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Cellular and Molecular Life Sciences :... Aug 2007Aldose reductase and aldehyde reductase belong to the aldo-keto reductase superfamily of enzymes whose members are responsible for a wide variety of biological... (Review)
Review
Aldose reductase and aldehyde reductase belong to the aldo-keto reductase superfamily of enzymes whose members are responsible for a wide variety of biological functions. Aldose reductase has been identified as the first enzyme involved in the polyol pathway of glucose metabolism which converts glucose into sorbitol. Glucose over-utilization through the polyol pathway has been linked to tissue-based pathologies associated with diabetes complications, which make the development of a potent aldose reductase inhibitor an obvious and attractive strategy to prevent or delay the onset and progression of the complications. Structural studies of aldose reductase and the homologous aldehyde reductase in complex with inhibitor were carried out to explain the difference in the potency of enzyme inhibition. The aim of this review is to provide a comprehensive summary of previous studies to aid the development of aldose reductase inhibitors that may have less toxicity problems than the currently available ones.
Topics: Aldehyde Reductase; Amino Acid Substitution; Animals; Catalytic Domain; Diabetes Mellitus; Enzyme Inhibitors; Glucose; Humans; Imidazolidines; In Vitro Techniques; Models, Molecular; Mutagenesis, Site-Directed; Protein Conformation; Recombinant Proteins
PubMed: 17497245
DOI: 10.1007/s00018-007-6514-3 -
Applied Microbiology and Biotechnology Jan 2011The Escherichia coli NADPH-dependent aldehyde reductase YqhD has contributed to a variety of metabolic engineering projects for production of biorenewable fuels and... (Review)
Review
The Escherichia coli NADPH-dependent aldehyde reductase YqhD has contributed to a variety of metabolic engineering projects for production of biorenewable fuels and chemicals. As a scavenger of toxic aldehydes produced by lipid peroxidation, YqhD has reductase activity for a broad range of short-chain aldehydes, including butyraldehyde, glyceraldehyde, malondialdehyde, isobutyraldehyde, methylglyoxal, propanealdehyde, acrolein, furfural, glyoxal, 3-hydroxypropionaldehyde, glycolaldehyde, acetaldehyde, and acetol. This reductase activity has proven useful for the production of biorenewable fuels and chemicals, such as isobutanol and 1,3- and 1,2-propanediol; additional capability exists for production of 1-butanol, 1-propanol, and allyl alcohol. A drawback of this reductase activity is the diversion of valuable NADPH away from biosynthesis. This YqhD-mediated NADPH depletion provides sufficient burden to contribute to growth inhibition by furfural and 5-hydroxymethyl furfural, inhibitory contaminants of biomass hydrolysate. The structure of YqhD has been characterized, with identification of a Zn atom in the active site. Directed engineering efforts have improved utilization of 3-hydroxypropionaldehyde and NADPH. Most recently, two independent projects have demonstrated regulation of yqhD by YqhC, where YqhC appears to function as an aldehyde sensor.
Topics: Alcohols; Aldehyde Reductase; Aldehydes; Biofuels; Escherichia coli; Escherichia coli Proteins; Industrial Microbiology; Substrate Specificity
PubMed: 20924577
DOI: 10.1007/s00253-010-2912-9 -
Expert Opinion on Therapeutic Patents Mar 2019Aldose reductase (ALR2) is both the key enzyme of the polyol pathway, whose activation under hyperglycemic conditions leads to the development of chronic diabetic... (Review)
Review
INTRODUCTION
Aldose reductase (ALR2) is both the key enzyme of the polyol pathway, whose activation under hyperglycemic conditions leads to the development of chronic diabetic complications, and the crucial promoter of inflammatory and cytotoxic conditions, even under a normoglycemic status. Accordingly, it represents an excellent drug target and a huge effort is being done to disclose novel compounds able to inhibit it.
AREAS COVERED
This literature survey summarizes patents and patent applications published over the last 5 years and filed for natural, semi-synthetic and synthetic ALR2 inhibitors. Compounds described have been discussed and analyzed from both chemical and functional angles.
EXPERT OPINION
Several ALR2 inhibitors with a promising pre-clinical ability to address diabetic complications and inflammatory diseases are being developed during the observed timeframe. Natural compounds and plant extracts are the prevalent ones, thus confirming the use of phytopharmaceuticals as an increasingly pursued therapeutic trend also in the ALR2 inhibitors field. Intriguing hints may be taken from synthetic derivatives, the most significant ones being represented by the differential inhibitors ARDIs. Differently from classical ARIs, these compounds should fire up the therapeutic efficacy of the class while minimizing its side effects, thus overcoming the existing limits of this kind of inhibitors.
Topics: Aldehyde Reductase; Animals; Diabetes Complications; Drug Design; Enzyme Inhibitors; Humans; Inflammation; Patents as Topic
PubMed: 30760060
DOI: 10.1080/13543776.2019.1582646 -
Molecular Vision Sep 1998The three-dimensional structures of aldose reductase and aldehyde reductase, members of the aldo-keto reductase superfamily, are composed of similar alpha/beta... (Review)
Review
The three-dimensional structures of aldose reductase and aldehyde reductase, members of the aldo-keto reductase superfamily, are composed of similar alpha/beta TIM-barrels. However, examination of the structures reveals that the inhibitor-binding site of aldose reductase differs from that of aldehyde reductase due to the participation of non-conserved residues in its formation. This information will be useful in the design of inhibitors to prevent or delay diabetic retinopathy. A review of the structures of the inhibitor-binding sites is presented.
