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Catalytic Site Atlas Version 2.2.12
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CSA entry for 2acu
Original Entry
Title:
Oxidoreductase
Compound:
Aldose reductase (e.c.1.1.1.21) mutant with tyr 48 replaced by his (y48h) complexed with nadp+ and citrat
Mutant:
No
UniProt/Swiss-Prot:
P15121-ALDR_HUMAN
EC Class:
1.1.1.21
Other CSA Entries:
Overview of all sites for 2acu
Homologues of 2acu
Entries for UniProt/Swiss-Prot: P15121
Entries for EC: 1.1.1.21
Other Databases:
PDB entry: 2acu
PDBsum entry: 2acu
UniProt/Swiss-Prot: P15121
IntEnz entry: 1.1.1.21
Literature Report:
Introduction:
Human Aldehyde Reductase, sourced from Homo sapiens is a member of the aldo-keto reductase superfamily. It catalyses the NADPH-dependent reduction of a wide range of carbonyl compounds such as sugars, aldehyde metabolites, corticosteroid hormones and xenobiotic aldehydes. Interest in this enzyme stems from it's ability to reduce glucose and galactose, causing diabetic and galactosemic complications affecting the lens, retina, nerves and kidneys.
Mechanism:
1. The pro-R hydrogen of NADPH is transferred to the re face of the carbonyl group of the substrate.
2. The forming alcohol group is protonated by Tyr 48, which acts as a general acid. The Tyr 48 anion is stabilised electrostatically by Lys 77. Lys 77 is stabilised by Asp 43.
Sites:

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Found by:
Literature reference 

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
316 0Sidechain
Substrate
The pro-R hydrogen of NADPH is transferred to the re face of the carbonyl group of the substrate.
Evidence from paper Evidence concerns Evidence type
Evidence from paper listed as having "No PubMed ID available." below. Current protein Residue is positioned appropriately (ligand position known)
Evidence from paper listed as having "No PubMed ID available." below. Current protein Kinetic studies
PubMed ID 8117659 Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
ASPA 43 44Sidechain
ElectrostaticResidue
Asp 43 electrostatically stabilises Lys 77.
Evidence from paper Evidence concerns Evidence type
Evidence from paper listed as having "No PubMed ID available." below. Current protein Mutagenesis of residue
Evidence from paper listed as having "No PubMed ID available." below. Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
HISA 48 49Sidechain
Acid/baseSubstrate
The forming alcohol group is protonated by Tyr 48, which acts as a general acid.
Evidence from paper Evidence concerns Evidence type
PubMed ID 8117659 Current protein Mutagenesis of residue
PubMed ID 8117659 Current protein Residue is positioned appropriately (ligand position known)
Evidence from paper listed as having "No PubMed ID available." below. Current protein Mutagenesis of residue
PubMed ID 8117659 Current protein Computer modelling
PubMed ID 8117659 Current protein Kinetic studies
PubMed ID 8117659 Current protein Chemical modification of residue
Evidence from paper listed as having "No PubMed ID available." below. Current protein Computer modelling

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
LYSA 77 78Sidechain
ElectrostaticResidue
Lys 77 stabilises the Tyr 48 anion.
Evidence from paper Evidence concerns Evidence type
Evidence from paper listed as having "No PubMed ID available." below. Current protein Residue is positioned appropriately (ligand position known)
Evidence from paper listed as having "No PubMed ID available." below. Current protein Mutagenesis of residue
PubMed ID 8117659 Current protein Mutagenesis of residue
PubMed ID 8117659 Current protein Residue is positioned appropriately (ligand position known)
Notes:

References:
1
Computer Simulation Studies of the Catalytic Mechanism of Human Aldose Reducatse
P. Varnai and A. Warshel
J. Am. Chem. 122, 3849-3860 (2000)
No PubMed ID available
2
Tyrosine-48 is the proton donor and histidine-110 directs substrate stereochemical selectivity in the reduction reaction of human aldose reductase: enzyme kinetics and crystal structure of the Y48H mutant enzyme.
K. M. Bohren and C. E. Grimshaw and C. J. Lai and D. H. Harrison and D. Ringe and G. A. Petsko and K. H. Gabbay
Biochemistry 33, (8) 2021-32, (1994).
8117659
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