Delta(3,5)-delta(2,4)-dienoyl-CoA isomerase

 

Fatty acids are metabolised by sequential removal of two-carbon units by oxidation at the beta-carbon. Only saturated fatty acids or unsaturated fatty acids with double bonds extending from even-numbered carbon atoms can enter the main beta-oxidation pathway, so double bonds at odd-numbered carbon atoms in unsaturated fatty acids has to be converted to even-numbered double bonds to enter beta-oxidation. Dienoyl-CoA isomerase catalyses the conversion of 3-trans,5-cis dienoyl-CoA into 2-trans,4-trans dienoyl-CoA.

The enzyme is present in mitochondria and peroxisomes. It uses fatty acyl substrates with side-chains ranging at least from C8 to C20. The reaction used as example uses a C8 compund as substrate. This enzyme also exhibits delta(3,5,7)-delta(2,4,6)-trienoyl-CoA isomerase activity [PMID:11278886].

 

Reference Protein and Structure

Sequence
Q62651 UniProt (5.3.3.-) IPR001753 (Sequence Homologues) (PDB Homologues)
Biological species
Rattus norvegicus (Norway rat) Uniprot
PDB
1dci - DIENOYL-COA ISOMERASE (1.5 Å) PDBe PDBsum 1dci
Catalytic CATH Domains
3.90.226.10 CATHdb (see all for 1dci)
Click To Show Structure

Enzyme Reaction (EC:5.3.3.-)

(3E,5Z)-tetradecadienoyl-CoA(4-)
CHEBI:71586ChEBI
→
trans,trans-deca-2,4-dienoyl-CoA(4-)
CHEBI:62244ChEBI

Enzyme Mechanism

Introduction

Glu196 acts as a base to abstract a proton from C2 to initiate the shifting of the double bonds. Asp204 donates a proton to C6 to complete the reaction.

Catalytic Residues Roles

UniProt PDB* (1dci)
Glu196 Glu196(144)A Acts as a base to abstract a proton from C2. hydrogen bond acceptor, proton acceptor, polar/non-polar interaction
Asp204 Asp204(152)A Acts as an acid to donate a proton to C6. proton donor, polar/non-polar interaction
Asp176 Asp176(124)A Activates Glu196 to act as a general acid/base. The hydrogen bond between Glu196 and Asp176 plays an important role in increasing the pKa of Glu196 to the level required for catalysis [PMID:9739087]. activator, hydrogen bond donor, electrostatic stabiliser
Gly173 (main-N), Ile117 (main-N) Gly173(121)A (main-N), Ile117(65)A (main-N) Form an oxyanion hole, binding the C=O group of the CoA substrate. These residues hold the substrate in place and help stabilise the negatively charged transition state formed. transition state 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

proton transfer, assisted tautomerisation (not keto-enol), native state of enzyme regenerated, overall product formed, proton relay, overall reactant used

References

  1. Modis Y et al. (1998), Structure, 6, 957-970. The crystal structure of dienoyl-CoA isomerase at 1.5 å resolution reveals the importance of aspartate and glutamate sidechains for catalysis. DOI:10.1016/s0969-2126(98)00098-7. PMID:9739087.
  2. Zhang D et al. (2001), J Biol Chem, 276, 13622-13627. Delta 3,5,delta 2,4-dienoyl-CoA isomerase is a multifunctional isomerase. A structural and mechanistic study. DOI:10.1074/jbc.M011315200. PMID:11278886.

Step 1. Glu196 OE2 atom abstracts a proton from C2 of the substrate, initiating a rearrangement of double bonds, causing Asp204 to donate its proton to C6 of the substrate. This is facilitated by the binding of the thioester oxygen atom in the oxyanion hole formed by the peptide nitrogens of Ile117 and of Gly173. At the end of this step, the enzyme is ready to perform the reverse isomerisation reaction.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Glu196(144)A polar/non-polar interaction, hydrogen bond acceptor
Asp176(124)A activator, hydrogen bond donor, electrostatic stabiliser
Asp204(152)A polar/non-polar interaction
Ile117(65)A (main-N) transition state stabiliser
Gly173(121)A (main-N) transition state stabiliser
Asp204(152)A proton donor
Glu196(144)A proton acceptor

Chemical Components

proton transfer, assisted tautomerisation (not keto-enol), native state of enzyme regenerated, overall product formed, proton relay, overall reactant used
Download: Image, Marvin File

Step 1. Glu196 OE2 atom abstracts a proton from C2 of the substrate, initiating a rearrangement of double bonds, causing Asp204 to donate its proton to C6 of the substrate. This is facilitated by the binding of the thioester oxygen atom in the oxyanion hole formed by the peptide nitrogens of Ile117 and of Gly173. At the end of this step, the enzyme is ready to perform the reverse isomerisation reaction.

Products.

Contributors

Daniel E. Almonacid, Sophie T. Williams, Mei Leung, Gemma L. Holliday