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Catalytic Site Atlas Version 2.2.12
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CSA entry for 1o04
Original Entry
Title:
Oxidoreductase
Compound:
Aldehyde dehydrogenase, mitochondrial precursor
Mutant:
Yes
UniProt/Swiss-Prot:
P05091-DHAM_HUMAN
EC Class:
1.2.1.3
Other CSA Entries:
Overview of all sites for 1o04
Homologues of 1o04
Entries for UniProt/Swiss-Prot: P05091
Entries for EC: 1.2.1.3
Other Databases:
PDB entry: 1o04
PDBsum entry: 1o04
UniProt/Swiss-Prot: P05091
IntEnz entry: 1.2.1.3
Literature Report:
Introduction:
Aldehyde dehydrogenase(ALDH) catalyses the oxidation of toxic aldehydes to their corresponding acids, using NAD. The human mitochondrial form of ALDH is called class 2 ALDH.
Mechanism:
The catalysis follows a sequential mechanism in which NAD+ binds prior to aldehyde. The aldehyde then undergoes nucleophilic attack by Cys302, forming a covalent intermediate. Next, the carbonyl hydride is transferred to the A-side of the nicotinamide ring. In the rate-limiting step, Glu268 activates a water molecule for nucleophilic attack at the acyl-sulphur bond, releasing the acid product prior to NADH dissociation. Lys192 and Glu399 stabilise the transition state during the hydride transfer.
Sites:

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Found by:
Literature reference 

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
6505 0
Substrate
It accepts a hydride from the aldehyde to oxidise it to the corresponding acid.
Evidence from paper Evidence concerns Evidence type
PubMed ID 9228056 Current protein Ligand is essential for catalysis

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
LYSA 192 209Sidechain
ElectrostaticTransition state
It stabilises the transition state during hydride transfer from the enzyme-substrate intermediate to NAD+.
Evidence from paper Evidence concerns Evidence type
PubMed ID 9228057 Current protein Mutagenesis of residue

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
GLUA 268 285Sidechain
Acid/baseWater
It acts as a base to deprotonate a water molecule for nucleophilic attack at the acyl-sulphur bond.
Evidence from paper Evidence concerns Evidence type
PubMed ID 7819202 Current protein Mutagenesis of residue

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
SERA 302 319Sidechain
NucleophileSubstrate
It acts as a nucleophile to attack the aldehyde to form a covalent enzyme-substrate intermediate.
Evidence from paper Evidence concerns Evidence type
PubMed ID 7873540 Current protein Mutagenesis of residue

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
GLUA 399 416Sidechain
ElectrostaticTransition state
It stabilises the transition state during hydride transfer from the enzyme-substrate intermediate to NAD+.
Evidence from paper Evidence concerns Evidence type
PubMed ID 9228057 Current protein Mutagenesis of residue
References:
1
Investigation of the active site cysteine residue of rat liver mitochondrial aldehyde dehydrogenase by site-directed mutagenesis.
J. Farr├ęs and T. T. Wang and S. J. Cunningham and H. Weiner
Biochemistry 34, (8) 2592-8, (1995).
7873540
2
Involvement of glutamate 268 in the active site of human liver mitochondrial (class 2) aldehyde dehydrogenase as probed by site-directed mutagenesis.
X. Wang and H. Weiner
Biochemistry 34, (1) 237-43, (1995).
7819202
3
Involvement of glutamate 399 and lysine 192 in the mechanism of human liver mitochondrial aldehyde dehydrogenase.
L. Ni and S. Sheikh and H. Weiner
J Biol Chem 272, (30) 18823-6, (1997).
9228057
4
The potential roles of the conserved amino acids in human liver mitochondrial aldehyde dehydrogenase.
S. Sheikh and L. Ni and T. D. Hurley and H. Weiner
J Biol Chem 272, (30) 18817-22, (1997).
9228056
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