because phosphorylated hexoses are charged, and thus more difficult to transport out of a cell.

In patients with [[essential fructosuria]], metabolism of fructose by hexokinase to fructose-6-phosphate is the primary method of metabolizing dietary fructose; this pathway is not significant in normal individuals.

==Size of different isoforms==
Most bacterial hexokinases are approximately 50 kD in size. Multicellular organisms including  plants and animals often have more than one hexokinase isoform. Most are about 100 kD 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 in subcellular locations and kinetics with respect to different substrates and 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 (below 1 mM). Hexokinases I and II follow [[Michaelis-Menten kinetics]] at physiologic concentrations of substrates.{{citation needed|date=April 2016}} 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/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. It is the hexokinase found in muscle and heart. Hexokinase II is also located at the mitochondria outer membrane so it can have direct access to ATP.<ref>{{cite web|url=http://www.uniprot.org/uniprot/P52789#subcellular_location|website=uniprot.org|title=Hexokinase data on Uniprot}}</ref>
* Hexokinase III/C is substrate-inhibited by glucose at physiologic concentrations. Little is known about the regulatory characteristics of this isoform.

===Hexokinase IV ("glucokinase")===
Mammalian hexokinase IV, also referred to as [[glucokinase]], differs from other hexokinases in kinetics and functions.

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.

Hexokinase IV is monomeric, about 50kD, displays positive cooperativity with glucose, and is not [[allosterically]] inhibited by its product, glucose-6-phosphate.

Hexokinase IV 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.

==In glycolysis==
Glucose is unique in that it can be used to produce ATP by all cells in both the presence and absence of molecular oxygen (O<sub>2</sub>). The first step in [[glycolysis]] is the [[phosphorylation]] of glucose by hexokinase.

{{Enzymatic Reaction
|forward_enzyme=Hexokinase
|reverse_enzyme=
|substrate=<small>D</small>-[[Glucose]]
|product=α-<small>D</small>-[[Glucose-6-phosphate]]
|reaction_direction_(forward/reversible/reverse)=forward
|minor_forward_substrate(s)=[[adenosine triphosphate|ATP]]
|minor_forward_product(s)  =[[adenosine diphosphate|ADP]]
|minor_reverse_substrate(s)=
|minor_reverse_product(s)  =
|substrate_image=D-glucose wpmp.svg
|product_image=Alpha-D-glucose-6-phosphate wpmp.png
}}
{{KEGG compound|C00031}} {{KEGG enzyme|2.7.1.1}} {{KEGG compound|C00668}} {{KEGG reaction|R01786}}

By catalyzing the phosphorylation of glucose to yield glucose 6-phosphate, hexokinases maintain the downhill concentration gradient that favors the facilitated transport of glucose into cells. This reaction also initiates all physiologically relevant pathways of glucose utilization, including [[glycolysis]] and the [[pentose phosphate pathway]].<ref>{{cite journal | doi = 10.1038/sj.onc.1209595 | last1 = Robey | first1 = RB | last2 = Hay | first2 = N | year = 2006 | title = Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt | url = | journal = Oncogene | volume = 25 | issue = 34| pages = 4683–96 | pmid = 16892082 }}</ref> The addition of a charged [[phosphate]] group at the 6-position of hexoses also ensures 'trapping' of glucose and 2-deoxyhexose glucose analogs (e.g. 2-deoxyglucose, and 2-fluoro-2-deoxyglucose) within cells, as charged hexose phosphates cannot easily cross the cell membrane.

==Association with mitochondria==
Hexokinases I and II 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 ATP generated by mitochondria, 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 |vauthors=Bustamante E, Pedersen P |title=High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase |journal=Proc Natl Acad Sci USA |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 |pmc=431708 |bibcode=1977PNAS...74.3735B}}</ref> for the extremely high glycolytic rates that take place aerobically in tumor cells (the so-called Warburg effect described by [[Otto Heinrich Warburg]] in 1930).

== Hydropathy plot ==
[[File:HydropathyPlot.jpg|thumb|400px|alt=Hydropathy plot|Hydropathy plot of hexokinase]]
The potential transmembrane portions of a protein can be detected by hydropathy analysis. A hydropathy analysis uses an algorithm that quantifies the hydrophobic character at each position along the polypeptide chain. One of the accepted [[hydropathy scales]] is that of Kyte and Doolittle which relies on the generation of hydropathy plots. In these plots, the negative numbers represent hydrophilic regions and the positive numbers represent hydrophobic regions on the y-axis. A potential transmembrane domain is about 20 amino acids long on the x-axis.

A hydropathy analysis of hexokinase in yeast has been created by these standards. It appears as if hexokinase possesses a single potential transmembrane domain located around amino acid 400. Therefore, hexokinase is most likely not an integral membrane protein in yeast.<ref>Bowen, R. A. Molecular Toolkit: Protein Hydrophobicity Plots. Colorado State University, 1998. Web. 15 Nov. 2010. <http://www.vivo.colostate.edu/molkit/index.html></ref>

== See also ==
*[[Allostery]]
*[[Enzyme catalysis]]
*[[Flexible linker]]
*[[Fluorescent glucose biosensors]]
*[[Glucokinase]]
*[[Glycolysis]]
*[[Glycogen]]
*[[Glucose 6-phosphatase]]
*[[Insulin]]
*[[Protein dynamics#Global flexibility: multiple domains|Protein domain dynamics]]
*[[Protein domain#Domains and protein flexibility|Protein flexibility]]

==References==
{{reflist}}

{{glycolysis}}
{{Glycolysis enzymes}}
{{Kinases}}
{{Enzymes}}
{{Portal bar|Molecular and Cellular Biology|border=no}}

{{Use dmy dates|date=December 2010}}

[[Category:EC 2.7.1]]
[[Category:Moonlighting proteins]]

Hexokinase deficiency is a genetic autosomal recessive disease that causes Chronic Haemolytic Anaemia.  Chronic Haemolytic Anaemia is caused by a mutation in the HK gene, which codes for the HK enzyme. The mutation causes a reduction of the HK activity, which causes hexokinase deficiency. <ref>{{cite web|title=Hexokinase deficiency|url=http://www.enerca.org/anaemias/38/hexokinase-deficiency|website=Enerca|publisher=Enerca|accessdate=04-6-17}}</ref>