Summary: Hexokinase
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Hexokinase Edit Wikipedia article
| Hexokinase | |||||||||
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Crystal structures of hexokinase 1 from Kluyveromyces lactis.[1]
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| Identifiers | |||||||||
| EC number | 2.7.1.1 | ||||||||
| CAS number | 9001-51-8 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
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| hexokinase 1 | |
|---|---|
| Identifiers | |
| Symbol | HK1 |
| Entrez | 3098 |
| HUGO | 4922 |
| OMIM | 142600 |
| RefSeq | NM_000188 |
| UniProt | P19367 |
| Other data | |
| Locus | Chr. 10 q22 |
| hexokinase 2 | |
|---|---|
| Identifiers | |
| Symbol | HK2 |
| Entrez | 3099 |
| HUGO | 4923 |
| OMIM | 601125 |
| RefSeq | NM_000189 |
| UniProt | P52789 |
| Other data | |
| Locus | Chr. 2 p13 |
| hexokinase 3 (white cell) | |
|---|---|
| Identifiers | |
| Symbol | HK3 |
| Entrez | 3101 |
| HUGO | 4925 |
| OMIM | 142570 |
| RefSeq | NM_002115 |
| UniProt | P52790 |
| Other data | |
| Locus | Chr. 5 q35.2 |
| Hexokinase_1 | |||||||||
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crystal structure of human glucokinase
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| Identifiers | |||||||||
| Symbol | Hexokinase_1 | ||||||||
| Pfam | PF00349 | ||||||||
| Pfam clan | CL0108 | ||||||||
| InterPro | IPR022672 | ||||||||
| PROSITE | PDOC00370 | ||||||||
| SCOP | 1cza | ||||||||
| SUPERFAMILY | 1cza | ||||||||
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| Hexokinase_2 | |||||||||
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rat brain hexokinase type i complex with glucose and inhibitor glucose-6-phosphate
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| Identifiers | |||||||||
| Symbol | Hexokinase_2 | ||||||||
| Pfam | PF03727 | ||||||||
| Pfam clan | CL0108 | ||||||||
| InterPro | IPR022673 | ||||||||
| PROSITE | PDOC00370 | ||||||||
| SCOP | 1cza | ||||||||
| SUPERFAMILY | 1cza | ||||||||
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A hexokinase is an enzyme that phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important 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. All hexokinases are capable of phosphorylating several hexoses but glucokinase acts with a 50-fold lower substrate affinity and its main hexose substrate is glucose.
Contents
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 plants to humans and other vertebrates. They are categorized as actin fold proteins, sharing a common ATP binding site core that is surrounded by more variable sequences which determine substrate affinities and other properties.
Several hexokinase isoforms or isozymes that provide different functions can occur in a single species.
Reaction
The intracellular reactions mediated by hexokinases can be typified as:
- Hexose-CH2OH + MgATP2−
→ Hexose-CH2O-PO2−
3 + MgADP−
+ H+
where hexose-CH2OH represents any of several hexoses (like glucose) that contain an accessible -CH2OH moiety. 
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 mammalian hexokinase isozymes (EC 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-Km" 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] All three are strongly inhibited by their product, glucose-6-phosphate. Molecular weights 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.[2]
- 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 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 cells of the pancreatic islets, it serves as a glucose sensor to control insulin release, and similarly controls glucagon release in the alpha cells. In hepatocytes 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 (O2). The first step in glycolysis is the phosphorylation of glucose by hexokinase.
| D-Glucose | Hexokinase | α-D-Glucose-6-phosphate | |
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| ATP | ADP | ||
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Compound C00031 at KEGG Pathway Database. Enzyme 2.7.1.1 at KEGG Pathway Database. Compound C00668 at KEGG Pathway Database. Reaction R01786 at KEGG Pathway Database.
