Aldose reductase structures: implications for mechanism and inhibition

Abstract

During chronic hyperglycaemia, elevated vascular glucose level causes increased flux through the polyol pathway, which induces functional and morphological changes associated with secondary diabetic complications. Inhibitors of aldose reductase (ARIs) have been widely investigated as potential therapeutic agents, but to date only epalrestat is successfully marketed for treatment of diabetic neuropathy, in Japan. Promising compounds during in vitro studies or in trials with animal models have failed to proceed beyond clinical trials and to everyday use, due to a lack of efficacy or adverse side effects attributed to lack of inhibitor specificity and likely inhibition of the related aldehyde reductase (ALR1). Knowledge of the catalytic mechanism and structures of the current inhibitors complexed with ALR2 are means by which more specific and tightly bound inhibitors can be discovered. This review will provide an overview of the proposed catalytic mechanism and the current state of structure-based drug design.

Protein Tyrosine Phosphatase 1B and α-Glucosidase Inhibitory Phlorotannins from Edible Brown Algae,Ecklonia stoloniferaandEisenia bicyclis

“…Dieckol (5 000 /C-5 000 ), 148.1 (C-2 00 ), 148.01 (C-2), 147.9 (C-9 00 ), 147.7 (C-9), 145.1 (C-5a 00 ), 145.0 (C-5a), 144.2 (C-4 00 ), 144.1 (C-4 000 ), 139.4 (C-10a), 139.3 (C-10a 00 ), 127.3 (C-4 000 ), 127.0 (C-9a), 126.5 (C-1), 126.4 (C-1 00 ), 125.7 (C-9a 00 ), 125.5 (C-4a 00 ), 125.4 (C-4a), 100.7 (C-8 00 ), 100.6 (C-8), 100.3 (C-3), 100.2 (C-3 00 ), 98.5 (C-4 0 ), 97.0 (C-2 000 , 6 000 ), 96.7 (C-6 00 ), 96.6 (C-6 0 ), 96.2 (C-2 0 /C-6 0 ). …”

“…Since the individual extracts and fractions showed significant inhibitory activities, column chromatography was performed to isolate six phlorotannins, phloroglucinol (1), dioxinodehydroeckol (2), eckol (3), phlorofurofucoeckol-A (4), dieckol (5), and 7-phloroeckol (6). Phlorotannins 3-6 were potent and noncompetitive PTP1B inhibitors with IC 50 values ranging from 0.56 to 2.64 M; 4-6 exhibited the most potent -glucosidase inhibition with IC 50 values ranging from 1.37 to 6.13 M. Interestingly, 4 and 6 were noncompetitive, while 5 exhibited competitive inhibition in an -glucosidase assay.…”

“…3) In particular, a persistently increased blood glucose level in diabetic patients is considered the primary instigator for the pathogenesis of long-term diabetic complications, including retinopathy, cataractogenesis, nephropathy, and neuropathy. 4,5) Postprandial hyperglycemia also plays a critical role in the development of type II diabetes and associated cardiovascular complications. 6) Modulating postprandial hyperglycemia may therefore play a crucial role in the treatment and prevention of diabetes and its complications.…”

Evaluation of in vitro aldose reductase inhibitory potential of different fraction of Hybanthus enneaspermus Linn F. Muell

“…Prolonged exposure to chronic hyperglycemia in diabetes can lead to various complications, affecting the cardiovascular, renal, neurological and visual systems, such as lens, retina, nerves and kidney, which are insulininsensitive, and are the target organs for complications such as cataracts, retinopathy, neuropathy and nephropathy [4] . Several mechanisms such as increased aldose reductaserelated polyol pathway, increased advanced glycation end product formation, and excessive oxidative stress are involved in this process [5,6] . Aldose reductase is found in almost all mammalian cells, but at high levels in organs such as the cornea, lens, retina, kidney, myelin sheath and sciatic nerves, which are affected by diabetic complications [7] .…”

Alterations of aldose reductase and superoxide dismutase activities by some chromonyl-2, 4-thiazolidinedione derivatives

“…Among the numerous mechanisms triggered by the chronic exposure to high levels of glucose the ones that are very clearly related to hyperglycemia are increased advanced glycation end product (AGE) formation, glucose auto-oxidation, the activation of protein kinase C (PKC) isoforms and increased aldose reductase (AR)-related polyol pathway Özlem Yıldırım -Neda Amirzadeh-Khiabani -Meltem Ceylan-Ünlüsoy -Net Daş-Evcimen -Mutlu Sarıkaya -Rahmiye Ertan 250 (13). Aldose reductase (AR; EC 1.1.1.21), a member of the NADPH dependent aldo-keto reductase family, is a cytosolic, monomeric oxidoreductase enzyme that catalyzes the conversion of glucose to sorbitol in the first and rate-limiting step of the polyol pathway of glucose metabolism (9,10,22). AR enzyme not only reduces glucose to sorbitol but also decreases the formation of toxic aldehydes (4,11,16).…”