Aldose 1-epimerase

 

Aldose 1-epimerase, also known as galactose mutarotase, catalyses the interconversion of beta-D-galactose and alpha-D-galactose, as well as other sugars such as glucose. It is required for normal galactose metabolism, and catalyses the first step of the Leloir pathway. The net result of the pathway is the conversion of beta-D-galactose into alpha-D-glucose-1-phosphate. The enzyme shows an approximately four-fold preference for galactose over gulcose.

Mutations of enzymes involved in this pathway are often associated with galactosemia. This hereditary disease presents early onset of cataracts, typically within the first two years of life and in severe cases it can result in liver, kidney and brain damage.

 

Reference Protein and Structure

Sequence
Q96C23 UniProt (5.1.3.3) IPR015443 (Sequence Homologues) (PDB Homologues)
Biological species
Homo sapiens (Human) Uniprot
PDB
1snz - Crystal structure of apo human galactose mutarotase (2.2 Å) PDBe PDBsum 1snz
Catalytic CATH Domains
2.70.98.10 CATHdb (see all for 1snz)
Click To Show Structure

Enzyme Reaction (EC:5.1.3.3)

beta-D-glucose
CHEBI:15903ChEBI
→
alpha-D-glucose
CHEBI:17925ChEBI
Alternative enzyme names: Aldose mutarotase, Mutarotase,

Enzyme Mechanism

Introduction

Simultaneous protonation of the oxygen ring by His176 and deprotonation of the hydroxyl attached to carbon-1 by Glu307 results in ring opening. Reversal of these protonation events results in ring closure and reversal of configuration about carbon-1.

Catalytic Residues Roles

UniProt PDB* (1snz)
Glu307 Glu307(309)A Positioned within 2.8 angstroms of the 1-hydroxyl group of galactose and may serve as the catalytic base in the first step. hydrogen bond acceptor, hydrogen bond donor, proton acceptor, proton donor, activator
His107 His107(109)A Acts to stabilise its neighbouring His176 through hydrogen bonding [PMID:12717027]. hydrogen bond acceptor, electrostatic stabiliser
His176 His176(178)A Positioned within 2.8 angstroms of the ring oxygen and may serve as the catalytic acid in the first step. hydrogen bond acceptor, hydrogen bond donor, proton acceptor, proton donor, activator
*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

proton transfer, intramolecular nucleophilic addition, intermediate formation, overall product formed, native state of enzyme regenerated

References

  1. Thoden JB et al. (2003), Protein Sci, 12, 1051-1059. The catalytic mechanism of galactose mutarotase. DOI:10.1110/ps.0243203. PMID:12717027.
  2. Thoden JB et al. (2004), J Biol Chem, 279, 23431-23437. Molecular Structure of Human Galactose Mutarotase. DOI:10.1074/jbc.m402347200. PMID:15026423.
  3. Timson DJ et al. (2003), FEBS Lett, 543, 21-24. Identification and characterisation of human aldose 1-epimerase. DOI:10.1016/s0014-5793(03)00364-8. PMID:12753898.
  4. Beebe JA et al. (1998), Biochemistry, 37, 14989-14997. Galactose Mutarotase:  Purification, Characterization, and Investigations of Two Important Histidine Residues†. DOI:10.1021/bi9816047. PMID:9778377.

Step 1. The carboxylate group of Glu307 abstracts the C1 hydroxyl proton and initiates ring opening with concomitant deprotonation of His176.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Glu307(309)A activator, hydrogen bond acceptor
His107(109)A hydrogen bond acceptor, electrostatic stabiliser
His176(178)A activator, hydrogen bond donor, proton donor
Glu307(309)A proton acceptor

Chemical Components

proton transfer, ingold: intramolecular nucleophilic addition, intermediate formation

Step 2. Bond rotation between C1 and C2 is followed by abstraction of the C5 oxygen, and donation of a proton back to the C1 oxygen, forming the product.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Glu307(309)A activator, hydrogen bond donor
His107(109)A hydrogen bond acceptor, electrostatic stabiliser
His176(178)A activator, hydrogen bond acceptor, proton acceptor
Glu307(309)A proton donor

Chemical Components

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

Step 1. The carboxylate group of Glu307 abstracts the C1 hydroxyl proton and initiates ring opening with concomitant deprotonation of His176.

Step 2. Bond rotation between C1 and C2 is followed by abstraction of the C5 oxygen, and donation of a proton back to the C1 oxygen, forming the product.

Products.

Contributors

Sophie T. Williams, Gemma L. Holliday