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Kidney International Nov 1989The distribution of NADPH-dependent reductase activity in the rat cortex, outer medulla and inner medulla was investigated through biochemical and histochemical methods....
The distribution of NADPH-dependent reductase activity in the rat cortex, outer medulla and inner medulla was investigated through biochemical and histochemical methods. Biochemical studies revealed reductase activity to be present in all three regions of the kidney with the highest specific activity observed in the inner medulla, followed by the cortex and the outer medulla. Activity in all three regions was inhibited by the aldose reductase inhibitors sorbinil, tolrestat and 7-hydroxychromone-2-carboxylic acid. Based on substrate utilization and response to sulfate on the inhibitors, the inner medulla contains primarily aldose reductase (EC 1.1.1.21) while the cortex contains primarily aldehyde reductase (EC 1.1.1.2). The outer medulla contains a mixture of both enzymes. This distribution was confirmed by a radioimmunoassay for aldose reductase. Immunohistochemical investigations of the rat kidney with antibodies against rat lens aldose reductase and rat kidney aldehyde reductase revealed a similar distribution of these enzymes. Aldehyde reductase was immunohistochemically detected only in the cortex where it was localized in the proximal convoluted tubules. Immunoreactive aldose reductase was detected in Henle's loop at both the inner stripe of the outer medulla and in the inner medulla, and in the collecting tubules and the epithelial cell lining the pelvis of the inner medulla near the papilla. No specific immunohistochemical staining for aldose reductase was observed in the cortex. A similar immunohistochemical distribution of aldose reductase was also observed in the human kidney with antibodies against human placental aldose reductase.
Topics: Alcohol Dehydrogenase; Aldehyde Reductase; Animals; Female; Humans; Immunoenzyme Techniques; Kidney; Radioimmunoassay; Rats; Rats, Inbred Strains; Sugar Alcohol Dehydrogenases
PubMed: 2515341
DOI: 10.1038/ki.1989.270 -
Sensors (Basel, Switzerland) Sep 2022In this work, the enzyme aldehyde reductase, also known as aldose reductase, was synthesized and cloned from a human gene. Spectrophotometric measurements show that in...
In this work, the enzyme aldehyde reductase, also known as aldose reductase, was synthesized and cloned from a human gene. Spectrophotometric measurements show that in presence of the nicotinamide adenine dinucleotide phosphate cofactor (NADPH), the aldehyde reductase catalyzed the reduction of glucose to sorbitol. Electrochemical measurements performed on an electrodeposited poly(methylene green)-modified gold electrode showed that in the presence of the enzyme aldehyde reductase, the electrocatalytic oxidation current of NADPH decreased drastically after the addition of glucose. These results demonstrate that aldehyde reductase is an enzyme that allows the construction of an efficient electrochemical glucose biosensor based on glucose reduction.
Topics: Aldehyde Reductase; Glucose; Gold; Humans; NADP; Sorbitol
PubMed: 36236202
DOI: 10.3390/s22197105 -
Biomedicine & Pharmacotherapy =... Jan 2019Hyperglycemia invoke number of pathways resulting in development of diabetic retinopathy (DR), including protein kinase C activation, increased expression of VEGF,... (Review)
Review
Hyperglycemia invoke number of pathways resulting in development of diabetic retinopathy (DR), including protein kinase C activation, increased expression of VEGF, advanced glycation end product (AGEs) formation and activation of polyol pathway, among which the pathophysiology of aldose reductase (ALR2) of the polyol pathway is evident by more than a decade of research. Subtle involvement of ALR2 in invoking various pathways of diabetic complications has caused an increase in attention towards the identification of novel aldose reductase inhibitors (ARIs). Numerous ARIs of different classes were employed in the treatment of diabetic complications initially, but few came into light as drugs. Though no ALR2 inhibitor has been used for the treatment or control of DR, Epalrestat has been used worldwide for treating diabetic neuropathy. This review critically analyses different treatments available for diabetic retinopathy, their limitations and the importance of the development of novel inhibitors of ALR2 that could prevent progression of DR, by causing a direct or indirect effect on controlling factors associated with DR.
Topics: Aldehyde Reductase; Animals; Diabetic Retinopathy; Drug Delivery Systems; Enzyme Inhibitors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; PPAR gamma; Protein Kinase Inhibitors; Treatment Outcome
PubMed: 30551523
DOI: 10.1016/j.biopha.2018.10.185 -
IUCrJ Jul 2023The Fe-dependent E. coli enzyme FucO catalyzes the reversible interconversion of short-chain (S)-lactaldehyde and (S)-1,2-propanediol, using NADH and NAD as cofactors,...
