Aldose Reductase

Aldose reductase catalyzes the NADPH-dependent conversion of glucose to sorbitol, the first step in polyol pathway of glucose metabolism. The second and last step in the pathway is catalyzed by sorbitol dehydrogenase, which catalyzes the NAD-linked oxidation of sorbitol to fructose. Thus, the polyol pathway results in conversion of glucose to fructose with stoichiometric utilization of NADPH and production of NADH.

105346-34-7
FR-62765
105346-34-7
B0084-358923
Zopolrestat
110703-94-1
112733-06-9
Zenarestat
112733-06-9
1355612-71-3
Aldose reductase-IN-1
1355612-71-3
147254-64-6
Raniestat
147254-64-6
EBPC
4450-98-0
51411-04-2
Alrestatin
51411-04-2
51876-97-2
Alrestatin (sodium)
51876-97-2
72702-95-5
Ponalrestat
72702-95-5
82159-09-9
Epalrestat
82159-09-9
82964-04-3
Tolrestat
82964-04-3
961-29-5
Isoliquiritigenin
961-29-5

Background


Aldose reductase may be considered a prototypical enzyme of the aldo-keto reductase enzyme superfamily. The enzyme comprises 315 amino acid residues and folds into a β/α-barrel structural motif composed of eight parallel β strands. Adjacent strands are connected by eight peripheral α-helical segments running anti-parallel to the β sheet. The catalytic active site situated in the barrel core.

Aldose Reductase is a cytosolic enzyme not uniformly distributed among tissues but present in most mammalian cells. The polyol pathway was first identified in the seminal vesicles by Hers, who demonstrated the conversion of blood glucose into fructose, as an energy source of sperm cells. Aldose Reductase messenger ribonucleic acid is highly expressed in the lens, the retina and the sciatic nerve which are, the major target organs of diabetic complications.

Human Aldose Reductase (AR) is implicated in the diversion of glucose to the sorbitol pathway (Polyol pathway). The polyol pathway involves two enzymatic reactions: the first is the reduction of glucose to sorbitol by the action of aldose reductase and the second oxidation of sorbitol to fructose by the action of sorbitol dehydrogenase. More glucose is shunted down the polyol pathway to form sorbitol in diabetes. Sorbitol is a hyperosmotic sugar and its accumulation may be responsible for some of the complications arising from diabetes. Therefore there has been a push to develop aldose reductase inhibitors. Glucose is a relatively poor substrate for AKR1B1 suggesting that this enzyme has other functions.

Aldose Reductase exhibits broad substrate specificity for both hydrophilic and hydrophobic aldehydes. The reduction of biogenic aldehydes derived from the catabolism of the catecholamines and serotonin by the action of monoamine oxidase is catalyzed by aldose reductase and the structurally related enzyme aldehyde reductase. These enzymes also catalyze the reduction of isocorticosteroids which are intermediates in the catabolism of the corticosteroid hormones. Aldose Reductase in the adrenal gland was reported as a major reductase for isocaproaldehyde, which is a product of the side chain cleavage of cholesterol. It was shown that progesterone and 17α-hydroxyprogesterone, which are the precursors of androgens, estrogens and glucucorticoids are endogenous substrates for bovine aldose reductase. The lack of catalytic activity of mouse aldose reductase for the steroid nucleus could be attributed to a subtle difference in the amino acid residues constituting the active site. Low inhibition constants for these steroids introduced the possibility that tissues containing high levels of endogenous steroids significantly affect the availability of glucose to the mouse enzyme. Therefore it can be postulated that the physiological or functional roles of aldose reductase differ considerably among tissues as well as among animal species.

A large number of structurally diverse compounds have been identified as potent aldose reductase inhibitors. The currently known synthetic aldose reductase inhibitors can be divided into three main classes according to their structures, (i) Acetic acid derivatives include tolrestat and epalrestat; (ii) cyclic imides such as sorbinil; and (iii) phenylsulfonylnitromethane derivatives such as ZD 5522.

Reference:Naveen Kunaparaju. ISOLATION AND CHARACTERIZATION OF ALDOSE REDUCTASE INHIBITORS FROM WRIGHTIA TINCTORIA R.BR. SEEDS