Hexokinase (Englisch)

8/2/2019 Hexokinase (Englisch)

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Glucokinase 1

Glucokinase

Glucokinase (hexokinase 4)

Based on PDB entry 1GLK.

Available structures

PDB1GLK

[1], 1V4S

[2], 1V4T

[3], 3A0I

[4], 3F9M

[5], 3FGU

[6], 3FR0

[7], 3H1V

[8], 3ID8

[9], 3IDH

[10], 3IMX

[11]

Identifiers

Symbols GCK[12]

; FGQTL3; GK; GLK; HHF3; HK4; HKIV; HXKP; LGLK; MODY2

External IDsOMIM: 138079

[13]MGI: 1270854

[14]HomoloGene: 55440

[15]GeneCards: GCK Gene

[16]

EC number2.7.1.2

[17]
http://www.genome.jp/dbget-bin/www_bget?enzyme+2.7.1.2http://en.wikipedia.org/w/index.php?title=Enzyme_Commission_numberhttp://www.genecards.org/cgi-bin/carddisp.pl?id_type=entrezgene&id=2645http://en.wikipedia.org/w/index.php?title=GeneCardshttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=homologene&dopt=HomoloGene&list_uids=55440http://en.wikipedia.org/w/index.php?title=HomoloGenehttp://www.informatics.jax.org/searches/accession_report.cgi?id=MGI:1270854http://en.wikipedia.org/w/index.php?title=Mouse_Genome_Informaticshttp://omim.org/entry/138079http://en.wikipedia.org/w/index.php?title=Mendelian_Inheritance_in_Manhttp://www.genenames.org/data/hgnc_data.php?hgnc_id=4195http://en.wikipedia.org/w/index.php?title=Human_Genome_Organisationhttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3IMXhttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3IDHhttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3ID8http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3H1Vhttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3FR0http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3FGUhttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3F9Mhttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3A0Ihttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=1V4Thttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=1V4Shttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=1GLKhttp://en.wikipedia.org/w/index.php?title=Protein_Data_Bankhttp://en.wikipedia.org/w/index.php?title=Protein_Data_Bankhttp://en.wikipedia.org/w/index.php?title=File:Glucokinase-1GLK.png


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Glucokinase 2

Gene Ontology

Molecular functionnucleotide binding

[18]

glucokinase activity[19]

glucokinase activity[19]

protein binding[20]

ATP binding[21]

glucose binding[22]

kinase activity[23]

transferase activity[24]

Cellular componentnucleoplasm

[25]

cytosol[26]

cytosol[26]

Biological processcarbohydrate metabolic process

[27]

regulation of glycolysis[28]

hexose transport[29]

regulation of glucose transport[30]

glucose transport[31]

endocrine pancreas development[32]

positive regulation of insulin secretion[33]

cellular response to insulin stimulus[34]

glucose homeostasis[35]

cellular response to leptin stimulus[36]

negative regulation of gluconeogenesis[37]

positive regulation of glycogen biosynthetic process[38]

regulation of insulin secretion[39]

glucose 6-phosphate metabolic process[40]

glucose 6-phosphate metabolic process[40]

detection of glucose[41]

transmembrane transport[42]

Sources: Amigo[43]

/ QuickGO[44]

RNA expression pattern

More reference expression data[45]

Orthologs

Species Human Mouse

Entrez2645

[46]103988

[47]

EnsemblENSG00000106633

[48]ENSMUSG00000041798

[49]

UniProt P35557[50]

Q5SVI5[51]

RefSeq (mRNA) NM_000162.3[52] NM_010292.4[53]

RefSeq (protein)NP_000153.1

[54]NP_034422.2

[55]
http://en.wikipedia.org/w/index.php?title=Entrezhttp://en.wikipedia.org/w/index.php?title=Entrezhttp://en.wikipedia.org/w/index.php?title=Ensemblhttp://en.wikipedia.org/w/index.php?title=UniProthttp://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_034422.2http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_000153.1http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_010292.4http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_000162.3http://www.uniprot.org/uniprot/Q5SVI5http://www.uniprot.org/uniprot/P35557http://en.wikipedia.org/w/index.php?title=UniProthttp://www.ensembl.org/Mus_musculus/geneview?gene=ENSMUSG00000041798;db=corehttp://www.ensembl.org/Homo_sapiens/geneview?gene=ENSG00000106633;db=corehttp://en.wikipedia.org/w/index.php?title=Ensemblhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=retrieve&dopt=default&list_uids=103988&rn=1http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=retrieve&dopt=default&list_uids=2645&rn=1http://en.wikipedia.org/w/index.php?title=Entrezhttp://biogps.org/gene/2645/http://en.wikipedia.org/w/index.php?title=File:PBB_GE_GCK_211167_s_at_tn.pnghttp://www.ebi.ac.uk/QuickGO/GProtein?ac=P35557http://amigo.geneontology.org/cgi-bin/amigo/gp-assoc.cgi?gp=UniProtKB:P35557http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0055085http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0051594http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0051156http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0051156http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0050796http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0045725http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0045721http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0044320http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0042593http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0032869http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0032024http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0031018http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0015758http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0010827http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0008645http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0006110http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0005975http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0005829http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0005829http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0005654http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0016740http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0016301http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0005536http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0005524http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0005515http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0004340http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0004340http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0000166http://en.wikipedia.org/w/index.php?title=Gene_Ontology


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Glucokinase 3

Location (UCSC)Chr 7:

44.1844.24 Mb[56]

Chr 11:

5.85.85 Mb[57]

PubMed search [58] [59]

Glucokinase

Identifiers

EC number 2.7.1.2[60]

CAS number9001-36-9

[61]

Databases

IntEnzIntEnz view

[62]

BRENDABRENDA entry

[63]

ExPASy NiceZyme view[64]

KEGGKEGG entry

[65]

MetaCycmetabolic pathway

[66]

PRIAM profile[67]

PDB structuresRCSB PDB

[68]PDBe

[69]PDBsum

[70]

Gene OntologyAmiGO

[71]/ EGO

[72]

Search

PMC articles[73]

PubMed articles[74]

Glucokinase (EC 2.7.1.2[75]

) is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate.

Glucokinase occurs in cells in the liver, pancreas, gut, and brain of humans and most other vertebrates. In each of

these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor,

triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a

meal or when fasting. Mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia.

Glucokinase (GK) is a hexokinase isozyme, related homologously and by evolution to at least three other

hexokinases.[76] All of the hexokinases can mediate phosphorylation of glucose to glucose-6-phosphate (G6P),

which is the first step of both glycogen synthesis and glycolysis. However, glucokinase is coded by a separate gene

and its distinctive kinetic properties allow it to serve a different set of functions. Glucokinase has a lower affinity for

glucose than the other hexokinases do, and its activity is localized to a few cell types, leaving the other three

hexokinases as more important preparers of glucose for glycolysis and glycogen synthesis for most tissues and

organs. Because of this reduced affinity, the activity of glucokinase, under usual physiological conditions, varies

