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
(1.2.1.3, 1.2.1.47)
(Sequence Homologues)
(PDB Homologues)
- Biological species
-
Gadus morhua callarias (Baltic cod)
- PDB
-
1a4s
- BETAINE ALDEHYDE DEHYDROGENASE FROM COD LIVER
(2.1 Å)
- Catalytic CATH Domains
-
3.40.309.10
3.40.605.10
(see all for 1a4s)
- Cofactors
- Water (1)
Enzyme Reaction (EC:1.2.1.8)
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 |
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 stepReferences
- 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.
- 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.
- 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.
Step 1. Cys297 initiates a nucleophilic attack on the carbonyl carbon of betaine aldehyde in an addition reaction.
Download: Image, Marvin FileCatalytic 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
Step 2. The oxyanion collapses, eliminating a hydride ion, which adds to NAD.
Download: Image, Marvin FileCatalytic 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
Step 3. Glu263 deprotonates water, which initiates a nucleophilic attack on the carbonyl carbon of the covalently bound substrate in an addition reaction.
Download: Image, Marvin FileCatalytic 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 |
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