The Fe-dependent E. coli enzyme FucO catalyzes the reversible interconversion of short-chain (S)-lactaldehyde and (S)-1,2-propanediol, using NADH and NAD as cofactors, respectively. Laboratory-directed evolution experiments have been carried out previously using phenylacetaldehyde as the substrate for screening catalytic activity with bulky substrates, which are very poorly reduced by wild-type FucO. These experiments identified the N151G/L259V double mutant (dubbed DA1472) as the most active variant with this substrate via a two-step evolutionary pathway, in which each step consisted of one point mutation. Here the crystal structures of DA1472 and its parent D93 (L259V) are reported, showing that these amino acid substitutions provide more space in the active site, though they do not cause changes in the main-chain conformation. The catalytic activity of DA1472 with the physiological substrate (S)-lactaldehyde and a series of substituted phenylacetaldehyde derivatives were systematically quantified and compared with that of wild-type as well as with the corresponding point-mutation variants (N151G and L259V). There is a 9000-fold increase in activity, when expressed as k/K values, for DA1472 compared with wild-type FucO for the phenylacetaldehyde substrate. The crystal structure of DA1472 complexed with a non-reactive analog of this substrate (3,4-dimethoxyphenylacetamide) suggests the mode of binding of the bulky group of the new substrate. These combined structure-function studies therefore explain the dramatic increase in catalytic activity of the DA1472 variant for bulky aldehyde substrates. The structure comparisons also suggest why the active site in which Fe is replaced by Zn is not able to support catalysis.
Topics: Aldehyde Reductase; Escherichia coli; Substrate Specificity; Kinetics; Catalytic Domain
PubMed: 37261425
DOI: 10.1107/S205225252300444X -
Journal of Neurochemistry Mar 2018The increased glucose flux into the polyol pathway via aldose reductase (AR) is recognized as a major contributing factor for the pathogenesis of diabetic neuropathy,...
The increased glucose flux into the polyol pathway via aldose reductase (AR) is recognized as a major contributing factor for the pathogenesis of diabetic neuropathy, whereas little is known about the functional significance of AR in the peripheral nervous system. Spontaneously immortalized Schwann cell lines established from long-term cultures of AR-deficient and normal C57BL/6 mouse dorsal root ganglia and peripheral nerves can be useful tools for studying the physiological and pathological roles of AR. These cell lines, designated as immortalized knockout AR Schwann cells 1 (IKARS1) and 1970C3, respectively, demonstrated distinctive Schwann cell phenotypes, such as spindle-shaped morphology and immunoreactivity to S100, p75 neurotrophin receptor, and vimentin, and extracellular release of neurotrophic factors. Conditioned media obtained from these cells promoted neuronal survival and neurite outgrowth of cultured adult mouse dorsal root ganglia neurons. Microarray and real-time RT-PCR analyses revealed significantly down-regulated mRNA expression of polyol pathway-related enzymes, sorbitol dehydrogenase and ketohexokinase, in IKARS1 cells compared with those in 1970C3 cells. In contrast, significantly up-regulated mRNA expression of aldo-keto reductases (AKR1B7 and AKR1B8) and aldehyde dehydrogenases (ALDH1L2, ALDH5A1, and ALDH7A1) was detected in IKARS1 cells compared with 1970C3 cells. Exposure to reactive aldehydes (3-deoxyglucosone, methylglyoxal, and 4-hydroxynonenal) significantly up-regulated the mRNA expression of AKR1B7 and AKR1B8 in IKARS1 cells, but not in 1970C3 cells. Because no significant differences in viability between these two cell lines after exposure to these aldehydes were observed, it can be assumed that the aldehyde detoxification is taken over by AKR1B7 and AKR1B8 in the absence of AR.
Topics: Aldehyde Reductase; Aldehydes; Animals; Cell Culture Techniques; Cell Line; Cell Survival; Culture Media, Conditioned; Female; Ganglia, Spinal; Male; Mice, Inbred C57BL; Mice, Knockout; Neurons; Peripheral Nerves; Polymers; RNA, Messenger; Schwann Cells; Signal Transduction; Up-Regulation
PubMed: 29238976
DOI: 10.1111/jnc.14277 -
BMC Biotechnology Oct 2021Published biocatalytic routes for accessing enantiopure 2-phenylpropanol using oxidoreductases afforded maximal product titers of only 80 mM. Enzyme deactivation was...
BACKGROUND
Published biocatalytic routes for accessing enantiopure 2-phenylpropanol using oxidoreductases afforded maximal product titers of only 80 mM. Enzyme deactivation was identified as the major limitation and was attributed to adduct formation of the aldehyde substrate with amino acid residues of the reductase.