substantially according to the concentration of glucose.[77]
http://en.wikipedia.org/w/index.php?title=Physiological_conditionhttp://en.wikipedia.org/w/index.php?title=Enzyme_kineticshttp://en.wikipedia.org/w/index.php?title=Genehttp://en.wikipedia.org/w/index.php?title=Genetic_codehttp://en.wikipedia.org/w/index.php?title=Glycolysishttp://en.wikipedia.org/w/index.php?title=Glycogenhttp://en.wikipedia.org/w/index.php?title=Evolutionhttp://en.wikipedia.org/w/index.php?title=Homology_%28biology%29http://en.wikipedia.org/w/index.php?title=Isozymehttp://en.wikipedia.org/w/index.php?title=Hexokinasehttp://en.wikipedia.org/w/index.php?title=Hypoglycemiahttp://en.wikipedia.org/w/index.php?title=Diabetes_mellitushttp://en.wikipedia.org/w/index.php?title=Genehttp://en.wikipedia.org/w/index.php?title=Mutationhttp://en.wikipedia.org/w/index.php?title=Fastinghttp://en.wikipedia.org/w/index.php?title=Sensorhttp://en.wikipedia.org/w/index.php?title=Metabolismhttp://en.wikipedia.org/w/index.php?title=Carbohydratehttp://en.wikipedia.org/w/index.php?title=Vertebratehttp://en.wikipedia.org/w/index.php?title=Brainhttp://en.wikipedia.org/w/index.php?title=Gut_%28zoology%29http://en.wikipedia.org/w/index.php?title=Pancreashttp://en.wikipedia.org/w/index.php?title=Liverhttp://en.wikipedia.org/w/index.php?title=Cell_%28biology%29http://en.wikipedia.org/w/index.php?title=Glucose-6-phosphatehttp://en.wikipedia.org/w/index.php?title=Glucosehttp://en.wikipedia.org/w/index.php?title=Phosphorylationhttp://en.wikipedia.org/w/index.php?title=Enzymehttp://enzyme.expasy.org/EC/2.7.1.2http://en.wikipedia.org/w/index.php?title=Enzyme_Commission_numberhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&term=2.7.1.2%5BEC/RN%20Number%5Dhttp://en.wikipedia.org/w/index.php?title=PubMedhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&term=2.7.1.2%5BEC/RN%20Number%5D%20AND%20pubmed%20pmc%20local%5Bsb%5Dhttp://en.wikipedia.org/w/index.php?title=PubMed_Centralhttp://www.ebi.ac.uk/ego/DisplayGoTerm?id=GO:0004340&format=normalhttp://amigo.geneontology.org/cgi-bin/amigo/go.cgi?query=GO:0004340&view=detailshttp://en.wikipedia.org/w/index.php?title=Gene_Ontologyhttp://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/enzymes/GetPage.pl?ec_number=2.7.1.2http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/enzyme/?ec=2.7.1.2http://www.rcsb.org/pdb/search/smartSubquery.do?smartSearchSubtype=EnzymeClassificationQuery&Enzyme_Classification=2.7.1.2http://en.wikipedia.org/w/index.php?title=Protein_Data_Bankhttp://priam.prabi.fr/cgi-bin/PRIAM_profiles_CurrentRelease.pl?EC=2.7.1.2http://en.wikipedia.org/w/index.php?title=PRIAM_enzyme_specific_profileshttp://biocyc.org/META/substring-search?type=NIL&object=2.7.1.2http://en.wikipedia.org/w/index.php?title=MetaCychttp://www.genome.ad.jp/dbget-bin/www_bget?enzyme+2.7.1.2http://en.wikipedia.org/w/index.php?title=KEGGhttp://www.expasy.org/enzyme/2.7.1.2http://en.wikipedia.org/w/index.php?title=ExPASyhttp://www.brenda-enzymes.org/php/result_flat.php4?ecno=2.7.1.2http://en.wikipedia.org/w/index.php?title=BRENDAhttp://www.ebi.ac.uk/intenz/query?cmd=SearchEC&ec=2.7.1.2http://en.wikipedia.org/w/index.php?title=IntEnzhttp://toolserver.org/~magnus/cas.php?language=en&cas=9001-36-9&title=http://en.wikipedia.org/w/index.php?title=CAS_registry_numberhttp://www.chem.qmul.ac.uk/iubmb/enzyme/EC2/7/1/2.htmlhttp://en.wikipedia.org/w/index.php?title=Enzyme_Commission_numberhttp://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Link&LinkName=gene_pubmed&from_uid=103988http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Link&LinkName=gene_pubmed&from_uid=2645http://en.wikipedia.org/w/index.php?title=PubMedhttp://genome.ucsc.edu/cgi-bin/hgTracks?org=Mouse&db=mm9&position=chr11:5800823-5850084http://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg19&position=chr7:44183872-44237769


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Glucokinase 4

Nomenclature

Alternative names for this enzyme are: human hexokinase IV, hexokinase D, and

ATP:D-hexose 6-phosphotransferase, EC 2.7.1.1 (previously 2.7.1.2). The common name, glucokinase, is derived

from its relative specificity for glucose under physiologic conditions.

Some biochemists have argued that the name glucokinase should be abandoned as misleading, as this enzyme can

phosphorylate other hexoses in the right conditions, and there are distantly related enzymes in bacteria with more

absolute specificity for glucose that better deserve the name and the EC 2.7.1.2[78]

.[77][79]

Nevertheless, glucokinase

remains the name preferred in the contexts of medicine and mammalian physiology.

Another mammalian glucose kinase, ADP-specific glucokinase, was discovered in 2004.[80]

The gene is distinct and

similar to that of primitive organisms. It is dependent on ADP rather than ATP (suggesting the possibility of more

effective function during hypoxia), and the metabolic role and importance remain to be elucidated.

Catalysis

Substrates and productsThe principal substrate of physiologic importance of glucokinase is glucose, and the most important product is

glucose-6-phosphate (G6P). The other necessary substrate, from which the phosphate is derived, is adenosine

triphosphate (ATP), which is converted to adenosine diphosphate (ADP) when the phosphate is removed. The

reaction catalyzed by glucokinase is:

ATP participates in the reaction in a form complexed to magnesium (Mg) as a cofactor. Furthermore, under certain

conditions, glucokinase, like other hexokinases, can induce phosphorylation of other hexoses (6 carbon sugars) and

similar molecules. Therefore the general glucokinase reaction is more accurately described as[79]

:

Hexose + MgATP2- hexose-PO32- + MgADP- + H+

Among the hexose substrates are mannose, fructose, and glucosamine, but the affinity of glucokinase for these

requires concentrations not found in cells for significant activity.[81]
http://en.wikipedia.org/w/index.php?title=Glucosaminehttp://en.wikipedia.org/w/index.php?title=Fructosehttp://en.wikipedia.org/w/index.php?title=Mannosehttp://en.wikipedia.org/w/index.php?title=Oxygenhttp://en.wikipedia.org/w/index.php?title=Phosphorushttp://en.wikipedia.org/w/index.php?title=Sugarhttp://en.wikipedia.org/w/index.php?title=Hexosehttp://en.wikipedia.org/w/index.php?title=Cofactor_%28biochemistry%29http://en.wikipedia.org/w/index.php?title=Magnesiumhttp://en.wikipedia.org/w/index.php?title=File:Glucokinase.pnghttp://en.wikipedia.org/w/index.php?title=Adenosine_diphosphatehttp://en.wikipedia.org/w/index.php?title=Adenosine_triphosphatehttp://en.wikipedia.org/w/index.php?title=Adenosine_triphosphatehttp://en.wikipedia.org/w/index.php?title=Glucose-6-phosphatehttp://en.wikipedia.org/w/index.php?title=Product_%28chemistry%29http://en.wikipedia.org/w/index.php?title=Glucosehttp://en.wikipedia.org/w/index.php?title=Substrate_%28biochemistry%29http://en.wikipedia.org/w/index.php?title=Hypoxia_%28medical%29http://en.wikipedia.org/w/index.php?title=Adenosine_diphosphatehttp://en.wikipedia.org/w/index.php?title=ADP-specific_glucokinasehttp://en.wikipedia.org/w/index.php?title=Physiologyhttp://en.wikipedia.org/w/index.php?title=Medicinehttp://ca.expasy.org/cgi-bin/nicezyme.pl?2.7.1.2http://en.wikipedia.org/w/index.php?title=Enzyme_Commission_numberhttp://en.wikipedia.org/w/index.php?title=Bacteriumhttp://en.wikipedia.org/w/index.php?title=Biochemistryhttp://en.wikipedia.org/w/index.php?title=Enzyme_Commission_number


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Glucokinase 5

Kinetics

Two important kinetic properties distinguish glucokinase from the other hexokinases, allowing it to function in a

special role as glucose sensor.

