Enzymes aldose reductase

Excessive activity of the enzyme aldose reductase sometimes accompanies diabetes. The net result is often accumulation of reduced sugars such as galactose in the lens of the eye and ensuing cataract formation. A1 restatin (43), an aldose reductase inhibitor, is one of the first agents found that holds promise of preventing diabetes-induced cataracts. The compound, actually used as its sodium salt, is prepared in straightforward manner by imide formation between 1,8-naphthalic anhydride (41) and glycine. ... 

The cataracts that can appear even in those diabetics whose disease is under control have been attributed to accumulation in the eye of sorbitol that results from the reduction of glucose by elevated levels of the enzyme aldose reductase that accompanies the disease. Inhibitors of that enzyme have been investigated as a means for controlling such cataracts. Known agents, as would be expected with enzyme inhibitors, tend to show marked differences in potency between optical isomers. The enantioselective synthesis of one of these compounds starts with the formation of an imine (12-3) of dihydrochromone (12-1) with the S form of the chiral... 

Potassium cyanide and ammonium carbonate react with 1-alkyl377 or 1-alkenylisatins363 generating. s/ /7 ohydantoins. These compounds are inhibitors of the enzyme aldose reductase, and have potential use as hypoglycemic agents (Scheme 92). 

ALDOSE REDUCTASE INHIBITORS (ARI) act at the enzyme aldose reductase, which is the first enzyme in the sorbitol (or polyol) pathway which converts glucose to sorbitol. It is thought that in hyperglycaemic states there may be an accumulation of sorbitol, leading to hyperosmotic pathology. ARI agents are under trial for use in the treatment of peripheral diabetic neuropathies, retinopathy and nephropathies. (These include tolrestat. also alrestatin, sorbinil, zenarestat and zopolrestat)... 

Xylitol is the probable connecting point between the D-xylose and L-arabi-nose metabolic pathways (Fig. 5). L-arabinose is the form found most abundantly in nature. Early work by Chaing and Knight showed that cell-free extracts of Penicillium chrysogenum convert L-arabinose to both L-ribose and L-xylulose through the intermediate, L-arabinitol (= L-arabitol) [80]. Only one enzyme, aldose reductase, appears to be responsible for the conversion of L-arabinose to L-arabinitol. Aldose reductase also acts on D-arabinose to produce D-arabitol. Witterveen et al. obtained a mutant of Aspergillus niger deficient in... 

In the early 1960s, scientists at the National Eye Institute (NEI) showed that cataracts (an obstruction of the lens of the eye) in animals with diabetes were due to the formation and accumulation of polyols (sugar alcohols). They discovered that an enzyme, aldose reductase, converts blood sugars (which are found in high levels in diabetics) into polyols. The sugar alcohols accumulate in cells, weaken the cell membrane, and eventually leak out of the cell, causing the cataracts. The discovery of aldose... 

Some of quercetin s potentially useful vs. potentially harmful properties have been reviewed by Alan Gaby, MD., in an editorial in the May 1998 issue of the Townsend Letter for Doctors Patients. It acts as an inhibitor for the enzyme phosphodiesterase, and hence may possibly act against asthma. Also, it may act against allergies by inhibiting the release of histamine. Quercetin is also an inhibitor for the enzyme aldose reductase, which is involved in diabetic complications. Perhaps most interestingly, it inhibits the enzyme reverse transcriptase (or RNA-directed DNA polymerase), involved in the action of retroviruses such as the AIDS virus or HIV (and retroviruses may also be involved in cancer formation). 

Inhibitors of the enzyme aldose reductase (which has a role in the development of cataract) have been synthesized from chromanones. Spirohydantoins and spiro-oxazolidines derived from chromanone are of interest, especially the (4S)(-)-enantiomer ( 102).106 107 Oxidation of chromanones in methanol-perchloric acid or trimethyl orthoformate has given moderately good yields of chromones together with minor amounts of 3-methoxychromanones.108 The 13C n.m.r spectrum of the benzochromanone fonsecin (103) has been analysed and its biosynthesis from a new type of polyketide chain folding demonstrated.109... 

Fructose can be synthesized from glucose in the polyol pathway. The polyol pathway is named for the first step of the pathway in which sugars are reduced to the sugar alcohol by the enzyme aldose reductase (Fig. 29.4) Glucose is reduced to the sugar alcohol sorbitol, and sorbitol is then oxidized to fructose. 

Sorbinil 282 is a compound of potential therapeutic interest, because it prevents or alleviates the chronic complications of diabetes mellitus, due to its ability to inhibit the enzyme aldose reductase. Sarges et al. prepared 282 and its enantiomer by the reaction sequence shown in Scheme 12.71, involving a brucine resolution of the racemic hydantoin precursor 284. " The free base of brucine forms a crystalline complex with 282, whereas the other enantiomer of 282 only forms a crystalline complex with brucine hydrochloride. Since this resolution technique does not work with certain congeners of sorbinil, a synthesis via an asymmetric induction sequence (Scheme 12.72) has also been developed that seems generically applicable to optically active spiro hydantoins. Both methodsrequired 2,3-dihydro-6-fluoro-47/-l-benzopyran-4-one 283 and the introduction of the amino acid functionality... 

Epalrestat inhibits the enzyme aldose reductase, which converts glucose to sorbitol. The accumulation of sorbitol may play a role in some diabetic complications. 

Inhibition of various cellular enzymes aldose reductase, histidine decarboxylase, prostaglandin synthetase, lipoxygenase, ascorbic acid oxidase, catechol-0-methyltransferase, ohosohodiesterase Various flavones 10" - 10" M 16,21,22, 28,39,45,81... 

Figure I. The fungal and bacterial pathways for D-xylose and L-arabinose catabolism. All pathways have in common that D-xylulose 5-phosphate is produced. The enzymes in the bacterial pathways are xylose isomerase and xylulokinase for the D-xylose pathway and L-arabinose isomerase, ribulokinase and L-ribulosephosphate 4-epimerase for the L-arabinose pathway. The fungal D-xylose pathway has the enzymes aldose reductase, xylitol dehydrogenase and xylulokinase. The enzymes in the L-arabinose pathways ofmold and yeast are aldose reductase, L-arabinitol 4-dehydrogenase, L-xylulose reductase, xylitol dehydrogenase and xylulokinase. The differences between the mold and yeast pathway are in the cofactor requirements.

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