RESULTS
A single point mutant of Candida tenuis xylose reductase (CtXR D51A) with very high catalytic efficiency (43·10 s M) for (S)-2-phenylpropanal was found. The enzyme showed high enantioselectivity for the (S)-enantiomer but was deactivated by 0.5 mM substrate within 2 h. A whole-cell biocatalyst expressing the engineered reductase and a yeast formate dehydrogenase for NADH-recycling provided substantial stabilization of the reductase. The relatively slow in situ racemization of 2-phenylpropanal and the still limited biocatalyst stability required a subtle adjustment of the substrate-to-catalyst ratio. A value of 3.4 g/g was selected as a suitable compromise between product ee and the conversion ratio. A catalyst loading of 40 g was used to convert 1 M racemic 2-phenylpropanal into 843 mM (115 g/L) (S)-phenylpropanol with 93.1% ee.
CONCLUSION
The current industrial production of profenols mainly relies on hydrolases. The bioreduction route established here represents an alternative method for the production of profenols that is competitive with hydrolase-catalyzed kinetic resolutions.
Topics: Aldehyde Reductase; Candida; Kinetics; Propanols; Substrate Specificity
PubMed: 34635076
DOI: 10.1186/s12896-021-00715-5 -
The Journal of Biological Chemistry Jun 1989Aldehyde 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... (Comparative Study)
Comparative Study
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. These enzymes are implicated in the development of diabetic complications by catalyzing the reduction of glucose to sorbitol. Enzyme inhibition as a direct pharmacokinetic approach to the prevention of diabetic complications resulting from the hyperglycemia of diabetes has not been effective because of nonspecificity of the inhibitors and some appreciable side effects. To understand the structural and evolutionary relationship of these enzymes, we cloned and sequenced cDNAs coding for aldose and aldehyde reductases from human liver and placental cDNA libraries. Human placental aldose reductase (open reading frame of 316 amino acids) has a 65% identity (identical plus conservative substitutions) to human liver and placental aldehyde reductase (open reading frame of 325 amino acids). The two sequences have significant identity to 2,5-diketogluconic acid reductase from corynebacterium, frog rho-crystallin, and bovine lung prostaglandin F synthase (reductase). Southern hybridization analysis of human genomic DNA indicates a multigene system for aldose reductase, suggesting the existence of additional proteins. Thus, the aldo-keto reductase superfamily of proteins may have a more significant and hitherto not fully appreciated role in general cellular metabolism.
Topics: Alcohol Oxidoreductases; Aldehyde Reductase; Amino Acid Sequence; Base Sequence; Blotting, Northern; Blotting, Southern; DNA; Humans; Liver; Molecular Sequence Data; Multigene Family; Placenta; Sequence Homology, Nucleic Acid; Sugar Alcohol Dehydrogenases
PubMed: 2498333
DOI: No ID Found -
Diabetes Jul 2024Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. Because many genes associate with DKD, multiomics approaches were used to narrow the list...
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. Because many genes associate with DKD, multiomics approaches were used to narrow the list of functional genes, gene products, and related pathways providing insights into the pathophysiological mechanisms of DKD. The Kidney Precision Medicine Project human kidney single-cell RNA-sequencing (scRNA-seq) data set and Mendeley Data on human kidney cortex biopsy proteomics were used. The R package Seurat was used to analyze scRNA-seq data and data from a subset of proximal tubule cells. PathfindR was applied for pathway analysis in cell type-specific differentially expressed genes and the R limma package was used to analyze differential protein expression in kidney cortex. A total of 790 differentially expressed genes were identified in proximal tubule cells, including 530 upregulated and 260 downregulated transcripts. Compared with differentially expressed proteins, 24 genes or proteins were in common. An integrated analysis combining protein quantitative trait loci, genome-wide association study hits (namely, estimated glomerular filtration rate), and a plasma metabolomics analysis was performed using baseline metabolites predictive of DKD progression in our longitudinal Diabetes Heart Study samples. The aldo-keto reductase family 1 member A1 gene (AKR1A1) was revealed as a potential molecular hub for DKD cellular dysfunction in several cross-linked pathways featured by deficiency of this enzyme.