1. Glucokinase has a lower affinity for glucose than the other hexokinases. Glucokinase changes conformation

and/or function in parallel with rising glucose concentrations in the physiologically important range of 4-10

mmol/L (72-180 mg/dl). It is half-saturated at a glucose concentration of about 8 mmol/L (144 mg/dl). [82][83]

2. Glucokinase is not inhibited by its product, glucose-6-phosphate.[82]

This allows continued signal output (e.g., to

trigger insulin release) amid significant amounts of its product[83]

These two features allow it to regulate a "supply-driven" metabolic pathway. That is, the rate of reaction is driven by

the supply of glucose, not by the demand for end products.

Another distinctive property of glucokinase is its moderate cooperativity with glucose, with a Hill coefficient (nH

) of

about 1.7.[83]

Glucokinase has only a single binding site for glucose and is the only monomeric regulatory enzyme

known to display substrate cooperativity. The nature of the cooperativity has been postulated to involve a "slow

transition" between two different enzyme states with different rates of activity. If the dominant state depends upon

glucose concentration, it would produce an apparent cooperativity similar to that observed.[84]

Because of this cooperativity, the kinetic interaction of glucokinase with glucose does not follow classical

Michaelis-Menten kinetics. Rather than aKm

for glucose, it is more accurate to describe a half-saturation level S0.5

,

which is the concentration at which the enzyme is 50% saturated and active.

The S0.5

and nH extrapolate to an "inflection point"of the curve describing enzyme activity as a function of glucose

concentration at about 4 mmol/L.[85]

In other words, at a glucose concentration of about 72 mg/dl, which is near the

low end of the normal range, glucokinase activity is most sensitive to small changes in glucose concentration.

The kinetic relationship with the other substrate, MgATP, can be described by classical Michaelis-Menten kinetics,

with an affinity at about 0.3-0.4 mmol/L, well below a typical intracellular concentration of 2.5 mmol/L. The fact

that there is nearly always an excess of ATP available implies that ATP concentration rarely influences glucokinase

activity.

The maximum specific activity (kcat

, also known as the turnover rate) of glucokinase when saturated with both

substrates is 62/s.[82]

A "minimal mathematical model"has been devised based on the above kinetic information to predict the beta cell

glucose phosphorylation rate (BGPR) of normal ("wild type") glucokinase and the known mutations. The BGPR for

wild type glucokinase is about 28% at a glucose concentration of 5 mmol/l, indicating that the enzyme is running at

28% of capacity at the usual threshold glucose for triggering insulin release.

Mechanism

The sulfhydryl groups of several cysteines surround the glucose binding site. All except cys 230 are essential for the

catalytic process, forming multiple disulfide bridges during interaction with the substrates and regulators. At least in

the beta cells, the ratio of active to inactive glucokinase molecules is at least partly determined by the balance of

oxidation of sulfhydryl groups or reduction of disulfide bridges.

These sulfhydryl groups are quite sensitive to the oxidation status of the cells, making glucokinase one of the

components most vulnerable to oxidative stress, especially in the beta cells.
http://en.wikipedia.org/w/index.php?title=Oxidationhttp://en.wikipedia.org/w/index.php?title=Disulfide_bridgehttp://en.wikipedia.org/w/index.php?title=Cysteinehttp://en.wikipedia.org/w/index.php?title=Sulfhydrylhttp://en.wikipedia.org/w/index.php?title=Michaelis-Menten_kineticshttp://en.wikipedia.org/w/index.php?title=Hill_coefficienthttp://en.wikipedia.org/w/index.php?title=Cooperativityhttp://en.wikipedia.org/w/index.php?title=Insulinhttp://en.wikipedia.org/w/index.php?title=Deciliterhttp://en.wikipedia.org/w/index.php?title=Milligramhttp://en.wikipedia.org/w/index.php?title=Molar_solutionhttp://en.wikipedia.org/w/index.php?title=Enzyme_kinetics


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Glucokinase 6

Structure

Glucokinase

Structures ofEscherichia coli ATP-dependent glucokinase.[86]

Identifiers

Symbol Glucokinase

PfamPF02685

[87]

Pfam clanCL0108

[88]

InterProIPR003836

[89]

SCOP1q18

[90]

SUPERFAMILY1q18

[91]

Available protein structures:

Pfamstructures

[92]

PDBRCSB PDB

[93]; PDBe

[94]

PDBsumstructure summary

[95]

Glucokinase is a monomeric protein of 465 amino acids and a molecular weight of about 50 kD. There are at least

two clefts, one for the active site, binding glucose and MgATP, and the other for a putative allosteric activator that

has not yet been identified.

[96][97]

This is about half the size of the other mammalian hexokinases, which retain a degree of dimeric structure. Several

sequences and the three-dimensional structure of the key active sites. The ATP binding domain, for example, are

shared with hexokinases, bacterial glucokinases, and other proteins, and the common structure is termed an actin

fold.
http://en.wikipedia.org/w/index.php?title=Activatorhttp://en.wikipedia.org/w/index.php?title=Allosterichttp://en.wikipedia.org/w/index.php?title=Active_sitehttp://en.wikipedia.org/w/index.php?title=Kilodaltonhttp://en.wikipedia.org/w/index.php?title=Molecular_weighthttp://en.wikipedia.org/w/index.php?title=Amino_acidhttp://en.wikipedia.org/w/index.php?title=Monomerhttp://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPfamStr.pl?pfam_id=PF02685http://en.wikipedia.org/w/index.php?title=PDBsumhttp://www.ebi.ac.uk/pdbe-srv/PDBeXplore/pfam/?pfam=PF02685http://www.rcsb.org/pdb/search/smartSubquery.do?smartSearchSubtype=PfamIdQuery&pfamID=PF02685http://en.wikipedia.org/w/index.php?title=Protein_Data_Bankhttp://pfam.sanger.ac.uk/family/PF02685#tabview=tab8http://en.wikipedia.org/w/index.php?title=Pfamhttp://supfam.org/SUPERFAMILY/cgi-bin/search.cgi?search_field=1q18http://en.wikipedia.org/w/index.php?title=SUPERFAMILYhttp://scop.mrc-lmb.cam.ac.uk/scop/search.cgi?tlev=fa;&pdb=1q18http://en.wikipedia.org/w/index.php?title=Structural_Classification_of_Proteinshttp://www.ebi.ac.uk/interpro/DisplayIproEntry?ac=IPR003836http://en.wikipedia.org/w/index.php?title=InterProhttp://pfam.sanger.ac.uk/clan/CL0108http://en.wikipedia.org/w/index.php?title=Pfamhttp://pfam.sanger.ac.uk/family?acc=PF02685http://en.wikipedia.org/w/index.php?title=Pfamhttp://en.wikipedia.org/w/index.php?title=File%3APDB_1q18_EBI.jpg


