Disease relevance of AKR1B1

• Because aldose reductase has been implicated in the etiology of diabetic complications, acceptance of steroid substrates may offer new implications for therapy [1].
• Expression of the AR cDNA in Escherichia coli resulted in the synthesis of a protein with a molecular weight of approximately 35 kD which can be immunoprecipitated specifically with antiserum raised against PP9 [2].
• Cultured bovine retinal capillary pericytes (BRP) were used to investigate the effect of an aldose reductase inhibitor, tolrestat, and an inhibitor of advanced glycation end products (AGE) formation, aminoguanidine, on glucose toxicity [3].
• Non-tryptophan fluorescence and high molecular weight protein formation in lens crystallins of rats with chronic galactosemia: prevention by the aldose reductase inhibitor sorbinil [4].
• Aldose reductase inhibitors, when administered from the onset of hyperglycemia, prevent the progression of polyol accumulation-linked complications [5].

Psychiatry related information on AKR1B1

• This dramatic change in stereospecificity may account for the reported apparent cooperative behavior exhibited also by highly purified electrophoretically homogeneous preparations of aldose reductase [6].

High impact information on AKR1B1

• Three seemingly independent biochemical pathways are involved in the pathogenesis: glucose-induced activation of protein kinase C isoforms; increased formation of glucose-derived advanced glycation end-products; and increased glucose flux through the aldose reductase pathway [7].
• These components include a recognition unit or receptor (for example, the beta-adrenergic receptor (beta AR) for catecholamines or the 'light receptor' rhodopsin), a guanine nucleotide regulatory or transducing protein, and an effector enzyme (for example, adenylate cyclase or cyclic GMP phosphodiesterase) [8].
• Elevating glucose concentration in culture media from 100 to 400 mg/dl led to a 100% increase in sorbitol levels, which could be inhibited completely by sorbinil, an aldose reductase inhibitor [9].
• Elevated cellular sorbitol levels resulting from conversion of increased glucose by aldose reductase might deplete cellular myoinositol content, which could then lower inositol phosphates (InsPs) and diacylglycerol levels, key regulators of protein kinase C (PKC) [9].
• Thiamine and benfotiamine reduce aldose reductase mRNA expression, activity, sorbitol concentrations, and intracellular glucose while increasing the expression and activity of transketolase, for which it is a coenzyme, in human endothelial cells and bovine retinal pericytes cultured in high glucose [10].

Chemical compound and disease context of AKR1B1

• Whatever the behaviour of AR2, many studies have showed that sorbitol production is not an initiating aetiological factor in the development of diabetic complications in humans [11].
• Sorbitol formation from glucose, catalyzed by the enzyme aldose reductase, is believed to play a role in the development of certain chronic complications of diabetes mellitus [12].
• Properties of ICI 128,436, a novel aldose reductase inhibitor, and its effects on diabetic complications in the rat [13].
• These results indicate that M16209 and M16287 are potent aldose reductase inhibitors, which could be applicable to treatment for diabetic complications [14].
• An antiserum against the synthetic disaccharide abequose 1 leads to 3 alpha rhamnose (AR), representative of Salmonella O-antigen 8, coupled to bovine serum albumin (BSA) was used for diagnosis of Salmonella bacteria by indirect immunofluorescence (IFL) and by co-agglutination (COA) using sensitized protein A-containing staphylococci [15].

Biological context of AKR1B1

• On the other hand, the 20 alpha-hydroxysteroid dehydrogenase gene was strongly expressed in the endometrium at the time of luteolysis [16].
• The expression of all previously known prostaglandin F synthases (PGFSs), two newly discovered PGFS-like genes, and a 20 alpha-hydroxysteroid dehydrogenase was studied by Northern blot and reverse transcription PCR [16].
• The aldose reductase was shown to contain no carbohydrate despite the fact that the enzyme contains the consensus sequence -Asn-Lys-Thr- for N-linked glycosylation [17].
• A computer homology search of the 20 alpha-HSD cDNA performed against the GenBank DNA sequence database revealed it to be identical with bovine lens aldose reductase (alditol:NADPH oxidoreductase; EC 1.1.1.21), and a literature search reveals the deduced amino acid sequence to be identical with that reported for the bovine enzyme [1].
• Aldehyde reductase [EC 1.1.1.2] and aldose reductase [EC 1.1.1.21] are monomeric NADPH-dependent oxidoreductases having wide substrate specificities for carbonyl compounds [18].

