(3R)-hydroxyacyl-CoA dehydrogenase

 

Mammalian peroxisomal multifunctional enzyme type 2 (MFE-2) is important in the beta-oxidation of very-long-chain and alpha-methyl-branched fatty acids as well as the synthesis of bile acids. It has three units: a dehydrogenase unit, an sterol carrier protein (SCP) -like unit and a central hydratase unit.

This entry represents the dehydrogenase unit oxidises the C3 hydroxyl group of (3R)-hydroxyacyl-CoA molecules to obtain the corresponding (3R)-ketoacyl-CoA. It belongs to the short chain alcohol dehydrogenase/reductase (SDR) superfamily.

 

Reference Protein and Structure

Sequence
P97852 UniProt (4.2.1.107, 4.2.1.119, 1.1.1.n12) IPR002347 (Sequence Homologues) (PDB Homologues)
Biological species
Rattus norvegicus (Norway rat) Uniprot
PDB
1gz6 - (3R)-HYDROXYACYL-COA DEHYDROGENASE FRAGMENT OF RAT PEROXISOMAL MULTIFUNCTIONAL ENZYME TYPE 2 (2.38 Å) PDBe PDBsum 1gz6
Catalytic CATH Domains
3.40.50.720 CATHdb (see all for 1gz6)
Click To Show Structure

Enzyme Reaction (EC:1.1.1.-)

(R)-3-hydroxyacyl-CoA(4-)
CHEBI:57319ChEBI
+
NAD(1-)
CHEBI:57540ChEBI
→
3-oxoacyl-CoA(4-)
CHEBI:90726ChEBI
+
hydron
CHEBI:15378ChEBI
+
NADH(2-)
CHEBI:57945ChEBI

Enzyme Mechanism

Introduction

Lys 168 is protonated and decreases the pKa of Tyr 164 so that Tyr is deprotonated. Tyr 164 can then deprotonate the hydroxy group of 3-hydroxyacyl-CoA.

The reaction is concerted (E1-like elimination of H2) so that the deprotonation occurs at the same time as the C3 hydride is delivered to NAD+. Ser 151 may stabilise the transition state (it hydrogen bonds to the substrate hydroxyl group) but its role is thought to be mainly to ensure correct orientation of the substrate.

The oxidised product is 3-ketoacyl CoA.

Catalytic Residues Roles

UniProt PDB* (1gz6)
Tyr164 Tyr164A Tyr 164 exists in the deprotonated form. It acts as a general base to deprotonate the hydroxy group of the substrate. proton shuttle (general acid/base)
Lys168 Lys168A Lys 168 lowers the pKa of Tyr 164 so that Tyr can exist in its deprotonated form. activator, electrostatic stabiliser
*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

References

  1. Haapalainen AM et al. (2003), Structure, 11, 87-97. Binary Structure of the Two-Domain (3R)-Hydroxyacyl-CoA Dehydrogenase from Rat Peroxisomal Multifunctional Enzyme Type 2 at 2.38 Å Resolution. DOI:10.1016/s0969-2126(02)00931-0. PMID:12517343.

Step 1.

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Catalytic Residues Roles

Residue Roles
Tyr164A proton shuttle (general acid/base)
Lys168A electrostatic stabiliser, activator

Chemical Components

Step 1.

Contributors

Gemma L. Holliday, Jonathan T. W. Ng