Glucokinase

 

Human glucokinase is a cytoplasmic enzyme that uses ATP to phosphorylate glucose imported into the cell to glucose 6-phosphate in glycolysis. It is classified as a glucokinase (EC 2.7.1.2) rather than a hexokinase (EC 2.7.1.1) on the basis of its substrate specificity: the enzyme shows much greater activity with glucose than with either mannose or galactose, and no activity with fructose. It is located in hepatacytes and pancreatic beta cells and important in maintaining the cells' glucose homeostasis.

 

Reference Protein and Structure

Sequence
P35557 UniProt (2.7.1.1) IPR003836 (Sequence Homologues) (PDB Homologues)
Biological species
Homo sapiens (Human) Uniprot
PDB
3idh - Human pancreatic glucokinase in complex with glucose (2.14 Å) PDBe PDBsum 3idh
Catalytic CATH Domains
3.30.420.40 CATHdb (see all for 3idh)
Cofactors
Magnesium(2+) (1), Water (3)
Click To Show Structure

Enzyme Reaction (EC:2.7.1.2)

ATP(4-)
CHEBI:30616ChEBI
+
D-glucopyranose
CHEBI:4167ChEBI
→
ADP(3-)
CHEBI:456216ChEBI
+
hydron
CHEBI:15378ChEBI
+
D-glucopyranose 6-phosphate(2-)
CHEBI:61548ChEBI
Alternative enzyme names: Glucokinase (phosphorylating), Glucose kinase,

Enzyme Mechanism

Introduction

Asp 100 acts as a general base to remove a proton from the O6 hydroxyl group of glucose, which can then attack the gamma phosphorous of ATP. Simultaneously, Lys 169 acts as an acid catalyst, protonating the gamma phosphate's O3. There is then subsequent proton transfer from Asp205 to Lys169 so that the enzyme is ready for another round of catalysis.

Catalytic Residues Roles

UniProt PDB* (3idh)
Asp205 Asp205(210)A Acts as a general base to activate the O6 hydroxyl group on glucose. metal ligand, proton acceptor, proton donor
Lys169 Lys169(174)A Acts as a general acid catalyst by protonating the gamma phosphate. proton acceptor, proton donor
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file; y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain; C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.

Chemical Components

bimolecular nucleophilic substitution, proton transfer, overall reactant used, overall product formed, proton relay, native state of enzyme regenerated

References

  1. Lunin VV et al. (2004), J Bacteriol, 186, 6915-6927. Crystal Structures of Escherichia coli ATP-Dependent Glucokinase and Its Complex with Glucose. DOI:10.1128/jb.186.20.6915-6927.2004. PMID:15466045.
  2. Petit P et al. (2011), Acta Crystallogr D Biol Crystallogr, 67, 929-935. The active conformation of human glucokinase is not altered by allosteric activators. DOI:10.1107/S0907444911036729. PMID:22101819.
  3. Zhang J et al. (2009), PLoS One, 4, e6304-. Lys169 of human glucokinase is a determinant for glucose phosphorylation: implication for the atomic mechanism of glucokinase catalysis. DOI:10.1371/journal.pone.0006304. PMID:19617908.

Step 1. Asp205 deprotonates the 6' OH of glucose, increasing its nucleophilicity to then attack the gamma phosphate on ATP. Lys 169 protonates the gamma phosphate concomitantly.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Asp205(210)A metal ligand
Lys169(174)A proton donor
Asp205(210)A proton acceptor

Chemical Components

ingold: bimolecular nucleophilic substitution, proton transfer, overall reactant used, overall product formed

Step 2. Proton transfer from Asp205 to Lys169 via the gamma phosphate non-bridging O.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Asp205(210)A metal ligand
Lys169(174)A proton acceptor
Asp205(210)A proton donor

Chemical Components

proton relay, proton transfer, native state of enzyme regenerated, overall product formed
Download: Image, Marvin File

Step 1. Asp205 deprotonates the 6' OH of glucose, increasing its nucleophilicity to then attack the gamma phosphate on ATP. Lys 169 protonates the gamma phosphate concomitantly.

Step 2. Proton transfer from Asp205 to Lys169 via the gamma phosphate non-bridging O.

Products.

Contributors

Steven Smith, Gemma L. Holliday, Morwenna Hall