Anatomical context of AKR1B1

• Despite the absence of a typical signal sequence, the human aldose reductase is partially translocated into the periplasm of the E. coli cells, where it is present in an enzymatically active form [2].
• In conclusion, aldose reductase inhibition counteracts diabetes-induced nitrosative stress and PARP activation in sciatic nerve and retina [19].
• Immunohistochemical localization of aldose reductase. I. Enzyme purification and antibody preparation--localization in peripheral nerve, artery, and testis [20].
• All three aldose reductase inhibitors completely prevented or markedly reduced these hemodynamic and vascular filtration changes and increases in tissue sorbitol levels in the anterior uvea, posterior uvea, retina, sciatic nerve, and granulation tissue [21].
• The addition of an aldose reductase inhibitor (ICI-128436, Statil) did not significantly affect the high-glucose-induced reduction of D-alpha-tocopherol binding, although it reduced sorbitol levels in the cells compared with those from cells cultured in high concentrations of glucose [22].

Associations of AKR1B1 with chemical compounds

• An aldose reductase with 20 alpha-hydroxysteroid dehydrogenase activity is most likely the enzyme responsible for the production of prostaglandin f2 alpha in the bovine endometrium [16].
• Further, the enzyme purified to homogeneity by following activity with 17-hydroxyprogesterone as a substrate was shown to reduce glucose, glyceraldehyde, and benzaldehyde (all classic aldose reductase substrates) [1].
• The amino acid sequence of rat liver 3 alpha-HSD bears no significant homology with 3 beta-, 17 beta- or 11 beta-hydroxysteroid dehydrogenases but has striking homology with bovine lung prostaglandin F synthase (69% homology at the amino acid level and 74% homology at the nucleotide level) which is a member of the aldehyde/aldose reductase family [23].
• The deduced amino acid sequence also indicates that maturation of aldose reductase involves removal of the N-terminal methionine [24].
• Aldose reductase inhibitor fidarestat prevents retinal oxidative stress and vascular endothelial growth factor overexpression in streptozotocin-diabetic rats [25].

Other interactions of AKR1B1

• The effectiveness of cysteine and cysteinylglycine to act as protein thiolating agents was investigated using bovine lens aldose reductase (ALR2) as the protein target [26].
• The regulation of GLUT-3 and aldose reductase mRNA in retinal endothelial cells and retinal pericytes was studied in response to variations in the extracellular concentration of hexoses [27].
• The simultaneous introduction of sorbinil, an aldose reductase inhibitor, to the galactose medium not only prevented the decrease in microsomal prostaglandin biosynthesis and PGH synthase activity, but also the detrimental morphological complications [28].
• Two enzymes are involved in the polyol pathway: an aldose reductase that reduces glucose in sorbitol followed by its oxidation in fructose by sorbitol dehydrogenase [29].
• Effect of bovine small intestine thioredoxin on aldose reductase activity [30].

Analytical, diagnostic and therapeutic context of AKR1B1

• Sequence analysis of bovine lens aldose reductase [17].
• Molecular cloning of testicular 20 alpha-hydroxysteroid dehydrogenase: identity with aldose reductase [1].
• Prevention of hemodynamic and vascular albumin filtration changes in diabetic rats by aldose reductase inhibitors [21].
• Transketolase and aldose reductase mRNA expression was determined by reverse transcription-PCR, and their activity was measured spectrophotometrically; sorbitol concentrations were quantified by gas chromatography-mass spectrometry and intracellular glucose concentrations by fluorescent enzyme-linked immunosorbent assay method [10].
• Titration of adrenodoxin reductase with NADH, instead of NADPH, provides a curved titration plot rather than the sharp break seen with NADPH, and permits calculation of a potential for the AR/ARH2 couple of -0.291 V, close to that of NAD(P)H (-0.316 V) [31].

References