Betaine-aldehyde dehydrogenase

 

Aldehyde dehydrogenases (ALDHs) catalyse the irreversible oxidation of a broad range of aldehydes to the corresponding acids. The substrates that ALDH work on include aliphatic and aromatic aldehydes, but also 2-enoic, 2-hydroxy, and 2-halogenated aldehydes. ALDHs are important components of cellular pathways that metabolise aldehydes and they have been ascribed important functions in cellular detoxification and defence systems.

 

Reference Protein and Structure

Sequence
P56533 UniProt (1.2.1.3, 1.2.1.47) IPR015590 (Sequence Homologues) (PDB Homologues)
Biological species
Gadus morhua callarias (Baltic cod) Uniprot
PDB
1a4s - BETAINE ALDEHYDE DEHYDROGENASE FROM COD LIVER (2.1 Å) PDBe PDBsum 1a4s
Catalytic CATH Domains
3.40.309.10 CATHdb 3.40.605.10 CATHdb (see all for 1a4s)
Cofactors
Water (1)
Click To Show Structure

Enzyme Reaction (EC:1.2.1.8)

betaine aldehyde
CHEBI:15710ChEBI
+
water
CHEBI:15377ChEBI
+
NAD(1-)
CHEBI:57540ChEBI
glycine betaine
CHEBI:17750ChEBI
+
hydron
CHEBI:15378ChEBI
+
NADH(2-)
CHEBI:57945ChEBI
Alternative enzyme names: BADH, Betaine aldehyde dehydrogenase, Betaine aldehyde oxidase, BetB,

Enzyme Mechanism

Introduction

Cys297 initiates a nucleophilic attack on the carbonyl carbon of betaine aldehyde, giving a negatively charged tetrahedral transition state. This is stabilised by the oxyanion hole. The oxyanion collapses and a hydride ion is transferred to NAD+. A hydroxide ion initiates a nucleophilic attack on the carbonyl of the now covalently bound substrate, again forming an oxyanion. When this collapses, the substrate-enzyme bond is broken.

Catalytic Residues Roles

UniProt PDB* (1a4s)
Asn166 (main-N) Asn166A (main-N) Forms part of the oxyanion hole to stabilise the negatively charged transition state. hydrogen bond donor, electrostatic stabiliser
Glu263 Glu263A Deprotonates cysteine to activate it as a nucleophile in the first step; deprotonates water to activate it as a nucleophile in the second step. Then forms the first stage in a proton relay to transfer the protons to the bulk solvent. hydrogen bond acceptor, hydrogen bond donor, proton acceptor, proton donor
Glu477 Glu477A Forms part of the proton relay to shuttle protons from the active site to the bulk solvent. proton relay, proton acceptor, proton donor
Cys297 Cys297A When deprotonated, the sidechain is a nucleophile which attacks the substrate carbonyl. The backbone NH also forms part of the oxyanion hole to stabilise the negatively charged transition state. covalently attached, nucleofuge, nucleophile
*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, enzyme-substrate complex formation, hydride transfer, unimolecular elimination by the conjugate base, aromatic bimolecular nucleophilic addition, proton transfer, enzyme-substrate complex cleavage, native state of enzyme regenerated, inferred reaction step

References

  1. González-Segura L et al. (2009), J Mol Biol, 385, 542-557. The Crystal Structure of A Ternary Complex of Betaine Aldehyde Dehydrogenase from Pseudomonas aeruginosa Provides New Insight into the Reaction Mechanism and Shows A Novel Binding Mode of the 2′-Phosphate of NADP+ and A Novel Cation Binding Site. DOI:10.1016/j.jmb.2008.10.082. PMID:19013472.
  2. Moore SA et al. (1998), Structure, 6, 1541-1551. Sheep liver cytosolic aldehyde dehydrogenase: the structure reveals the basis for the retinal specificity of class 1 aldehyde dehydrogenases. DOI:10.1016/s0969-2126(98)00152-x. PMID:9862807.
  3. Johansson K et al. (1998), Protein Sci, 7, 2106-2117. Structure of betaine aldehyde dehydrogenase at 2.1 Å resolution. DOI:10.1002/pro.5560071007. PMID:9792097.

Catalytic Residues Roles

Residue Roles
Glu263A hydrogen bond acceptor
Asn166A (main-N) hydrogen bond donor
Cys297A nucleophile

Chemical Components

ingold: bimolecular nucleophilic addition, enzyme-substrate complex formation

Catalytic Residues Roles

Residue Roles
Cys297A covalently attached
Glu263A hydrogen bond acceptor
Asn166A (main-N) hydrogen bond donor, electrostatic stabiliser

Chemical Components

hydride transfer, ingold: unimolecular elimination by the conjugate base, ingold: aromatic bimolecular nucleophilic addition

Catalytic Residues Roles

Residue Roles
Cys297A covalently attached
Glu263A hydrogen bond acceptor
Asn166A (main-N) hydrogen bond donor
Glu263A proton acceptor

Chemical Components

ingold: bimolecular nucleophilic addition, proton transfer, enzyme-substrate complex formation

Catalytic Residues Roles

Residue Roles
Asn166A (main-N) hydrogen bond donor, electrostatic stabiliser
Cys297A nucleofuge

Chemical Components

ingold: unimolecular elimination by the conjugate base, enzyme-substrate complex cleavage

Catalytic Residues Roles

Residue Roles
Glu263A hydrogen bond donor
Glu477A proton relay, proton donor, proton acceptor
Glu263A proton donor

Chemical Components

proton transfer, native state of enzyme regenerated, inferred reaction step

Contributors

Gemma L. Holliday, Daniel E. Almonacid, Gail J. Bartlett, Craig Porter, James W. Murray