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Glucokinase 7

Genetics

Human glucokinase is coded for by the GCK gene on chromosome 7. This single autosomal gene has 10

exons.[98][99]

Genes for glucokinase in other animals are homologous to human GCK.[82][100]

A distinctive feature of the gene is that it begins with two promoter regions.[101]

The first exon from the 5' end

contains two tissue-specific promoter regions. Transcription can begin at either promoter (depending on the tissue)

so that the same gene can produce a slightly different molecule in liver and in other tissues. The two isoforms of

glucokinase differ only by 13-15 amino acids at the N-terminal end of the molecule, which produces only a minimal

difference in structure. The two isoforms have the same kinetic and functional characteristics.[77]

The first promoter from the 5' end, referred to as the "upstream" or neuroendocrine promoter, is active in

pancreatic islet cells, neural tissue, and enterocytes (small intestine cells) to produce the "neuroendocrine isoform" of

glucokinase.[101]

The second promoter, the "downstream" or liver promoter, is active in hepatocytes and directs

production of the "liver isoform".[102]

The two promoters have little or no sequence homology and are separated by a

30 kbp sequence which, as of yet, has not been shown to incur any functional differences between isoforms.[77]

The

two promoters are functionally exclusive and governed by distinct sets of regulatory factors, so that glucokinase

expression can be regulated separately in different tissue types.[77]

The two promoters correspond to two broad

categories of glucokinase function: In liver, glucokinase acts as the gateway for the "bulk processing" of available

glucose, while, in the neuroendocrine cells, it acts as a sensor, triggering cell responses that affect body-wide

carbohydrate metabolism.

Distribution among organ systems

Glucokinase has been discovered in specific cells in four types of mammalian tissue: liver, pancreas, small intestine,

and brain. All play crucial roles in responding to rising or falling levels of blood glucose.

The predominant cells of the liver are the hepatocytes, and GK is found exclusively in these cells. During

digestion of a carbohydrate meal, when blood glucose is plentiful and insulin levels are high, hepatocytes remove

glucose from the blood and store it as glycogen. After completion of digestion and absorption, the liver

manufactures glucose from both non-glucose substrates (gluconeogenesis) and glycogen (glycogenolysis), and

exports it into the blood, to maintain adequate blood glucose levels during fasting. Because GK activity rises

rapidly as the glucose concentration rises, it serves as a central metabolic switch to shift hepatic carbohydrate

metabolism between fed and fasting states. Phosphorylation of glucose to glucose-6-phosphate by GK facilitates

storage of glucose as glycogen and disposal by glycolysis. The separate liver promoter allows glucokinase to be

regulated differently in hepatocytes than in the neuroendocrine cells.

Neuroendocrine cells of the pancreas, gut, and brain share some common aspects of glucokinase production,

regulation, and function.[103]

These tissues are collectively referred to as "neuroendocrine" cells in this context.

Beta cells and alpha cells of the pancreatic islets Beta cells release insulin in response to rising levels of glucose. Insulin enables many types of cells to

import and use glucose, and signals the liver to synthesize glycogen. Alpha cells produce less glucagon in

response to rising glucose levels, and more glucagon if blood glucose is low. Glucagon serves as a signal to

the liver to break down glycogen and release glucose into the blood. Glucokinase in beta cells serves as a

glucose sensor, amplifying insulin secretion as blood glucose rises.

Glucose-sensitive neurons of the hypothalamus

In response to rising or falling levels of glucose, cells in the hypothalamus polarize or depolarize. Among

the neuroendocrine reactions of the central nervous system to hypoglycemia is activation of the adrenergic

responses of the autonomic nervous system. Glucokinase likely serves as a glucose signal here as well.

Glucokinase has also been found in cells of the anterior pituitary.

Enterocytes of the small intestine
http://en.wikipedia.org/w/index.php?title=Central_nervous_systemhttp://en.wikipedia.org/w/index.php?title=Hypoglycemiahttp://en.wikipedia.org/w/index.php?title=Autonomic_nervous_systemhttp://en.wikipedia.org/w/index.php?title=Autonomic_nervous_systemhttp://en.wikipedia.org/w/index.php?title=Pituitaryhttp://en.wikipedia.org/w/index.php?title=Enterocytehttp://en.wikipedia.org/w/index.php?title=Central_nervous_systemhttp://en.wikipedia.org/w/index.php?title=Hypoglycemiahttp://en.wikipedia.org/w/index.php?title=Autonomic_nervous_systemhttp://en.wikipedia.org/w/index.php?title=Pituitaryhttp://en.wikipedia.org/w/index.php?title=Enterocytehttp://en.wikipedia.org/w/index.php?title=Enterocytehttp://en.wikipedia.org/w/index.php?title=Pituitaryhttp://en.wikipedia.org/w/index.php?title=Autonomic_nervous_systemhttp://en.wikipedia.org/w/index.php?title=Adrenergichttp://en.wikipedia.org/w/index.php?title=Hypoglycemiahttp://en.wikipedia.org/w/index.php?title=Central_nervous_systemhttp://en.wikipedia.org/w/index.php?title=Hypothalamushttp://en.wikipedia.org/w/index.php?title=Neuronhttp://en.wikipedia.org/w/index.php?title=Glucagonhttp://en.wikipedia.org/w/index.php?title=Insulinhttp://en.wikipedia.org/w/index.php?title=Islethttp://en.wikipedia.org/w/index.php?title=Alpha_cellhttp://en.wikipedia.org/w/index.php?title=Beta_cellhttp://en.wikipedia.org/w/index.php?title=Glycogenolysishttp://en.wikipedia.org/w/index.php?title=Gluconeogenesishttp://en.wikipedia.org/w/index.php?title=Glycogenhttp://en.wikipedia.org/w/index.php?title=Insulinhttp://en.wikipedia.org/w/index.php?title=Digestionhttp://en.wikipedia.org/w/index.php?title=Hepatocytehttp://en.wikipedia.org/w/index.php?title=Blood_glucosehttp://en.wikipedia.org/w/index.php?title=Small_intestinehttp://en.wikipedia.org/w/index.php?title=Base_pairhttp://en.wikipedia.org/w/index.php?title=Hepatocytehttp://en.wikipedia.org/w/index.php?title=Small_intestinehttp://en.wikipedia.org/w/index.php?title=N-terminal_endhttp://en.wikipedia.org/w/index.php?title=Amino_acidhttp://en.wikipedia.org/w/index.php?title=Isoformhttp://en.wikipedia.org/w/index.php?title=Transcription_%28genetics%29http://en.wikipedia.org/w/index.php?title=Exonhttp://en.wikipedia.org/w/index.php?title=Promoter_%28biology%29http://en.wikipedia.org/w/index.php?title=Exonhttp://en.wikipedia.org/w/index.php?title=Autosomehttp://en.wikipedia.org/w/index.php?title=Chromosome_7http://en.wikipedia.org/w/index.php?title=Gene


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Glucokinase 8

This is the least-understood of the glucokinase sensor systems. It seems likely that responses to incoming

glucose during digestion play a role in the incretin amplification of insulin secretion during a meal, or in the

generation of satiety signals from gut to brain.