Topics: Diabetic Nephropathies; Humans; Biomarkers; Aldehyde Reductase; Proteomics; Genome-Wide Association Study; Male; Kidney Tubules, Proximal; Female; Middle Aged; Multiomics
PubMed: 38394643
DOI: 10.2337/db23-0540 -
Current Cancer Drug Targets Jun 2011It is strongly established by numerous studies that oxidative stress-induced inflammation is one of the major causative agents in a variety of cancers. Various factors... (Review)
Review
It is strongly established by numerous studies that oxidative stress-induced inflammation is one of the major causative agents in a variety of cancers. Various factors such as bacterial, viral, parasitic infections, chemical irritants, carcinogens are involved in the initiation of oxidative stress-mediated inflammation. Chronic and persistent inflammation promotes the formation of cancerous tumors. Recent investigations strongly suggest that aldose reductase [AR; AKR1B1], a member of aldo-keto reductase superfamily of proteins, is the mediator of inflammatory signals induced by growth factors, cytokines, chemokines, carcinogens etc. Further, AR reduced product(s) of lipid derived aldehydes and their metabolites such as glutathionyl 1,4-dihydroxynonanol (GS-DHN) have been shown to be involved in the activation of transcription factors such as NF-κB and AP-1 which transcribe the genes of inflammatory cytokines. The increased inflammatory cytokines and growth factors promote cell proliferation, a main feature involved in the tumorigenesis process. Inhibition of AR has been shown to prevent cancer cell growth in vitro and in vivo models. In this review, we have described the possible association between AR with oxidative stress- and inflammation- initiated carcinogenesis. A thorough understanding of the role of AR in the inflammation -associated cancers could lead to the use of AR inhibitors as novel chemotherapeutic agents against cancer.
Topics: Aldehyde Reductase; Animals; Anticarcinogenic Agents; Antineoplastic Agents; Cachexia; Drug Resistance, Neoplasm; Enzyme Inhibitors; Humans; Inflammation Mediators; Isoenzymes; Molecular Targeted Therapy; Neoplasms; Oxidative Stress
PubMed: 21486217
DOI: 10.2174/156800911795655958 -
The Cochrane Database of Systematic... Oct 2007Polyneuropathy, a common complication of diabetes mellitus, causes pain and sensory and motor deficits in the limbs, and is also an important independent predictor of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Polyneuropathy, a common complication of diabetes mellitus, causes pain and sensory and motor deficits in the limbs, and is also an important independent predictor of foot ulceration. Inhibiting the metabolism of glucose by the polyol pathway using aldose reductase inhibitors is a potential mechanism to slow or reverse the neuropathy's progression.
OBJECTIVES
To assess the effects of aldose reductase inhibitors on the progression of symptoms, signs or functional disability in diabetic polyneuropathy.
SEARCH STRATEGY
We searched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (from January 1966 to May 2007), EMBASE (from January 1980 to May 2007) and LILACS (from 1982 to May 2007). We reviewed bibliographies of randomized trials identified, and contacted authors and experts in the field.
SELECTION CRITERIA
We included randomized controlled trials comparing an aldose reductase inhibitor with control, and lasting at least six months. The primary outcome measure was change in neurological function, measured in various ways, including strength testing, sensory examination, and composite scores of neurological examination. Secondary outcome measures were nerve conduction studies, neuropathic symptoms, quality of life, occurrence of foot ulcers and adverse effects.
DATA COLLECTION AND ANALYSIS
Trials included in the review were selected and assessed independently by at least two of us. Methodological criteria and study results were recorded on data extraction forms.
MAIN RESULTS
Thirty-two randomized controlled trials meeting the inclusion criteria were identified. Many had significant methodological flaws. Change in neurological function, our primary outcome measure, was assessed in 29 trials, but sufficient data for meta-analysis were only available in 13 studies, involving 879 treated participants and 909 controls. There was no overall significant difference between the treated and control groups (SMD -0.25, 95% CI -0.56 to 0.05), although one subgroup analysis (four trials using tolrestat) favored treatment. A benefit for neuropathic symptoms was suggested by a group of trials using a dichotomized endpoint (improvement or not), but this was contradicted by another group of trials which measured symptoms on a continuous scale. There was no overall benefit on nerve conduction parameters (27 studies) or foot ulceration (one study). Quality of life was not assessed in any of the studies. While most adverse events were infrequent and minor, three compounds had dose limiting adverse events that lead to their withdrawal from human use: severe hypersensitivity reactions with sorbinil, elevation of creatinine with zenarestat, and alteration of liver function with tolrestat.
AUTHORS' CONCLUSIONS
We found no statistically significant difference between aldose reductase inhibitors and placebo in the treatment of diabetic polyneuropathy. Any future clinical trials of aldose reductase inhibitors should be restricted to compounds proven to have substantial biological or preclinical advantages over previously tested agents.
Topics: Aldehyde Reductase; Diabetic Neuropathies; Enzyme Inhibitors; Humans; Peripheral Nervous System Diseases; Polyneuropathies; Randomized Controlled Trials as Topic
PubMed: 17943821
DOI: 10.1002/14651858.CD004572.pub2