3-hydroxyisobutyryl-CoA hydrolase

 

Hydrolyses 3-hydroxyisobutyryl-CoA (HIBYL-CoA), a saline catabolite. Has high activity toward isobutyryl-CoA. Could be an isobutyryl-CoA dehydrogenase that functions in valine catabolism. Also hydrolyses 3-hydroxypropanoyl-CoA. Involved in the pathway L-valine degradation, which is part of Amino-acid degradation. A member of the crotonase superfamily.

 

Reference Protein and Structure

Sequence
Q6NVY1 UniProt (3.1.2.4) IPR032259 (Sequence Homologues) (PDB Homologues)
Biological species
Homo sapiens (Human) Uniprot
PDB
3bpt - Crystal structure of human beta-hydroxyisobutyryl-CoA hydrolase in complex with quercetin (1.5 Å) PDBe PDBsum 3bpt
Catalytic CATH Domains
3.90.226.40 CATHdb (see all for 3bpt)
Click To Show Structure

Enzyme Reaction (EC:3.1.2.4)

water
CHEBI:15377ChEBI
+
3-hydroxy-2-methylpropanoyl-CoA(4-)
CHEBI:57340ChEBI
→
3-hydroxyisobutyrate
CHEBI:11805ChEBI
+
coenzyme A(4-)
CHEBI:57287ChEBI
+
hydron
CHEBI:15378ChEBI
Alternative enzyme names: 3-hydroxy-isobutyryl CoA hydrolase, HIB CoA deacylase,

Enzyme Mechanism

Introduction

Glu169 nucleophilicly attacks the carboxylate group on the substrate to generate an anhydride intermediate. This is facilitated by the binding of the thioester oxygen atom to an oxyanion hole formed by the peptide nitrogens of Gly98 and of Gly146. The anhydride intermediate undergoes internal elimination to produce CoA and an intermediate. A water molecule, activated by Asp177A, attacks the carbonyl carbon of the covalently attached Glu169A. The final intermediate undergoes internal elimination to liberate the Glu169A and producing 3-hydroxy-2-methylpropanoate.

Catalytic Residues Roles

UniProt PDB* (3bpt)
Gly146 (main-N), Gly98 (main-N) Gly146(116)A (main-N), Gly98(68)A (main-N) Forms an oxyanion hole that stabilises the reactive intermediates and transition states formed during the course of the reaction. hydrogen bond donor, electrostatic stabiliser
Glu169 Glu169(139)A Acts as a catalytic nucleophile. It attacks the carbonyl group of the CoA substrate and is eliminated by Asp177 activated water covalently attached, hydrogen bond donor, nucleophile, polar interaction, proton donor, activator, electrofuge, electrophile
Asp177 Asp177(147)A Acts as a general acid/base. It first donates a proton to the CoA leaving group and then abstracts a proton from the catalytic water to initiate the cleavage of the enzyme-substrate bond formed. hydrogen bond acceptor, hydrogen bond donor, proton acceptor, proton donor, increase acidity
*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 addition, overall reactant used, intermediate formation, enzyme-substrate complex formation, unimolecular elimination by the conjugate base, proton transfer, intermediate collapse, overall product formed, intermediate terminated, enzyme-substrate complex cleavage, inferred reaction step, native state of enzyme regenerated

References

  1. Wong BJ et al. (2003), J Am Chem Soc, 125, 12076-12077. Divergent Function in the Crotonase Superfamily:  An Anhydride Intermediate in the Reaction Catalyzed by 3-Hydroxyisobutyryl-CoA Hydrolase. DOI:10.1021/ja037652i. PMID:14518977.
  2. Zolman BK et al. (2001), J Biol Chem, 276, 31037-31046. chy1, an Arabidopsis Mutant with Impaired beta -Oxidation, Is Defective in a Peroxisomal beta -Hydroxyisobutyryl-CoA Hydrolase. DOI:10.1074/jbc.m104679200. PMID:11404361.

Step 1. Glu169 nucleophilicly attacks the carboxylate group on the substrate to generate an anhydride intermediate. This is facilitated by the binding of the thioester oxygen atom to an oxyanion hole formed by the peptide nitrogens of Gly98 and of Gly146.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Gly146(116)A (main-N) electrostatic stabiliser, hydrogen bond donor
Gly98(68)A (main-N) electrostatic stabiliser, hydrogen bond donor
Asp177(147)A hydrogen bond donor
Glu169(139)A polar interaction, nucleophile

Chemical Components

ingold: bimolecular nucleophilic addition, overall reactant used, intermediate formation, enzyme-substrate complex formation

Step 2. The anhydride intermediate undergoes internal elimination to produce CoA and an intermediate.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Gly146(116)A (main-N) electrostatic stabiliser, hydrogen bond donor
Gly98(68)A (main-N) electrostatic stabiliser, hydrogen bond donor
Asp177(147)A hydrogen bond donor
Glu169(139)A covalently attached, activator
Asp177(147)A proton donor

Chemical Components

ingold: unimolecular elimination by the conjugate base, proton transfer, intermediate collapse, intermediate formation, overall product formed

Step 3. A water molecule, activated by Asp177A, attacks the carbonyl carbon of the covalently attached Glu169A.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Gly146(116)A (main-N) electrostatic stabiliser, hydrogen bond donor
Gly98(68)A (main-N) electrostatic stabiliser, hydrogen bond donor
Asp177(147)A hydrogen bond acceptor
Glu169(139)A covalently attached, electrophile
Asp177(147)A proton acceptor

Chemical Components

proton transfer, ingold: bimolecular nucleophilic addition, intermediate formation

Step 4. The final intermediate undergoes internal elimination to liberate the Glu169A and producing 3-hydroxy-2-methylpropanoate.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Gly146(116)A (main-N) electrostatic stabiliser, hydrogen bond donor
Gly98(68)A (main-N) electrostatic stabiliser, hydrogen bond donor
Asp177(147)A hydrogen bond donor
Glu169(139)A hydrogen bond donor, electrofuge

Chemical Components

ingold: unimolecular elimination by the conjugate base, proton transfer, intermediate terminated, overall product formed, enzyme-substrate complex cleavage

Step 5. Inferred return step in which a water molecule deprotonates Glu169.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Asp177(147)A increase acidity
Glu169(139)A proton donor

Chemical Components

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

Step 1. Glu169 nucleophilicly attacks the carboxylate group on the substrate to generate an anhydride intermediate. This is facilitated by the binding of the thioester oxygen atom to an oxyanion hole formed by the peptide nitrogens of Gly98 and of Gly146.

Step 2. The anhydride intermediate undergoes internal elimination to produce CoA and an intermediate.

Step 3. A water molecule, activated by Asp177A, attacks the carbonyl carbon of the covalently attached Glu169A.

Step 4. The final intermediate undergoes internal elimination to liberate the Glu169A and producing 3-hydroxy-2-methylpropanoate.

Step 5. Inferred return step in which a water molecule deprotonates Glu169.

Products.

Contributors

Daniel E. Almonacid, Sophie T. Williams, Gemma L. Holliday, James Willey