L-3-hydroxyacyl-CoA dehydrogenase

 

L-3-hydroxyacyl-CoA dehydrogenase reversibly catalyses the conversion of L-3-hydroxyacyl-CoA to the 3-ketoyl acid derivative by proton abstraction and concurrent oxidation by the NAD+ cofactor, the penultimate step in the beta-oxidation spiral, and involved in fatty acid metabolism.

 

Reference Protein and Structure

Sequence
Q16836 UniProt (1.1.1.35) IPR022694 (Sequence Homologues) (PDB Homologues)
Biological species
Homo sapiens (Human) Uniprot
PDB
2hdh - BIOCHEMICAL CHARACTERIZATION AND STRUCTURE DETERMINATION OF HUMAN HEART SHORT CHAIN L-3-HYDROXYACYL COA DEHYDROGENASE PROVIDE INSIGHT INTO CATALYTIC MECHANISM (2.2 Å) PDBe PDBsum 2hdh
Catalytic CATH Domains
3.40.50.720 CATHdb (see all for 2hdh)
Click To Show Structure

Enzyme Reaction (EC:1.1.1.35)

(S)-3-hydroxyacyl-CoA(4-)
CHEBI:57318ChEBI
+
NAD(1-)
CHEBI:57540ChEBI
→
3-oxoacyl-CoA(4-)
CHEBI:90726ChEBI
+
hydron
CHEBI:15378ChEBI
+
NADH(2-)
CHEBI:57945ChEBI
Alternative enzyme names: 1-specific DPN-linked beta-hydroxybutyric dehydrogenase, 3-L-hydroxyacyl-CoA dehydrogenase, 3-hydroxyacetyl-coenzyme A dehydrogenase, 3-hydroxyacyl coenzyme A dehydrogenase, 3-hydroxybutyryl-CoA dehydrogenase, 3-hydroxyisobutyryl-CoA dehydrogenase, 3-keto reductase, 3-beta-hydroxyacyl coenzyme A dehydrogenase, Beta-hydroxy acid dehydrogenase, Beta-hydroxyacyl CoA dehydrogenase, Beta-hydroxyacyl dehydrogenase, Beta-hydroxyacyl-coenzyme A synthetase, Beta-hydroxyacylcoenzyme A dehydrogenase, Beta-hydroxybutyrylcoenzyme A dehydrogenase, Beta-keto-reductase, Beta-ketoacyl-CoA reductase, L-3-hydroxyacyl CoA dehydrogenase, L-3-hydroxyacyl coenzyme A dehydrogenase,

Enzyme Mechanism

Introduction

The Glu-His diad, conserved across all functionally related enzymes, acts in concert to deprotonate the 3-OH of the substrate. The oxyanion intermediate collapses, eliminating a hydride to the C4 position of the NAD cofactor. A proton transfer step has been inferred to allow for active site regeneration.

Catalytic Residues Roles

UniProt PDB* (2hdh)
Asn220, Ser149 Asn208(197)A, Ser137(126)A Acts to stabilise the reactive intermediates and transition states formed during the course of the reaction. hydrogen bond donor, electrostatic stabiliser
Glu182 Glu170(159)A Activates the general acid/base histidine as part of a His-Glu catalytic dyad. increase basicity, hydrogen bond acceptor, electrostatic stabiliser
His170 His158(147)A Acts as a general acid/base. 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

proton transfer, overall reactant used, intermediate formation, hydride transfer, intermediate collapse, cofactor used, native state of cofactor is not regenerated, native state of enzyme regenerated, inferred reaction step

References

  1. Barycki JJ et al. (1999), Biochemistry, 38, 5786-5798. Biochemical Characterization and Crystal Structure Determination of Human Heart Short Chainl-3-Hydroxyacyl-CoA Dehydrogenase Provide Insights into Catalytic Mechanism†. DOI:10.1021/bi9829027. PMID:10231530.
  2. Barycki JJ et al. (2001), J Biol Chem, 276, 36718-36726. Glutamate 170 of Human L-3-Hydroxyacyl-CoA Dehydrogenase Is Required for Proper Orientation of the Catalytic Histidine and Structural Integrity of the Enzyme. DOI:10.1074/jbc.m104839200. PMID:11451959.

Step 1. The Glu-His diad, conserved across all functionally related enzymes, acts in concert to deprotonate the 3-OH of the substrate. While an initial proton abstraction is shown, there is no direct evidence to suggest that a concerted mechanism, or a hydride transfer followed by proton abstraction do not occur [PMID:10231530].

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Glu170(159)A hydrogen bond acceptor, electrostatic stabiliser, increase basicity
Asn208(197)A electrostatic stabiliser, hydrogen bond donor
Ser137(126)A hydrogen bond donor, electrostatic stabiliser
His158(147)A proton acceptor

Chemical Components

proton transfer, overall reactant used, intermediate formation

Step 2. The oxyanion intermediate collapses, eliminating a hydride to the C4 position of the NAD cofactor.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Glu170(159)A hydrogen bond acceptor, electrostatic stabiliser
Asn208(197)A electrostatic stabiliser, hydrogen bond donor
Ser137(126)A hydrogen bond donor, electrostatic stabiliser

Chemical Components

hydride transfer, overall reactant used, intermediate collapse, cofactor used, native state of cofactor is not regenerated

Step 3. A proton transfer step has been inferred to allow for active site regeneration.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Glu170(159)A hydrogen bond acceptor, electrostatic stabiliser
Asn208(197)A hydrogen bond donor
Ser137(126)A hydrogen bond donor
His158(147)A proton donor

Chemical Components

proton transfer, native state of enzyme regenerated, inferred reaction step
Download: Image, Marvin File

Step 1. The Glu-His diad, conserved across all functionally related enzymes, acts in concert to deprotonate the 3-OH of the substrate. While an initial proton abstraction is shown, there is no direct evidence to suggest that a concerted mechanism, or a hydride transfer followed by proton abstraction do not occur [PMID:10231530].

Step 2. The oxyanion intermediate collapses, eliminating a hydride to the C4 position of the NAD cofactor.

Step 3. A proton transfer step has been inferred to allow for active site regeneration.

Products.

Contributors

Sophie T. Williams, Gemma L. Holliday, Carine Berezin, Craig Porter