Distribution among species

Liver glucokinase occurs widely but not universally throughout vertebrate species. The gene structure and amino

acid sequence are highly conserved among most mammals (e.g., rat and human glucokinase is more than 80%

homologous). However, there are some unusual exceptions: For example, it has not been discovered in cats and bats,

though some reptiles, birds, amphibians, and fish have it. Whether glucokinase occurs similarly in the pancreas and

other organs has not yet been determined. It has been postulated that the presence of glucokinase in liver reflects the

ease with which carbohydrates can be included in the animals' diets.

Function and regulation

Most of the glucokinase in a mammal is found in the liver, and glucokinase provides approximately 95% of the

hexokinase activity in hepatocytes. Phosphorylation of glucose to glucose-6-phosphate (G6P) by glucokinase is thefirst step of both glycogen synthesis and glycolysis in the liver.

When ample glucose is available, glycogen synthesis proceeds at the periphery of the hepatocytes until the cells are

replete with glycogen. Excess glucose is then increasingly converted into triglycerides for export and storage in

adipose tissue. Glucokinase activity in the cytoplasm rises and falls with available glucose.

G6P, the product of glucokinase, is the principal substrate of glycogen synthesis, and glucokinase has a close

functional and regulatory association with glycogen synthesis. When maximally active, GK and glycogen synthase

appears to be located in the same peripheral areas of hepatocyte cytoplasm in which glycogen synthesis occurs. The

supply of G6P affects the rate of glycogen synthesis not only as the primary substrate, but by direct stimulation of

glycogen synthase and inhibition of glycogen phosphorylase.

Glucokinase activity can be rapidly amplified or damped in response to changes in the glucose supply, typically

resulting from eating and fasting. Regulation occurs at several levels and speeds, and is influenced by many factors

that affect mainly two general mechanisms:

1. Glucokinase activity can be amplified or reduced in minutes by actions of the glucokinase regulatory protein

(GKRP). The actions of this protein are influenced by small molecules such as glucose and fructose.

2. The amount of glucokinase can be increased by synthesis of new protein. Insulin is the principal signal for

increased transcription, operating mainly by way of a transcription factor called sterol regulatory element binding

protein-1c (SREBP1c) except in the liver. This occurs within an hour after a rise in insulin levels, as after a

carbohydrate meal.

Transcriptional

Insulin acting via the sterol regulatory element binding protein-1c (SREBP1c) is thought to be the most important

direct activator of glucokinase gene transcription in hepatocytes. SREBP1c is a basic helix-loop-helix zipper

(bHLHZ) transactivator. This class of transactivators bind to the "E box" sequence of genes for a number of

regulatory enzymes. The liver promoter in the first exon of the glucokinase gene includes such an E box, which

appears to be the principal insulin-response element of the gene in hepatocytes. It was previously thought that

SREBP1c must be present for transcription of glucokinase in hepatocytes however, it was recently shown that

glucokinase transcription was carried out normally in SREBP1c knock out mice. SREBP1c increases in response to a

high-carbohydrate diet, presumed as a direct effect of frequent insulin elevation. Increased transcription can be

detected in less than an hour after hepatocytes are exposed to rising insulin levels.
http://en.wikipedia.org/w/index.php?title=Basic_helix-loop-helix_leucine_zipper_transcription_factorshttp://en.wikipedia.org/w/index.php?title=Sterol_regulatory_element_binding_proteinhttp://en.wikipedia.org/w/index.php?title=Sterol_regulatory_element_binding_proteinhttp://en.wikipedia.org/w/index.php?title=Sterol_regulatory_element_binding_proteinhttp://en.wikipedia.org/w/index.php?title=Glycogen_phosphorylasehttp://en.wikipedia.org/w/index.php?title=Glycogen_synthasehttp://en.wikipedia.org/w/index.php?title=Adiposehttp://en.wikipedia.org/w/index.php?title=Triglyceridehttp://en.wikipedia.org/w/index.php?title=Glycolysishttp://en.wikipedia.org/w/index.php?title=Glycogenhttp://en.wikipedia.org/w/index.php?title=Glucose-6-phosphatehttp://en.wikipedia.org/w/index.php?title=Diet_%28nutrition%29http://en.wikipedia.org/w/index.php?title=Fishhttp://en.wikipedia.org/w/index.php?title=Amphibiahttp://en.wikipedia.org/w/index.php?title=Birdhttp://en.wikipedia.org/w/index.php?title=Reptilehttp://en.wikipedia.org/w/index.php?title=Bathttp://en.wikipedia.org/w/index.php?title=Cathttp://en.wikipedia.org/w/index.php?title=Incretin


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Glucokinase 9

Fructose-2,6-bisphosphate (F2,6P2) also stimulates GK transcription, it seems by way of Akt2 rather than SREBP1c.

It is not known whether this effect is one of the downstream effects of activation of insulin receptors or independent

of insulin action. Levels of F2,6P2

play other amplifying roles in glycolysis in hepatocytes.

Other transacting factors suspected of playing a role in liver cell transcription regulation include:

1. Hepatic nuclear factor-4-alpha (HNF4) is an orphan nuclear receptor important in the transcription of many

genes for enzymes of carbohydrate and lipid metabolism. It activates GCKtranscription.2. Upstream stimulatory factor 1 (USF1) is another basic helix-loop-helix zipper (bHLHZ) transactivator.

3. Hepatic nuclear factor 6 (HNF6) is a homeodomain transcriptional regulator of the "one-cut class." HNF6 is also

involved in regulation of transcription of gluconeogenic enzymes such as glucose-6-phosphatase and

phosphoenolpyruvate carboxykinase.

Hormonal and dietary

Insulin is by far the most important of the hormones that have direct or indirect effects on glucokinase expression

and activity in the liver. Insulin appears to affect both glucokinase transcription and activity through multiple direct

and indirect pathways. While rising portal vein glucose levels increase glucokinase activity, the concomitant rise of

insulin amplifies this effect by induction of glucokinase synthesis. Glucokinase transcription begins to rise within an

hour of rising insulin levels. Glucokinase transcription becomes nearly undetectable in prolonged starvation, severe

carbohydrate deprivation, or untreated insulin-deficient diabetes.

The mechanisms by which insulin induces glucokinase may involve both of the major intracellular pathways of

insulin action, the extracellular signal-regulated kinase (ERK 1/2) cascade, and the phosphoinositide 3-kinase

(PI3-K) cascade. The latter may operate via the FOXO1 transactivator.

However, as would be expected given its antagonistic effect on glycogen synthesis, glucagon and its intracellular

second messenger cAMP suppresses glucokinase transcription and activity, even in the presence of insulin.

Other hormones such as triiodothyronine (T3) and glucocorticoids provide permissive or stimulatory effects on

glucokinase in certain circumstances. Biotin and retinoic acid increase GCK mRNA transcription as well as GK

activity. Fatty acids in significant amounts amplify GK activity in the liver, while long chain acyl CoA inhibits it.

Hepatic

Glucokinase can be rapidly activated and inactivated in hepatocytes by a novel regulatory protein (glucokinase

regulatory protein), which operates to maintain an inactive reserve of GK, which can be made quickly available in

response to rising levels of portal vein glucose.[104]

GKRP moves between nucleus and cytoplasm of the hepatocytes and may be tethered to the microfilament

cytoskeleton. It forms reversible 1:1 complexes with GK, and can move it from the cytoplasm into the nucleus. It

acts as a competitive inhibitor with glucose, such that the enzyme activity is reduced to near-zero while bound.