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.[3] 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[4] 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
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.[5]
Deficiency
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. [6]
See also
- Allostery
- Enzyme catalysis
- Flexible linker
- Fluorescent glucose biosensors
- Glucokinase
- Glycolysis
- Glycogen
- Glucose 6-phosphatase
- Insulin
- Protein domain dynamics
- Protein flexibility
References
- ^ PDB: 3O08; Kuettner EB, Kettner K, Keim A, Svergun DI, Volke D (2010). "Crystal structure of dimeric KlHxk1 in crystal form I". doi:10.2210/pdb3o08/pdb.
- ^ "Hexokinase data on Uniprot". uniprot.org.
- ^ Robey, RB; Hay, N (2006). "Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt". Oncogene. 25 (34): 4683–96. doi:10.1038/sj.onc.1209595. PMID 16892082.
- ^ Bustamante E, Pedersen P (1977). "High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase". Proc Natl Acad Sci USA. 74 (9): 3735–9. Bibcode:1977PNAS...74.3735B. doi:10.1073/pnas.74.9.3735. PMC 431708
. PMID 198801. - ^ Bowen, R. A. Molecular Toolkit: Protein Hydrophobicity Plots. Colorado State University, 1998. Web. 15 Nov. 2010. <http://www.vivo.colostate.edu/molkit/index.html>
- ^ "Hexokinase deficiency". Enerca. Enerca. Retrieved 04-6-17. Check date values in:
|accessdate=(help)
This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Hexokinase Provide feedback
Hexokinase ( EC:2.7.1.1) contains two structurally similar domains represented by this family and PF03727. Some members of the family have two copies of each of these domains.
Literature references
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Bennett WS Jr, Steitz TA; , J Mol Biol 1980;140:211-230.: Structure of a complex between yeast hexokinase A and glucose. II. Detailed comparisons of conformation and active site configuration with the native hexokinase B monomer and dimer. PUBMED:7001032 EPMC:7001032
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Steitz TA; , J Mol Biol 1971;61:695-700.: Structure of yeast hexokinase-B. I. Preliminary x-ray studies and subunit structure. PUBMED:5133118 EPMC:5133118
Internal database links
| SCOOP: | ROK |
External database links
| HOMSTRAD: | hexokinase |
| PRINTS: | PR00475 |
| PROSITE: | PDOC00370 |
| SCOP: | 1cza |
This tab holds annotation information from the InterPro database.
InterPro entry IPR022672
Hexokinase is an important enzyme that catalyses the ATP-dependent conversion of aldo- and keto-hexose sugars to the hexose-6-phosphate (H6P). The enzyme can catalyse this reaction on glucose, fructose, sorbitol and glucosamine, and as such is the first step in a number of metabolic pathways [PUBMED:1783373]. The addition of a phosphate group to the sugar acts to trap it in a cell, since the negatively charged phosphate cannot easily traverse the plasma membrane.
The enzyme is widely distributed in eukaryotes. There are three isozymes of hexokinase in yeast (PI, PII and glucokinase): isozymes PI and PII phosphorylate both aldo- and keto-sugars; glucokinase is specific for aldo-hexoses. All three isozymes contain two domains [PUBMED:1783373]. Structural studies of yeast hexokinase reveal a well-defined catalytic pocket that binds ATP and hexose, allowing easy transfer of the phosphate from ATP to the sugar [PUBMED:10749890]. Vertebrates contain four hexokinase isozymes, designated I to IV, where types I to III contain a duplication of the two-domain yeast-type hexokinases. Both the N- and C-terminal halves bind hexose and H6P, though in types I an III only the C-terminal half supports catalysis, while both halves support catalysis in type II. The N-terminal half is the regulatory region. Type IV hexokinase is similar to the yeast enzyme in containing only the two domains, and is sometimes incorrectly referred to as glucokinase.
