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Catalytic Site Atlas

CSA LITERATURE entry for 1a4s

E.C. namebetaine-aldehyde dehydrogenase
SpeciesGadus callarias (Baltic cod)
E.C. Number (IntEnz) 1.2.1.8
CSA Homologues of 1a4sThere are 84 Homologs
CSA Entries With UniProtID P56533
CSA Entries With EC Number 1.2.1.8
PDBe Entry 1a4s
PDBSum Entry 1a4s
MACiE Entry M0100

Literature Report

IntroductionAldehyde 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.
MechansimCys297 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.
Reaction

Catalytic Sites for 1a4s

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
CysA297297macie:sideChainWhen 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.
CysA297297macie:mainChainAmideWhen 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.
GluA263263macie:sideChainDeprotonates 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.
AsnA166166macie:mainChainAmideForms part of the oxyanion hole to stabilise the negatively charged transition state.
GluA477477macie:sideChainForms part of the proton relay to shuttle protons from the active site to the bulk solvent.

Literature References

Notes:
Johansson K
Structure of betaine aldehyde dehydrogenase at 2.1 A resolution.
Protein Sci 1998 7 2106-2117
PubMed: 9792097
González-Segura L
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.
J Mol Biol 2009 385 542-557
PubMed: 19013472
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