GK:GKRP complexes are sequestered in the nucleus while glucose and fructose levels are low. Nuclear

sequestration may serve to protect GK from degradation by cytoplasmic proteases. GK can be rapidly released from

GKRP in response to rising levels of glucose. Unlike GK in beta cells, GK in hepatocytes is not associated with

mitochondria.

Fructose in tiny (micromolar) amounts (after phosphorylation by ketohexokinase to fructose-1-phosphate (F1P))

accelerates release of GK from GKRP. This sensitivity to the presence of small amounts of fructose allows GKRP,

GK, and ketohexokinase to act as a "fructose sensing system," which signals that a mixed carbohydrate meal is being

digested, and accelerates the utilization of glucose. However, fructose 6-phosphate (F6P) potentiates binding of GK

by GKRP. F6P decreases phosphorylation of glucose by GK when glycogenolysis or gluconeogenesis are underway.

F1P and F6P both bind to the same site on GKRP. It is postulated that they produce 2 different conformations ofGKRP, one able to bind GK and the other not.
http://en.wikipedia.org/w/index.php?title=Gluconeogenesishttp://en.wikipedia.org/w/index.php?title=Glycogenolysishttp://en.wikipedia.org/w/index.php?title=Fructose_6-phosphatehttp://en.wikipedia.org/w/index.php?title=Fructose-1-phosphatehttp://en.wikipedia.org/w/index.php?title=Ketohexokinasehttp://en.wikipedia.org/w/index.php?title=Fructosehttp://en.wikipedia.org/w/index.php?title=Proteasehttp://en.wikipedia.org/w/index.php?title=Cytoskeletonhttp://en.wikipedia.org/w/index.php?title=Cytoplasmhttp://en.wikipedia.org/w/index.php?title=Cell_nucleushttp://en.wikipedia.org/w/index.php?title=GKRPhttp://en.wikipedia.org/w/index.php?title=Glucokinase_regulatory_proteinhttp://en.wikipedia.org/w/index.php?title=Glucokinase_regulatory_proteinhttp://en.wikipedia.org/w/index.php?title=Long_chain_acyl_CoAhttp://en.wikipedia.org/w/index.php?title=Fatty_acidhttp://en.wikipedia.org/w/index.php?title=Retinoic_acidhttp://en.wikipedia.org/w/index.php?title=Biotinhttp://en.wikipedia.org/w/index.php?title=Glucocorticoidhttp://en.wikipedia.org/w/index.php?title=Triiodothyroninehttp://en.wikipedia.org/w/index.php?title=Cyclic_adenosine_monophosphatehttp://en.wikipedia.org/w/index.php?title=Second_messengerhttp://en.wikipedia.org/w/index.php?title=Glucagonhttp://en.wikipedia.org/w/index.php?title=Enzyme_induction_and_inhibitionhttp://en.wikipedia.org/w/index.php?title=Portal_veinhttp://en.wikipedia.org/w/index.php?title=Insulinhttp://en.wikipedia.org/w/index.php?title=Phosphoenolpyruvate_carboxykinasehttp://en.wikipedia.org/w/index.php?title=Glucose-6-phosphatasehttp://en.wikipedia.org/w/index.php?title=Gluconeogenesishttp://en.wikipedia.org/w/index.php?title=Hepatocyte_nuclear_factors%23HNF6http://en.wikipedia.org/w/index.php?title=Basic_helix-loop-helix_leucine_zipper_transcription_factorshttp://en.wikipedia.org/w/index.php?title=USF1http://en.wikipedia.org/w/index.php?title=Hepatocyte_nuclear_factor_4_alphahttp://en.wikipedia.org/w/index.php?title=Fructose-2%2C6-bisphosphate


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Glucokinase 10

Pancreatic

Although most of the glucokinase in the body is in the liver, smaller amounts in the beta and alpha cells of the

pancreas, certain hypothalamic neurons, and specific cells (enterocytes) of the gut play an increasingly appreciated

role in regulation of carbohydrate metabolism. In the context of glucokinase function, these cell types are

collectively referred to as neuroendocrine tissues, and they share some aspects of glucokinase regulation and

function, especially the common neuroendocrine promoter. Of the neuroendocrine cells, the beta cells of thepancreatic islets are the most-studied and best-understood. It is likely that many of the regulatory relationships

discovered in the beta cells will also exist in the other neuroendocrine tissues with glucokinase.

A signal for insulin

In islet beta cells, glucokinase activity serves as a principal control for the secretion of insulin in response to rising

levels of blood glucose. As G6P is consumed, increasing amounts of ATP initiate a series of processes that result in

release of insulin. One of the immediate consequences of increased cellular respiration is a rise in the NADH and

NADPH concentrations (collectively referred to as NAD(P)H). This shift in the redox status of the beta cells results

in rising intracellular calcium levels, closing of the KATP

channels, depolarization of the cell membrane, merging of

the insulin secretory granules with the membrane, and release of insulin into the blood.

It is as a signal for insulin release that glucokinase exerts the largest effect on blood sugar levels and overall

direction of carbohydrate metabolism. Glucose, in turn, influences both the immediate activity and the amount of

glucokinase produced in the beta cells.

Regulation in beta cells

Glucose immediately amplifies glucokinase activity by the cooperativity effect.

A second important rapid regulator of glucokinase activity in beta cells occurs by direct protein-protein interaction

between glucokinase and the "bifunctional enzyme" (phosphofructokinase-2/fructose-2,6-bisphosphatase), which

also plays a role in the regulation of glycolysis. This physical association stabilizes glucokinase in a catalytically

favorable conformation (somewhat opposite the effect of GKRP binding) that enhances its activity.

In as little as 15 minutes, glucose can stimulate GCK transcription and glucokinase synthesis by way of insulin.

Insulin is produced by the beta cells, but some of it acts on beta cell B-type insulin receptors, providing an autocrine

positive-feedback amplification of glucokinase activity. Further amplification occurs by insulin action (via A-type

receptors) to stimulate its own transcription.

Transcription of the GCKgene is initiated through the "upstream," or neuroendocrine, promoter. This promoter, in

contrast to the liver promoter, has elements homologous to other insulin-induced gene promoters. Among the

probable transacting factors are Pdx-1 and PPAR. Pdx-1 is a homeodomain transcription factor involved in the

differentiation of the pancreas. PPAR is a nuclear receptor that responds to glitazone drugs by enhancing insulin

sensitivity.

Association with insulin secretory granules

Much, but not all, of the glucokinase found in the cytoplasm of beta cells is associated with insulin secretory

granules and with mitochondria. The proportion thus "bound" falls rapidly in response to rising glucose and insulin

secretion. It has been suggested that binding serves a purpose similar to the hepatic glucokinase regulatory

proteinprotecting glucokinase from degradation so that it is rapidly available as the glucose rises. The effect is to

amplify the glucokinase response to glucose more rapidly than transcription could do so.[105]
http://en.wikipedia.org/w/index.php?title=PPAR%CE%B3http://en.wikipedia.org/w/index.php?title=Autocrinehttp://en.wikipedia.org/w/index.php?title=Insulin_receptorhttp://en.wikipedia.org/w/index.php?title=Potassium_channelhttp://en.wikipedia.org/w/index.php?title=Calciumhttp://en.wikipedia.org/w/index.php?title=NADPHhttp://en.wikipedia.org/w/index.php?title=NADHhttp://en.wikipedia.org/w/index.php?title=Insulinhttp://en.wikipedia.org/w/index.php?title=Beta_cell


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Glucokinase 11

Suppression of glucagon in alpha cells

It has also been proposed that glucokinase plays a role in the glucose sensing of the pancreatic alpha cells, but the

evidence is less consistent, and some researchers have found no evidence of glucokinase activity in these cells.

