Aldose reductase | |||||||||
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Identifiers | |||||||||
EC no. | 1.1.1.21 | ||||||||
CAS no. | 9028-31-3 | ||||||||
Databases | |||||||||
IntEnz | IntEnz view | ||||||||
BRENDA | BRENDA entry | ||||||||
ExPASy | NiceZyme view | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
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In enzymology, aldose reductase (or aldehyde reductase) (EC 1.1.1.21) is an enzyme in humans encoded by the gene AKR1B1. It is an cytosolic NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monosaccharides, and primarily known for catalyzing the reduction of glucose to sorbitol, the first step in polyol pathway of glucose metabolism. [1]
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. [1]
Galactose is also a substrate for the polyol pathway, but the corresponding keto sugar is not produced because sorbitol dehydrogenase is incapable of oxidizing galactitol. [2] Nevertheless, aldose reductase can catalyze the reduction of galactose to galactitol
The aldose reductase reaction, in particular the sorbitol produced, is important for the function of various organs in the body. For example, it is generally used as the first step in a synthesis of fructose from glucose; the second step is the oxidation of sorbitol to fructose catalyzed by sorbitol dehydrogenase. The main pathway from glucose to fructose (glycolysis) involves phosphorylation of glucose by hexokinase to form glucose 6-phosphate, followed by isomerization to fructose 6-phosphate and hydrolysis of the phosphate, but the sorbitol pathway is useful because it does not require the input of energy in the form of ATP:
Aldose reductase is also present in the lens, retina, Schwann cells of peripheral nerves, placenta and red blood cells.[ citation needed ]
In Drosophila, CG6084 encoded a highly conserved protein of human Aldo-keto reductase 1B. dAKR1B in hemocytes, is necessary and sufficient for the increasement of plasma sugar alcohols after gut infection. Increased sorbitol subsequently activated Metalloprotease 2, which cleaves PGRP-LC to activate systemic immune response in fat bodies. Thus, aldose reductase provides a critical metabolic checkpoint in the global inflammatory response. [3]
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. [4] Adjacent strands are connected by eight peripheral α-helical segments running anti-parallel to the β sheet. [5] The catalytic active site situated in the barrel core. [5] [6] The NADPH cofactor is situated at the top of the β/α barrel, with the nicotinamide ring projects down in the center of the barrel and pyrophosphate straddling the barrel lip. [1]
The reaction mechanism of aldose reductase in the direction of aldehyde reduction follows a sequential ordered path where NADPH binds, followed by the substrate. Binding of NADPH induces a conformational change (Enzyme•NADPH → Enzyme*•NADPH) that involves hinge-like movement of a surface loop (residues 213–217) so as to cover a portion of the NADPH in a manner similar to that of a safety belt. The alcohol product is formed via a transfer of the pro-R hydride of NADPH to the re face of the substrate's carbonyl carbon. Following release of the alcohol product, another conformational change occurs (E*•NADP+ → E•NADP+) in order to release NADP+. [8] Kinetic studies have shown that reorientation of this loop to permit release of NADP+ appears to represent the rate-limiting step in the direction of aldehyde reduction. [9] [10] [11] As the rate of coenzyme release limits the catalytic rate, it can be seen that perturbation of interactions that stabilize coenzyme binding can have dramatic effects on the maximum velocity (Vmax). [11]
The hydride that is transferred from NADP+ to glucose comes from C-4 of the nicotinamide ring at the base of the hydrophobic cavity. Thus, the position of this carbon defines the enzyme's active site. There exist three residues in the enzyme within a suitable distance of the C-4 that could be potential proton donors: Tyr-48, His-110 and Cys-298. Evolutionary, thermodynamic and molecular modeling evidence predicted Tyr-48 as the proton donor. This prediction was confirmed the results of mutagenesis studies. [5] [12] [13] Thus, a [hydrogen-bonding] interaction between the phenolic hydroxyl group of Tyr-48 and the ammonium side chain of Lys-77 is thought to help to facilitate hydride transfer. [5]
Diabetes mellitus is recognized as a leading cause of new cases of blindness, and is associated with increased risk for painful neuropathy, heart disease and kidney failure. Many theories have been advanced to explain mechanisms leading to diabetic complications, including stimulation of glucose metabolism by the polyol pathway. Additionally, the enzyme is located in the eye (cornea, retina, lens), kidney, and the myelin sheath–tissues that are often involved in diabetic complications. [14] Under normal glycemic conditions, only a small fraction of glucose is metabolized through the polyol pathway, as the majority is phosphorylated by hexokinase, and the resulting product, glucose-6-phosphate, is utilized as a substrate for glycolysis or pentose phosphate metabolism. [15] [16] However, in response to the chronic hyperglycemia found in diabetics, glucose flux through the polyol pathway is significantly increased. Up to 33% of total glucose utilization in some tissues can be through the polyol pathway. [17] Glucose concentrations are often elevated in diabetics and aldose reductase has long been believed to be responsible for diabetic complications involving a number of organs. Many aldose reductase inhibitors have been developed as drug candidates but virtually all have failed although some such as Epalrestat are commercially available in several countries. Additional reductase inhibitors such as Alrestatin, Exisulind, Imirestat, Zopolrestat, Tolrestat, Zenarestat, Caficrestat, Fidarestat, Govorestat, Ranirestat, Ponalrestat, Risarestat, Sorbinil, and Berberine, Poliumoside, Ganoderic acid [18] are currently in clinical trials. [19]
Aldose reductase inhibitors are a class of drugs being studied as a way to prevent eye and nerve damage in people with diabetes.