The different vertebrate isozymes differ in their catalysis, localisation and regulation, thereby contributing to the different patterns of glucose metabolism in different tissues [PUBMED:12756287]. Whereas types I to III can phosphorylate a variety of hexose sugars and are inhibited by glucose-6-phosphate (G6P), type IV is specific for glucose and shows no G6P inhibition. Type I enzyme may have a catabolic function, producing H6P for energy production in glycolysis; it is bound to the mitochondrial membrane, which enables the coordination of glycolysis with the TCA cycle. Types II and III enzyme may have anabolic functions, providing H6P for glycogen or lipid synthesis. Type IV enzyme is found in the liver and pancreatic beta-cells, where it is controlled by insulin (activation) and glucagon (inhibition). In pancreatic beta-cells, type IV enzyme acts as a glucose sensor to modify insulin secretion. Mutations in type IV hexokinase have been associated with diabetes mellitus.
Hexokinase (EC), a fructose and glucose phosphorylating enzyme, contains two structurally similar domains represented by this family and . Some hexokinases have two copies of each of these domains. This entry represents the N-terminal domain.
Gene Ontology
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
| Molecular function | ATP binding (GO:0005524) |
| phosphotransferase activity, alcohol group as acceptor (GO:0016773) | |
| Biological process | carbohydrate metabolic process (GO:0005975) |
Domain organisation
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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Pfam Clan
This family is a member of clan Actin_ATPase (CL0108), which has the following description:
The actin-like ATPase domain forms an alpha/beta canonical fold. The domain can be subdivided into 1A, 1B, 2A and 2B subdomains. Subdomains 1A and 1B share the same RNAseH-like fold (a five-stranded beta-sheet decorated by a number of alpha-helices). Domains 1A and 2A are conserved in all members of this superfamily, whereas domain 1B and 2B have a variable structure and are even missing from some homologues [1]. Within the actin-like ATPase domain the ATP-binding site is highly conserved. The phosphate part of the ATP is bound in a cleft between subdomains 1A and 2A, whereas the adenosine moiety is bound to residues from domains 2A and 2B[1].
The clan contains the following 34 members:
Acetate_kinase Actin Actin_micro ALP_N AnmK BcrAD_BadFG Carbam_trans_N DDR DUF1464 DUF2229 EutA FGGY_C FGGY_N FtsA Fumble GDA1_CD39 Glucokinase Hexokinase_1 Hexokinase_2 HGD-D HSP70 Hydant_A_N Hydantoinase_A HypF_C MreB_Mbl MutL Pan_kinase Peptidase_M22 PilM_2 Ppx-GppA RACo_C_ter ROK StbA T2SSLAlignments
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
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| Seed (423) |
Full (5127) |
Representative proteomes | UniProt (7887) |
NCBI (10332) |
Meta (6) |
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| RP15 (1091) |
RP35 (2469) |
RP55 (3817) |
RP75 (4879) |
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| Jalview | |||||||||
| HTML | |||||||||
| PP/heatmap | 1 | ||||||||
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| Seed (423) |
Full (5127) |
Representative proteomes | UniProt (7887) |
NCBI (10332) |
Meta (6) |
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| RP15 (1091) |
RP35 (2469) |
RP55 (3817) |
RP75 (4879) |
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| Raw Stockholm | |||||||||
| Gzipped | |||||||||
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logo
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
Trees
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
Curation
| Seed source: | Prosite |
| Previous IDs: | hexokinase; |
| Type: | Domain |
| Sequence Ontology: | SO:0000417 |
| Author: |
Sonnhammer ELL  , Finn RD , Griffiths-Jones SR
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| Number in seed: | 423 |
| Number in full: | 5127 |
| Average length of the domain: | 191.40 aa |
| Average identity of full alignment: | 34 % |
| Average coverage of the sequence by the domain: | 40.17 % |
HMM information
| HMM build commands: |
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
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| Model details: |
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| Model length: | 199 | ||||||||||||
| Family (HMM) version: | 21 | ||||||||||||
| Download: | download the raw HMM for this family |
Species distribution
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Colour assignments
Archea
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Eukaryota
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Unclassified
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Interactions
Structures
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Hexokinase_1 domain has been found. There are 117 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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