Alpha cells occur in pancreatic islets, mixed with beta and other cells. While beta cells respond to rising glucose

levels by secreting insulin, alpha cells respond by reducing glucagon secretion. When blood glucose concentration

falls to hypoglycemic levels, alpha cells release glucagon. Glucagon is a protein hormone that blocks the effect ofinsulin on hepatocytes, inducing glycogenolysis, gluconeogenesis, and reduced glucokinase activity in hepatocytes.

The degree to which glucose suppression of glucagon is a direct effect of glucose via glucokinase in alpha cells, or

an indirect effect mediated by insulin or other signals from beta cells, is still uncertain.

Hypothalamic

While all neurons use glucose for fuel, certain glucose-sensing neurons alter their firing rates in response to rising or

falling levels of glucose. These glucose-sensing neurons are concentrated primarily in the ventromedial nucleus and

arcuate nucleus of the hypothalamus, which regulate many aspects of glucose homeostasis (especially the response

to hypoglycemia), fuel utilization, satiety and appetite, and weight maintenance. These neurons are most sensitive to

glucose changes in the 0.5-3.5 mmol/L glucose range.

Glucokinase has been found in the brain in largely the same areas that contain glucose-sensing neurons, including

both of the hypothalamic nuclei. Inhibition of glucokinase abolishes the ventromedial nucleus response to a meal.

However, brain glucose levels are lower than plasma levels, typically 0.5-3.5 mmol/L. Although this range is

matches the sensitivity of the glucose-sensing neurons, it is below the optimal inflection sensitivity for glucokinase.

The presumption, based on indirect evidence and speculation, is that neuronal glucokinase is somehow exposed to

plasma glucose levels even in the neurons.

Enterocytes and incretin

While glucokinase has been shown to occur in certain cells (enterocytes) of the small intestine and stomach, itsfunction and regulation have not been worked out. It has been suggested that here, also, glucokinase serves as a

glucose sensor, allowing these cells to provide one of the earliest metabolic responses to incoming carbohydrates. It

is suspected that these cells are involved in incretin functions.

Clinical significance

Because insulin is one of, if not the most important, regulators of glucokinase synthesis, diabetes of all types

diminishes glucokinase synthesis and activity by a variety of mechanisms. Glucokinase activity is sensitive to

oxidative stress of cells, especially the beta cells.

Around 200 mutations of the human glucokinase gene GCKhave been discovered, that can change the efficiency of

glucose binding and phosphorylation, increasing or decreasing the sensitivity of beta cell insulin secretion in

response to glucose, and producing clinically significant hyperglycemia or hypoglycemia.
http://en.wikipedia.org/w/index.php?title=Hypoglycemiahttp://en.wikipedia.org/w/index.php?title=Hyperglycemiahttp://en.wikipedia.org/w/index.php?title=Genehttp://en.wikipedia.org/w/index.php?title=Mutationhttp://en.wikipedia.org/w/index.php?title=Diabeteshttp://en.wikipedia.org/w/index.php?title=Incretinhttp://en.wikipedia.org/w/index.php?title=Small_intestinehttp://en.wikipedia.org/w/index.php?title=Body_weighthttp://en.wikipedia.org/w/index.php?title=Appetitehttp://en.wikipedia.org/w/index.php?title=Satietyhttp://en.wikipedia.org/w/index.php?title=Hypothalamushttp://en.wikipedia.org/w/index.php?title=Arcuate_nucleushttp://en.wikipedia.org/w/index.php?title=Ventromedial_nucleushttp://en.wikipedia.org/w/index.php?title=Neuronhttp://en.wikipedia.org/w/index.php?title=Hypoglycemiahttp://en.wikipedia.org/w/index.php?title=Glucagonhttp://en.wikipedia.org/w/index.php?title=Alpha_cell


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Glucokinase 12

Diabetes

Over 190 of these mutations reduce the functional efficiency of the glucokinase molecule. Heterozygosity for alleles

with reduced enzyme activity results in a higher threshold for insulin release and persistent, mild hyperglycemia.

This condition is referred to as maturity onset diabetes of the young, type 2 (MODY2).

Homozygosity for GCKalleles with reduced function can cause severe congenital insulin deficiency, resulting in

persistent neonatal diabetes.

Hyperinsulinemic hypoglycemia

As of 2004, 5 mutations have been found to enhance insulin secretion. Heterozygosity for gain of function mutations

reduces the threshold glucose that triggers insulin release. This creates hypoglycemia of varying patterns, including

transient or persistent congenital hyperinsulinism, or fasting or reactive hypoglycemia appearing at an older age.

Homozygosity for gain of function mutations has not been found.

As a drug target

Several laboratories sponsored by pharmaceutical companies are researching molecules that activate glucokinase in

hope that it will be useful in the treatment of type 2 diabetes.[106]

References

[1] http:/ /www.rcsb. org/pdb/cgi/explore.cgi?pdbId=1GLK

[2] http:/ /www.rcsb. org/pdb/cgi/explore.cgi?pdbId=1V4S

[3] http:/ /www.rcsb. org/pdb/cgi/explore.cgi?pdbId=1V4T

[4] http:/ /www.rcsb. org/pdb/cgi/explore.cgi?pdbId=3A0I

[5] http:/ /www.rcsb. org/pdb/cgi/explore.cgi?pdbId=3F9M

[6] http:/ /www.rcsb. org/pdb/cgi/explore.cgi?pdbId=3FGU

[7] http:/ /www.rcsb. org/pdb/cgi/explore.cgi?pdbId=3FR0

[8] http:/ /www.rcsb. org/pdb/cgi/explore.cgi?pdbId=3H1V

[9] http:/ /www.rcsb. org/pdb/cgi/explore.cgi?pdbId=3ID8

[10] http://www.rcsb. org/pdb/cgi/explore. cgi?pdbId=3IDH

[11] http://www.rcsb. org/pdb/cgi/explore. cgi?pdbId=3IMX

[12] http://www.genenames. org/data/hgnc_data. php?hgnc_id=4195

[13] http://omim. org/entry/138079

[14] http://www.informatics. jax.org/searches/accession_report. cgi?id=MGI:1270854

[15] http://www.ncbi.nlm. nih.gov/entrez/query. fcgi?cmd=Retrieve& db=homologene& dopt=HomoloGene& list_uids=55440

[16] http://www.genecards. org/cgi-bin/carddisp. pl?id_type=entrezgene& id=2645

[17] http://www.genome. jp/dbget-bin/www_bget?enzyme+ 2. 7.1.2

[18] http://amigo. geneontology. org/cgi-bin/amigo/go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0000166














[32] http:/

/

amigo.

geneontology.

org/

cgi-bin/

amigo/

go.

cgi?view=details&

search_constraint=terms&

depth=0&

query=GO:0031018[33] http://amigo. geneontology. org/cgi-bin/amigo/go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0032024

http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0032869http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0032024http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0031018http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0015758http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0010827http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0008645http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0006110http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0005975http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0005829http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0005654http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0016740http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0016301http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0005536http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0005524http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0005515http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0004340http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&search_constraint=terms&depth=0&query=GO:0000166http://www.genome.jp/dbget-bin/www_bget?enzyme+2.7.1.2http://www.genecards.org/cgi-bin/carddisp.pl?id_type=entrezgene&id=2645http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=homologene&dopt=HomoloGene&list_uids=55440http://www.informatics.jax.org/searches/accession_report.cgi?id=MGI:1270854http://omim.org/entry/138079http://www.genenames.org/data/hgnc_data.php?hgnc_id=4195http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3IMXhttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3IDHhttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3ID8http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3H1Vhttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3FR0http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3FGUhttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3F9Mhttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3A0Ihttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=1V4Thttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=1V4Shttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=1GLKhttp://en.wikipedia.org/w/index.php?title=Diabetes_mellitus_type_2http://en.wikipedia.org/w/index.php?title=Pharmaceutical_companyhttp://en.wikipedia.org/w/index.php?title=Congenital_hyperinsulinismhttp://en.wikipedia.org/w/index.php?title=Neonatal_diabeteshttp://en.wikipedia.org/w/index.php?title=Homozygoushttp://en.wikipedia.org/w/index.php?title=Maturity_onset_diabetes_of_the_younghttp://en.wikipedia.org/w/index.php?title=Heterozygous


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Glucokinase 13









[43] http://amigo. geneontology. org/cgi-bin/amigo/gp-assoc. cgi?gp=UniProtKB:P35557

[44] http://www.ebi.ac.uk/QuickGO/GProtein?ac=P35557

[45] http://biogps. org/gene/2645/

[46] http://www.ncbi.nlm. nih.gov/entrez/query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=2645& rn=1

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[49] http://www.ensembl. org/Mus_musculus/geneview?gene=ENSMUSG00000041798;db=core

[50] http://www.uniprot. org/uniprot/P35557

[51] http://www.uniprot. org/uniprot/Q5SVI5

[52] http://www.ncbi.nlm. nih.gov/entrez/viewer. fcgi?val=NM_000162. 3

[53] http://www.ncbi.nlm. nih.gov/entrez/viewer. fcgi?val=NM_010292. 4

[54] http:/

/

www.

ncbi.

nlm.

nih.

gov/

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[56] http://genome. ucsc. edu/cgi-bin/hgTracks?org=Human& db=hg19& position=chr7:44183872-44237769

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[60] http://www.chem.qmul. ac.uk/iubmb/enzyme/EC2/7/1/2.html

[61] http://toolserver. org/~magnus/cas.php?language=en& cas=9001-36-9& title=

[62] http://www.ebi.ac.uk/intenz/query?cmd=SearchEC& ec=2.7. 1.2

[63] http://www.brenda-enzymes. org/php/result_flat. php4?ecno=2. 7. 1.2

[64] http://www.expasy. org/enzyme/2.7. 1.2

[65] http://www.genome. ad.jp/dbget-bin/www_bget?enzyme+ 2. 7.1. 2

[66] http://biocyc. org/META/substring-search?type=NIL& object=2. 7.1.2

[67] http://priam. prabi. fr/cgi-bin/PRIAM_profiles_CurrentRelease. pl?EC=2. 7.1.2

[68] http://www.rcsb. org/pdb/search/smartSubquery. do?smartSearchSubtype=EnzymeClassificationQuery& Enzyme_Classification=2. 7.1.

2

[69] http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/enzyme/?ec=2.7. 1.2

[70] http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/enzymes/GetPage. pl?ec_number=2. 7. 1. 2

[71] http://amigo. geneontology. org/cgi-bin/amigo/go. cgi?query=GO:0004340& view=details

[72] http://www.ebi.ac.uk/ego/DisplayGoTerm?id=GO:0004340& format=normal

[73] http://www.ncbi.nlm. nih.gov/entrez/query. fcgi?db=pubmed& term=2. 7.1.2%5BEC/

RN%20Number%5D%20AND%20pubmed%20pmc%20local%5Bsb%5D

[74] http://www.ncbi.nlm. nih.gov/entrez/query. fcgi?db=pubmed& term=2. 7.1.2%5BEC/RN%20Number%5D

[75] http://enzyme. expasy. org/EC/2. 7. 1.2

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html. Retrieved 4/1/2011.

External links

GeneReviews/NCBI/NIH/UW entry on Familial Hyperinsulinism (http://www.ncbi. nlm.nih.gov/books/

NBK1375/)

GeneReviews/NCBI/NIH/UW entry on Permanent Neonatal Diabetes Mellitus (http://www.ncbi.nlm.nih.gov/

bookshelf/br.fcgi?book=gene& part=dmn)

MeSH Glucokinase (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=& term=Glucokinase)
http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Glucokinasehttp://en.wikipedia.org/w/index.php?title=Medical_Subject_Headingshttp://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=dmnhttp://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=dmnhttp://www.ncbi.nlm.nih.gov/books/NBK1375/http://www.ncbi.nlm.nih.gov/books/NBK1375/http://www.nature.com/nrd/journal/v8/n5/abs/nrd2850.htmlhttp://www.nature.com/nrd/journal/v8/n5/abs/nrd2850.htmlhttp://www.jbc.org/cgi/pmidlookup?view=long&pmid=8106409http://www.jbc.org/cgi/pmidlookup?view=long&pmid=8106409http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2557341http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPfamStr.pl?pfam_id=PF02685http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/pfam/?pfam=PF02685http://www.rcsb.org/pdb/search/smartSubquery.do?smartSearchSubtype=PfamIdQuery&pfamID=PF02685http://pfam.sanger.ac.uk/family/PF02685#tabview=tab8http://supfam.org/SUPERFAMILY/cgi-bin/search.cgi?search_field=1q18http://scop.mrc-lmb.cam.ac.uk/scop/search.cgi?tlev=fa;&pdb=1q18http://www.ebi.ac.uk/interpro/DisplayIproEntry?ac=IPR003836http://pfam.sanger.ac.uk/clan/CL0108http://pfam.sanger.ac.uk/family?acc=PF02685http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=9519733


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Article Sources and Contributors 15

Article Sources and ContributorsGlucokinase Source: http://en.wikipedia.org/w/index.php?oldid=471335651 Contributors: Abergabe, Alexbateman, AlistairMcMillan, Alteripse, Antonone, Arcadian, Beetstra, Bobblewik,

Boghog, CDN99, CanisRufus, Ceyockey, Charon1, DabMachine, Delta G, Drphilharmonic, Dunro, Emirkalyoncu, Franzeska, Gaius Cornelius, Gene Nygaard, Graham87, HBeevers,

HappyApple, Ike9898, JaGa, Jag123, Jfdwolff, Jmun7616, John, K!roman, Kaarel, Killdevil, Knowledge Seeker, Lokicarbis, Mat8989, MiPe, Night of the Big Wind Turbo, Omerzu, Pleiotrope,

R'n'B, RelentlessRecusant, Rjwilmsi, Seren-dipper, Spyderhydrant, StatAustin, Stevenfruitsmaak, Szquirrel, TheTito, Thue, Tito4000, Truthflux, Viridae, Woohookitty, Zoicon5, 28 anonymous

edits

Image Sources, Licenses and Contributorsfile:Glucokinase-1GLK.png Source: http://en.wikipedia.org/w/index.php?title=File:Glucokinase-1GLK.png License: Public Domain Contributors: User Jag123 on en.wikipedia

file:PBB_GE_GCK_211167_s_at_tn.png Source: http://en.wikipedia.org/w/index.php?title=File:PBB_GE_GCK_211167_s_at_tn.png License: GNU Free Documentation License

Contributors: -

File:Glucokinase.png Source: http://en.wikipedia.org/w/index.php?title=File:Glucokinase.png License: Public Domain Contributors: Jmun7616

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Hexokinase (Englisch)