Sorbitol, less commonly known as glucitol, is a sugar alcohol with a sweet taste which the human body metabolizes slowly. It can be obtained by reduction of glucose, which changes the converted aldehyde group (−CHO) to a primary alcohol group (−CH2OH). Most sorbitol is made from potato starch, but it is also found in nature, for example in apples, pears, peaches, and prunes. It is converted to fructose by sorbitol-6-phosphate 2-dehydrogenase. Sorbitol is an isomer of mannitol, another sugar alcohol; the two differ only in the orientation of the hydroxyl group on carbon 2. While similar, the two sugar alcohols have very different sources in nature, melting points, and uses.
A dehydrogenase is an enzyme belonging to the group of oxidoreductases that oxidizes a substrate by reducing an electron acceptor, usually NAD+/NADP+ or a flavin coenzyme such as FAD or FMN. Like all catalysts, they catalyze reverse as well as forward reactions, and in some cases this has physiological significance: for example, alcohol dehydrogenase catalyzes the oxidation of ethanol to acetaldehyde in animals, but in yeast it catalyzes the production of ethanol from acetaldehyde.
Nicotinamide adenine dinucleotide phosphate, abbreviated NADP+ or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NADPH as a reducing agent ('hydrogen source'). NADPH is the reduced form, whereas NADP+ is the oxidized form. NADP+ is used by all forms of cellular life.
The polyol pathway is a two-step process that converts glucose to fructose. In this pathway glucose is reduced to sorbitol, which is subsequently oxidized to fructose. It is also called the sorbitol-aldose reductase pathway.
Sorbitol dehydrogenase is a cytosolic enzyme. In humans this protein is encoded by the SORD gene.
Ranirestat is an aldose reductase inhibitor being developed for the treatment of diabetic neuropathy by Dainippon Sumitomo Pharma and PharmaKyorin. It has been granted orphan drug status. The drug is to be used orally.
In enzymology, an aldose-6-phosphate reductase (NADPH) (EC 1.1.1.200) is an enzyme that catalyzes the chemical reaction
In enzymology, a fructose 5-dehydrogenase (NADP+) (EC 1.1.1.124) is an enzyme that catalyzes the chemical reaction
In enzymology, a L-iditol 2-dehydrogenase (EC 1.1.1.14) is an enzyme that catalyzes the chemical reaction
In enzymology, a phosphogluconate dehydrogenase (decarboxylating) (EC 1.1.1.44) is an enzyme that catalyzes the chemical reaction
In enzymology, a sorbose 5-dehydrogenase (NADP+) (EC 1.1.1.123) is an enzyme that catalyzes the chemical reaction
Aldo-keto reductase family 1, member B1 (AKR1B1) is an gene in humans that encodes the enzyme aldose reductase. It is a reduced nicotinamide-adenine dinucleotide phosphate (NADPH)-dependent enzyme catalyzing the reduction of various aldehydes and ketones to the corresponding alcohol. The involvement of AKR1B1 in oxidative stress diseases, cell signal transduction, and cell proliferation process endows AKR1B1 with potential as a therapeutic target.
Alcohol dehydrogenase [NADP+] also known as aldehyde reductase or aldo-keto reductase family 1 member A1 is an enzyme that in humans is encoded by the AKR1A1 gene. AKR1A1 belongs to the aldo-keto reductase (AKR) superfamily. It catalyzes the NADPH-dependent reduction of a variety of aromatic and aliphatic aldehydes to their corresponding alcohols and catalyzes the reduction of mevaldate to mevalonic acid and of glyceraldehyde to glycerol. Mutations in the AKR1A1 gene has been found associated with non-Hodgkin's lymphoma.
The aldo-keto reductase family is a family of proteins that are subdivided into 16 categories; these include a number of related monomeric NADPH-dependent oxidoreductases, such as aldehyde reductase, aldose reductase, prostaglandin F synthase, xylose reductase, rho crystallin, and many others.
Sorbinil (INN) is an aldose reductase inhibitor being investigated for treatment of diabetic complications including neuropathy and retinopathy. Aldose reductase is an enzyme present in lens and brain that removes excess glucose by converting it to sorbitol. Sorbitol accumulation can lead to the development of cataracts in the lens and neuropathy in peripheral nerves. Sorbinil has been shown to inhibit aldose reductase in human brain and placenta and calf and rat lens. Sorbinil reduced sorbitol accumulation in rat lens and sciatic nerve of diabetic rats orally administered 0.25 mg/kg sorbinil.
Alrestatin is an inhibitor of aldose reductase, an enzyme involved in the pathogenesis of complications of diabetes mellitus, including diabetic neuropathy.
Pseudohypoxia refers to a condition that mimics hypoxia, by having sufficient oxygen yet impaired mitochondrial respiration due to a deficiency of necessary co-enzymes, such as NAD+ and TPP. The increased cytosolic ratio of free NADH/NAD+ in cells (more NADH than NAD+) can be caused by diabetic hyperglycemia and by excessive alcohol consumption. Low levels of TPP results from thiamine deficiency.
Aldo-keto reductase family 1 member C2, also known as bile acid binding protein, 3α-hydroxysteroid dehydrogenase type 3 (3α-HSD3), and dihydrodiol dehydrogenase type 2, is an enzyme that in humans is encoded by the AKR1C2 gene.
In enzymology, a prostaglandin-F synthase (PGFS; EC 1.1.1.188) is an enzyme that catalyzes the chemical reaction: