36 research outputs found
Insight into the secondary structure of non-native proteins bound to a molecular chaperone alpha-crystallin. An isotope-edited infrared spectroscopic study
Insight into the secondary structure of non-native proteins bound to a molecular chaperone alpha-crystallin. An isotope-edited infrared spectroscopic study
7-Hydroxy-2-substituted-4-H-1-benzopyran-4-one derivatives as aldose reductase inhibitors: a SAR study
On the basis of the results of molecular modelling studies performed on the aldose reductase (ALR2) inhibitor 7-hydroxy-2-(4'-hydroxybenzyl)-4H-1-benzopyran-4-one (compound A) bound at the active site of the enzyme, we synthesised and tested on bovine and human ALR2 several derivatives modified at position 2 of the benzopyran moiety, in order to confirm the hypothesised binding mode of this compound. The substitution of the methylene bridge with the isosteric sulphur substituent gives an active derivative, while substitution with a polar NH causes a decrease in inhibitory activity; this is in accordance to the previously reported structure in which the methylene linker was found to be adjacent to a hydrophobic aminoacid (Leu300). Among the substituents at 4' position examined, the most favourable for inhibitory activity are those able to act as hydrogen bond donors, supporting the hypothesis of the importance of the interaction with Thr113 for the inhibition of the enzyme
Binding of 1-benzopyran-4-one derivatives to aldose reductase: a free energy perturbation study
Binding of 1-benzopyran-4-one derivatives to aldose reductase: A free energy perturbation study
The relative binding affinities to human aldose reductase (ALR2) of three new 7-hydroxy-2-benzyl-4H-1-benzopyran-4-one inhibitors were predicted by free energy perturbation (FEP) simulations. Molecular substitutions were specifically designed to investigate the role of hydrogen bonding at the active site of ALR2. Starting from the lead inhibitor 7-hydroxy-2-(4'-hydroxy-benzyl)-4H-1-benzopyran-4-one, the 4'-hydroxyl was mutated to methyl and to trifluoromethyl, and an hydroxyl at position 8 was additionally introduced. Once synthesized and tested as inhibitors of ALR2, the compounds displayed variations of K-i that were in qualitative to quantitative agreement with the calculated relative free energies of binding. The results, discussed in terms of balance between free energies of solvation and free energies of binding to ALR2, elucidate the importance of hydrogen bonding with Thr113 and with Trp111 and cofactor, and provide a rationale to the observed differences in binding affinities. (C) 2002 Elsevier Science Ltd. All rights reserved
Involvement of cysteine residues in glutathione dependent modification of human aldose reductase
Aldose Reductase Protects Against Early Atherosclerotic Lesion Formation In Apolipoprotein E-null Mice
RATIONALE:
Atherosclerotic lesion formation is associated with the accumulation of oxidized lipids. Products of lipid oxidation, particularly aldehydes, stimulate cytokine production and enhance monocyte adhesion; however, their contribution to atherosclerotic lesion formation remains unclear.
OBJECTIVE:
To test the hypothesis that inhibition of aldehyde removal by aldose reductase (AR), which metabolizes both free and phospholipid aldehydes, exacerbates atherosclerotic lesion formation.
METHODS AND RESULTS:
In atherosclerotic lesions of apolipoprotein (apo)E-null mice, AR protein was located in macrophage-rich regions and its abundance increased with lesion progression. Treatment of apoE-null mice with AR inhibitors sorbinil or tolrestat increased early lesion formation but did not affect the formation of advanced lesions. Early lesions of AR(-/-)/apoE(-/-) mice maintained on high-fat diet were significantly larger when compared with age-matched AR(+/+)/apoE(-/-) mice. The increase in lesion area attributable to deletion of the AR gene was seen in both male and female mice. Pharmacological inhibition or genetic ablation of AR also increased the lesion formation in male mice made diabetic by streptozotocin treatment. Lesions in AR(-/-)/apoE(-/-) mice exhibited increased collagen and macrophage content and a decrease in smooth muscle cells. AR(-/-)/apoE(-/-) mice displayed a greater accumulation of the AR substrate 4-hydroxy trans-2-nonenal (HNE) in the plasma and protein-HNE adducts in arterial lesions than AR(+/+)/apoE(-/-) mice.
CONCLUSIONS:
These observations indicate that AR is upregulated in atherosclerotic lesions and it protects against early stages of atherogenesis by removing toxic aldehydes generated in oxidized lipids.link_to_OA_fulltex