Disease relevance of AKR1A1

• To determine whether other AKR superfamily members can divert trans-dihydrodiols to o-quinones, the cDNA encoding human aldehyde reductase (AKR1A1) was isolated from hepatoma HepG2 cells using RT-PCR, subcloned into a prokaryotic expression vector, overexpressed in E. coli and purified to homogeneity in milligram amounts [1].
• Structures of human and porcine aldehyde reductase: an enzyme implicated in diabetic complications [2].
• Specifically, the Z 2 allele, in the presence of diabetes and/or hyperglycemia, is associated with increased ALDR1 expression [3].
• The ALR gene was expressed in Escherichia coli under the control of the tac promoter [4].
• In myelocytic leukemia cells, the major reductase was aldehyde reductase, and levels of aldose reductase were extremely low [5].

High impact information on AKR1A1

• AR2 but not AR1 mRNA was significantly increased some 11- to 18-fold by hyperosmolarity in several retinal pigment epithelial cell lines [6].
• Identification of the residues involved in the reaction catalysed by aldehyde reductase should aid in the development of drugs for the treatment of diabetic complications [7].
• Of these, 38 clones (81%) contained repetitive elements, either short interspersed transposable element (SINE or Alu elements), long terminal repeat (LTR), long interspersed transposable element (LINE), or satellite region (ALR/Alpha) DNA, and three additional clones were near Alu elements [8].
• Several hydroxysteroid dehydrogenases of the AKR1C subfamily catalyzed the reduction of HNE with higher activity than aldehyde reductase (AKR1A1) [9].
• The substrate specificities of human aldose reductase and aldehyde reductase toward trioses, triose phosphates, and related three-carbon aldehydes and ketones were evaluated [10].

Chemical compound and disease context of AKR1A1

• Fatty acid reductase from the bioluminescent bacterium Photobacterium phosphoreum, has been partially purified free of aldehyde reductase activity and with a low endogenous fatty acid content permitting the characterization of the aldehyde product of the reaction [11].

Biological context of AKR1A1

• This suggests that P450 1A1/P450 1B1 and AKR1A1 play competing roles in the metabolic activation of BP-7,8-diol and that the dominant pathway of BP-7,8-diol activation depends on the redox state of the cells [12].
• AKR1A1 was localized on chromosome 1p33-->p32 by fluorescence in situ hybridization [13].
• The crystal structure of porcine and human aldehyde reductase should allow in vitro mutagenesis to elucidate the mechanism of action for this enzyme and facilitate the effective design of specific inhibitors [2].
• The amino-acid sequence of porcine aldehyde reductase revealed a remarkable homology with human aldehyde reductase [2].
• Aldehyde reductase I activity is more susceptible than aldehyde reductase II activity to inhibition by p-hydroxymercuribenzoate, as reflected by IC50 values of 7.5 microM and 40 microM for aldehyde reductases I and II, respectively [14].

Anatomical context of AKR1A1

• These experiments revealed however, that the expression of AKR1A1 is restricted primarily to brain, kidney, liver and small intestine [15].
• TCDD induction of AKR1A1 transfectants provided a cell line that expressed both pathways [12].
• Northern blots of multiple tissues indicate that aldehyde reductase mRNA is present in all tissues examined and is most abundant in kidney, liver, and thyroid, which is consistent with the tissue enzyme distribution [16].
• Aldose reductase and aldehyde reductase were purified to homogeneity from multiple samples of human kidney cortex and medulla [17].
• Purification and characterization of human testis aldose and aldehyde reductase [18].

Associations of AKR1A1 with chemical compounds

• In contrast, AKR1A1 reduces a broad spectrum of carbonyl-containing compounds, displaying highest specific activity for SSA, 4-carboxybenzaldehyde, 4-nitrobenzaldehyde, pyridine-3-aldehyde, pyridine-4-aldehyde, 4-hydroxynonenal, phenylglyoxal, methylglyoxal, 2,3-hexanedione, 1, 2-NQ, 16-ketoestrone and d-glucuronic acid [15].
• Comparison between the kinetic properties of AKR7A2 and AKR1A1 showed that both recombinant enzymes exhibited roughly similar k(cat)/K(m) values for SSA, 1,2-NQ and 16-ketoestrone [15].
• ALR1 shows broad specificity for aldehydes but does not efficiently catalyze the reduction of glucose due to poor binding (Km = 2.5 M) [19].
• Other families include the prokaryotic AKRs, the plant chalcone reductases, the Shaker channels, and the ethoxyquin-inducible aflatoxin B1 aldehyde reductase [20].
• Comparison of the aldehyde reductase gene structure to all other characterized human genes of the aldo-keto reductase superfamily (aldose reductase, bile acid binder, and type I and type II 3alpha-hydroxysteroid dehydrogenases) indicates that it is more distantly related to these genes than they are among themselves [16].

Other interactions of AKR1A1

• Many of the compounds which are substrates for AKR1A1 also serve as substrates for AKR1B1, though the latter enzyme was shown to display a specific activity significantly less than that of AKR1A1 for most of the aromatic and aliphatic aldehydes studied [15].
• The competing activation of BP-7,8-diol by P450 1A1/P450 1B1 and AKR1A1 was studied with varied NADPH:NAD+ ratios [12].
• The high catalytic efficiency of AKR1A1 for potent proximate carcinogen trans-dihydrodiols and its presence in tissues that contain CYP1A1 and EH suggests that it plays an important role in this alternative pathway of PAH activation (supported by CA39504) [1].
• A nonspecific NADPH-dependent carbonyl reductase from human brain (formerly designated as aldehyde reductase 1; Ris, M. M., and von Wartburg, J. P. (1973) Eur. J. Biochem. 37, 69-77) has been purified to homogeneity [21].
• The high molecular weight aldehyde reductase exhibited properties similar to alcohol dehydrogenase; it had a single subunit of mol. wt 41,000 and a pI value of 10 to 10.5, and showed preference for NADH over NADPH as cofactor and sensitivity to SH-reagents, pyrazole, o-phenanthroline and isobutyramide [22].

Analytical, diagnostic and therapeutic context of AKR1A1

• 2. The molecular weight of aldose reductase and aldehyde reductase were estimated to be 36,000 and 38,000 by SDS-PAGE, and the pI values of these enzymes were found to be 5.9 and 5.1 by chromatofocusing, respectively [18].
• Aldose reductase (EC 1.1.1.21) and aldehyde reductase II (L-hexonate dehydrogenase, EC 1.1.1.2) have been purified to homogeneity from human erythrocytes by using ion-exchange chromatography, chromatofocusing, affinity chromatography, and Sephadex gel filtration [23].
• Inhibitory effects of fidarestat on aldose reductase and aldehyde reductase activity evaluated by a new method using HPLC with post-column spectrophotometric detection [24].
• Despite the lower apparent affinity of aldehyde reductase for aldose sugars (approximately 20- to 100-fold less) both enzymes reduced D-xylose, D-glucose, and D-galactose to their respective sugar alcohols in in vitro incubation studies where the generated sugar alcohols were identified by gas chromatography [25].
• ALDR1 genotype was assessed by PCR and fluorescent sequencing of the (A-C)n repeat locus, and ALDR1 messenger ribonucleic acid (mRNA) was measured by ribonuclease protection assay in peripheral blood mononuclear cells [3].

References