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61  structures 457  species 2  interactions 1869  sequences 20  architectures

Family: Hexokinase_2 (PF03727)

Summary: Hexokinase

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Hexokinase Edit Wikipedia article

Hexokinase
Hexokinase 3O08.png
Crystal structures of hexokinase 1 from Kluyveromyces lactis.[1]
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 / EGO
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
PDB 1v4t EBI.jpg
crystal structure of human glucokinase
Identifiers
Symbol Hexokinase_1
Pfam PF00349
Pfam clan CL0108
InterPro IPR022672
PROSITE PDOC00370
SCOP 1cza
SUPERFAMILY 1cza
Hexokinase_2
PDB 1bg3 EBI.jpg
rat brain hexokinase type i complex with glucose and inhibitor glucose-6-phosphate
Identifiers
Symbol Hexokinase_2
Pfam PF03727
Pfam clan CL0108
InterPro IPR022673
PROSITE PDOC00370
SCOP 1cza
SUPERFAMILY 1cza

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 the most important product.

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[edit]

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[edit]

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. Action of Hexokinase on Glucose

Consequences of hexose phosphorylation[edit]

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.

Size of different isoforms[edit]

Most bacterial hexokinases are approximately 50 kD in size. Multicellular organisms such as 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[edit]

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[edit]

Hexokinases I, II, and III are referred to as "low-Km" 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 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.
  • Hexokinase III/C is substrate-inhibited by glucose at physiologic concentrations. Little is known about the regulatory characteristics of this isoform.

Hexokinase IV ("glucokinase")[edit]

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.

Hexokinase in glycolysis[edit]

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
D-glucose wpmp.png   Alpha-D-glucose-6-phosphate wpmp.png
ATP ADP
Biochem reaction arrow forward YYNN horiz med.png
 
 

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.[2] 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[edit]

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[3] 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[edit]

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.[4]

See also[edit]

References[edit]

  1. ^ 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. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ Bowen, R. A. Molecular Toolkit: Protein Hydrophobicity Plots. Colorado State University, 1998. Web. 15 Nov. 2010. <http://www.vivo.colostate.edu/molkit/index.html>


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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 PF00349. Some members of the family have two copies of each of these domains.

Literature references

  1. 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

  2. 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


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR022673

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 members of the family have two copies of each of these domains. This entry represents the more C-terminal domain.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

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 29 members:

Acetate_kinase Actin BcrAD_BadFG CmcH_NodU DDR DUF1464 DUF1786 EutA FGGY_C FGGY_N FtsA Fumble GDA1_CD39 Glucokinase Hexokinase_1 Hexokinase_2 HSP70 Hydant_A_N Hydantoinase_A MreB_Mbl MutL Pan_kinase Peptidase_M22 PilM_2 Ppx-GppA ROK StbA T2SL UPF0075

Alignments

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(15)
Full
(1869)
Representative proteomes NCBI
(1816)
Meta
(6)
RP15
(215)
RP35
(418)
RP55
(718)
RP75
(998)
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  Seed
(15)
Full
(1869)
Representative proteomes NCBI
(1816)
Meta
(6)
RP15
(215)
RP35
(418)
RP55
(718)
RP75
(998)
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  Seed
(15)
Full
(1869)
Representative proteomes NCBI
(1816)
Meta
(6)
RP15
(215)
RP35
(418)
RP55
(718)
RP75
(998)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

Pfam alignments:

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Trees

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Curation and family details

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Curation View help on the curation process

Seed source: Prosite
Previous IDs: hexokinase2;
Type: Domain
Author: Sonnhammer ELL, Finn RD, Griffiths-Jones SR
Number in seed: 15
Number in full: 1869
Average length of the domain: 217.50 aa
Average identity of full alignment: 34 %
Average coverage of the sequence by the domain: 49.64 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.3 21.3
Trusted cut-off 21.4 21.4
Noise cut-off 19.6 21.2
Model length: 243
Family (HMM) version: 11
Download: download the raw HMM for this family

Species distribution

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Interactions

There are 2 interactions for this family. More...

Hexokinase_2 Hexokinase_1

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_2 domain has been found. There are 61 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 seqence.

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