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Literature summary extracted from

  • Carbone, V.; Giglio, M.; Chung, R.; Huyton, T.; Adams, J.; Maccari, R.; Ottana, R.; Hara, A.; El-Kabbani, O.
    Structure of aldehyde reductase in ternary complex with a 5-arylidene-2,4-thiazolidinedione aldose reductase inhibitor (2010), Eur. J. Med. Chem., 45, 1140-1145.
    View publication on PubMed

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
1.1.1.2 in ternary complex with NADPH and a 5-arylidene-2,4-thiazolidinedione aldose reductase inhibitor, [5-(3-carboxymethoxy-4-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl]acetic acid to 1.99 A resolution. The partially disordered inhibitor forms a tight network of hydrogen bonds with the active site residues Tyr50 and His113 and coenzyme. pi-Stacking interactions with several conserved active site tryptophan residues and hydrogen-bonding interactions with the non-conserved C-terminal residue Pro301 in aldehyde reductase ALR1 contribute to inhibitor selectivity. In particular for the potent inhibitor [5-(3-carboxymethoxy-4-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl]acetic acid, the rotameric state of the conserved residue Trp220 in ALR1, i.e Trp 219 in aldose reductase, is important in forming a pi-stacking interaction with the inhibitor in aldose reductase and contributes to the difference in the binding of the inhibitor to the enzymes Sus scrofa
1.1.1.2 purified aldehyde reductase, ALR1, in ternary complex with NADPH and [5-(3-carboxymethoxy-4-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl]acetic acid, hanging drop method, 17-18 mg/ml protein in 5 mM Tris-HCl, pH 6.5, containing 5 mM 2-mercaptoethanol, mixed with NADPH and inhibitor in a 1:20:3molar ratio, the reservoir solution contains 2.0 M ammonium sulfate, and 0.1 M Tris-HCl buffer, pH 8.5, 10 days, X-ray diffraction structure determination and analysis at 1.99 A resolution Sus scrofa

Inhibitors

EC Number Inhibitors Comment Organism Structure
1.1.1.2 additional information enzyme active site interactions with the 3-carboxymethoxy-4-methoxy-phenyl moiety of the inhibitor, binding structure, overview Sus scrofa
1.1.1.2 [5-(3-carboxymethoxy-4-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl]acetic acid crystallization data. The rotameric state of the conserved residue Trp220 in aldehyde reductase ALR1, i.e Trp 219 in aldose reductase ALR2, is important in forming a pi-stacking interaction with the inhibitor in aldose reductase and contributes to the difference in the binding of the inhibitor to the enzymes; i.e. CMD, a potent inhibitor of ALR2, but not for ALR1. For binding to ALR1, the partially disordered inhibitor forms a tight network of hydrogen bonds with the active site residues Tyr50 and His113 and NADPH, structure molecular modelling, overview. The non-conserved C-terminal residue Leu300 in ALR2, which is Pro301 in ALR1, contributes to inhibitor selectivity Sus scrofa
1.1.1.2 [5-(3-hydroxy-4-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl]acetic acid i.e. HMD, modelling of inhibitor-enzyme active site complex Sus scrofa
1.1.1.21 additional information enzyme active site interactions with the 3-carboxymethoxy-4-methoxy-phenyl moiety of the inhibitor, binding structure, overview Homo sapiens
1.1.1.21 [5-(3-carboxymethoxy-4-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl]acetic acid i.e. CMD, a potent inhibitor of ALR2, but not for ALR1, structure molecular modelling, overview. The non-conserved C-terminal residue Leu300 in ALR2, which is Pro301 in ALR1, contributes to inhibitor selectivity Homo sapiens
1.1.1.21 [5-(3-hydroxy-4-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl]acetic acid i.e. HMD, modelling of inhibitor-enzyme active site complex Homo sapiens

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
1.1.1.2 DL-glyceraldehyde + NADPH + H+ Sus scrofa
-
 DL-glycerol + NADP+
-
 ?
1.1.1.21 DL-glyceraldehyde + NADPH + H+ Homo sapiens
-
 DL-glycerol + NADP+
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
1.1.1.2 Sus scrofa
-
-
-
1.1.1.2 Sus scrofa P50578
-
-
1.1.1.21 Homo sapiens P15121
-
-

Source Tissue

EC Number Source Tissue Comment Organism Textmining
1.1.1.2 kidney
-
 Sus scrofa
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.1.1.2 DL-glyceraldehyde + NADPH + H+
-
 Sus scrofa DL-glycerol + NADP+
-
 ?
1.1.1.21 DL-glyceraldehyde + NADPH + H+
-
 Homo sapiens DL-glycerol + NADP+
-
 ?

Synonyms

EC Number Synonyms Comment Organism
1.1.1.2 aldehyde reductase
-
 Sus scrofa
1.1.1.2 ALR1
-
 Sus scrofa
1.1.1.21 aldose reductase
-
 Homo sapiens
1.1.1.21 ALR2
-
 Homo sapiens

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
1.1.1.21 6.7
-
 assay at Homo sapiens

Cofactor

EC Number Cofactor Comment Organism Structure
1.1.1.21 NADPH
-
 Homo sapiens

IC50 Value

EC Number IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
1.1.1.2 0.0054
-
 25°C, pH 6.7 Sus scrofa [5-(3-carboxymethoxy-4-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl]acetic acid
1.1.1.2 0.0054
-
 ALR1, pH not specified in the publication, temperature not specified in the publication Sus scrofa [5-(3-carboxymethoxy-4-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl]acetic acid
1.1.1.2 0.037
-
 25°C, pH 6.7 Sus scrofa [5-(3-hydroxy-4-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl]acetic acid
1.1.1.2 0.037
-
 ALR1, pH not specified in the publication, temperature not specified in the publication Sus scrofa [5-(3-hydroxy-4-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl]acetic acid
1.1.1.21 0.0002
-
 ALR2, pH 6.7, temperature not specified in the publication Homo sapiens [5-(3-carboxymethoxy-4-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl]acetic acid
1.1.1.21 0.00066
-
 ALR2, pH 6.7, temperature not specified in the publication Homo sapiens [5-(3-hydroxy-4-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl]acetic acid