Disease relevance of ALR2

• Aldose reductase is a promising target for the treatment of diabetic complications, and as such, has become the focus of various drug design projects [1].
• YUA001, a novel aldose reductase inhibitor isolated from alkalophilic Corynebacterium sp. YUA25. II. Chemical modification and biological activity [2].
• New aldose reductase inhibitors N99-596 A and B from Streptomyces [3].
• It exhibits potent aldose reductase inhibition activity and has no antimicrobial activity against some gram-positive or gram-negative bacteria, fungi and yeast [4].

High impact information on ALR2

• Novel NADPH-binding domain revealed by the crystal structure of aldose reductase [5].
• Under normal physiological conditions aldose reductase participates in osmoregulation, but under hyperglycaemic conditions it contributes to the onset and development of severe complications in diabetes [5].
• A 1.65 angstrom refined structure of a recombinant human placenta aldose reductase reveals that the enzyme contains a parallel beta 8/alpha 8-barrel motif and establishes a new motif for NADP-binding oxidoreductases [6].
• An unlikely sugar substrate site in the 1.65 A structure of the human aldose reductase holoenzyme implicated in diabetic complications [6].
• The tertiary structure of aldehyde reductase is similar to that of aldose reductase and consists of an alpha/beta-barrel with the active site located at the carboxy terminus of the strands of the barrel [7].

Chemical compound and disease context of ALR2

• BACKGROUND: Aldose reductase (AR) is an NADPH-dependent enzyme implicated in long-term diabetic complications [8].

Biological context of ALR2

• The binding modes of compounds at the active site of ALR2 were examined using flexible docking [9].
• However, from a consideration of their substrate specificities and the relevant Km and Vmax values, it is likely that it is ALR2 which plays a primary role in biogenic aldehyde metabolism [10].
• This 34 residue peptide exhibited considerable sequence homology to the region comprising residues 242 to 275 of human liver ALR1 and a similar region in rat lens ALR2, human muscle ALR2 and human placental ALR2 [11].
• The amino acid sequences of radioactive peptides resulting from the reaction of aldose reductase with [14C]phenylglyoxal followed by tryptic digestion and high performance liquid chromatography separation allowed identification of the modified arginine residues as R268 and R293 [12].
• It was found that AR inhibitory activity resides in the (-)-enantiomer 43 (AS-3201), which was 10 times more potent in inhibition of the AR (IC50 = 1.5 x 10(-8) M) and 500 times more potent in the in vivo activity (ED50 = 0.18 mg/kg/day for 5 days) than the corresponding (+)-enantiomer 44 (SX-3202) [13].

Anatomical context of ALR2

• In agreement with this observation, it was found to be a highly potent inhibitor of aldose reductase from rat sciatic nerve with greater than 98% inhibition at 1 microM, but it was practically devoid of activity against aldehyde reductases from rat liver and brain [14].
• The staining of podocytes in glomeruli of ox kidney with antiserum to aldose reductase is particularly prominent [15].
• Consequently, the intracellular glucose level is independent of the ambient glucose concentration and endothelial cells do not accumulate sorbitol under hyperglycaemic conditions since the affinity of aldose reductase for glucose is low [16].
• The aldose-reductase inhibitors, sorbinil and zopolrestat, little affected high D-glucose-attenuated endothelial cell proliferation, while the enhanced proliferation of smooth muscle cells was prevented by aldose-reductase inhibitors [17].
• Suppression of galactitol production by administration of an aldose reductase inhibitor resulted in the accumulation of the lactone in the lens, the testis, and the muscle, as well as in the circulation [18].

Associations of ALR2 with chemical compounds

• Location of an essential arginine residue in the primary structure of pig aldose reductase [19].
• The results indicated that phenethylamine derivatives nicely fit into the active pocket of ALR2 by forming various hydrogen bonding and hydrophobic interactions [9].
• Inactivation of ALR2 by [7-C14] phenylglyoxal in the absence of NADPH or NADP+ followed by tryptic digestion resulted in the isolation by HPLC of one major and one minor radioactive peptide [20].
• The minor radioactive peptide and the single radioactive peptide isolated from ALR2 inactivated in the presence of NADP+ contained chemically modified arg293 [20].
• The activation of ALR2 via formation of a Schiff's base suggests a possible mechanism of activation of the enzyme in vivo by glucose [11].

Physical interactions of ALR2

• Structure of aldehyde reductase holoenzyme in complex with the potent aldose reductase inhibitor fidarestat: implications for inhibitor binding and selectivity [21].

Other interactions of ALR2

• Both ALR1 and ALR2 may be involved in the reduction of isocorticosteroids [10].

Analytical, diagnostic and therapeutic context of ALR2

• ALR2 has been detected in homogenates of bovine kidney, heart, brain and lens, and estimation of the enzyme level in these tissues was accomplished by densitometric analysis of Western blots [22].
• Purification, crystallization and preliminary crystallographic analysis of porcine aldose reductase [23].
• Resolving isoforms of aldose reductase by preparative isoelectric focusing in the Rotofor [24].
• In this study, we applied both X-ray crystallography and mass spectrometry to characterize the interactions between aldose reductase and four representative inhibitors: AminoSNM, Imirestat, LCB3071, and IDD384 [25].
• Determination of AL01576 concentration in rat lenses and plasma by bioassay for aldose reductase activity measurements [26].

References