Topics: Aldehyde Reductase; Animals; Binding Sites; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Diabetic Retinopathy; Enzyme Inhibitors; Humans; Models, Molecular; Protein Structure, Tertiary
PubMed: 9756955
DOI: No ID Found -
Current Medicinal Chemistry Aug 2003Aldose-, aldehyde and renal specific oxido reductase (RSOR) belong to the family of aldo-keto reductases (AKRs). They are monomeric (alpha/beta)8-barrel proteins with a... (Review)
Review
Aldose-, aldehyde and renal specific oxido reductase (RSOR) belong to the family of aldo-keto reductases (AKRs). They are monomeric (alpha/beta)8-barrel proteins with a molecular weight ranging from 30 to 40 kDa, and at present include more than 60 members. Except for RSOR, they are expressed in a wide variety of animal and plant species and in various tissues. They catalyze NADPH-dependent reduction of various aliphatic and aromatic aldehyde and ketones. During the past three decades aldehyde reductase (AKR1A) and aldose reductase (AKR1B) have been extensively investigated, and the gene regulation of AKR1B has been noted to be heavily influenced by hyperglycemic state and high glucose ambience in various culture systems. AKR1B catalyzes the conversion of glucose to sorbitol in concert with a coenzyme, NADPH. The newly discovered RSOR has certain structural and functional similarities to AKR1B and seems to be relevant to the renal complications of diabetes mellitus. Like other AKRs, it has a NADPH binding motif, however, it is located at the N-terminus and it probably undergoes N-linked glycosylation in order to achieve functional substrate specificity. Besides the AKR3 motif, it has very little nucleotide or protein sequence homology with other members of the AKR family. Nevertheless, gene regulation of RSOR, like AKR1B, is heavily modulated by carbonyl, oxidative and osmotic stresses, and thus it is anticipated that its discovery would lead to the development of new inhibitors as well as gene therapy targets to alleviate the complications of diabetes mellitus in the future.
Topics: Aldehyde Reductase; Amino Acid Motifs; Amino Acid Sequence; Animals; Diabetes Mellitus; Gene Expression Regulation; Humans; Kidney; Molecular Sequence Data
PubMed: 12871137
DOI: 10.2174/0929867033457368 -
Cell Reports. Medicine Jun 2023Abnormal polyol metabolism is predominantly associated with diabetes, where excess glucose is converted to sorbitol by aldose reductase (AR). Recently, abnormal polyol...
Abnormal polyol metabolism is predominantly associated with diabetes, where excess glucose is converted to sorbitol by aldose reductase (AR). Recently, abnormal polyol metabolism has been implicated in phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG) and an AR inhibitor, epalrestat, proposed as a potential therapy. Considering that the PMM2 enzyme is not directly involved in polyol metabolism, the increased polyol production and epalrestat's therapeutic mechanism in PMM2-CDG remained elusive. PMM2-CDG, caused by PMM2 deficiency, presents with depleted GDP-mannose and abnormal glycosylation. Here, we show that, apart from glycosylation abnormalities, PMM2 deficiency affects intracellular glucose flux, resulting in polyol increase. Targeting AR with epalrestat decreases polyols and increases GDP-mannose both in patient-derived fibroblasts and in pmm2 mutant zebrafish. Using tracer studies, we demonstrate that AR inhibition diverts glucose flux away from polyol production toward the synthesis of sugar nucleotides, and ultimately glycosylation. Finally, PMM2-CDG individuals treated with epalrestat show a clinical and biochemical improvement.
Topics: Animals; Zebrafish; Glycosylation; Aldehyde Reductase; Mannose; Metabolomics
PubMed: 37257447
DOI: 10.1016/j.xcrm.2023.101056 -
Archives of Biochemistry and Biophysics Jul 1998The only major structural difference between aldehyde reductase, a primarily NADPH-dependent aldo-keto reductase, and aldose reductase, a dually coenzyme-specific...
The only major structural difference between aldehyde reductase, a primarily NADPH-dependent aldo-keto reductase, and aldose reductase, a dually coenzyme-specific (NADPH/NADH) member of the same superfamily, is an additional eight amino acid residues in the substrate/inhibitor binding site (C-terminal region) of aldehyde reductase. On the premise that this segment defines the substrate specificity of the enzyme, a mutant of aldehyde reductase lacking residues 306-313 was constructed. In contrast to wild-type enzyme, the mutant enzyme reduced a narrower range of aldehydes and the new substrate specificity was not similar to aldose reductase as might have been predicted. A major change in coenzyme specificity was observed, however, the mutant enzyme being distinctly NADH preferring(Km, NADH = 35 microM, compared to <5 mM for wild-type and Km, NADPH = 670 microM, compared to 35 microM for wild type). Upon analyzing coordinates of aldehyde and aldose reductase, we found that deletion of residues 306-313 may have created a truncated enzyme that retained the three-dimensional structural features of the enzyme's C-terminal segment. The change in substrate specificity could be explained by the new alignment of amino acids. The reversal of coenzyme specificity appeared to be due to a significant backbone shift initiated by the formation of a strong hydrogen bond between Tyr319 and Val300. A similar bond exists in aldose reductase (Tyr309-Ala299). It appears, therefore, that as far as coenzyme specificity is concerned, deletion of residues 306-313 has converted aldehyde reductase into an aldose reductase-like enzyme.
Topics: Aldehyde Reductase; Amino Acid Sequence; Amino Acid Substitution; Animals; Base Sequence; Kidney; Kinetics; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; NAD; NADP; Oxidation-Reduction; Peptide Fragments; Sequence Homology, Amino Acid; Structure-Activity Relationship; Substrate Specificity; Swine
PubMed: 9675019
DOI: 10.1006/abbi.1998.0721 -
Current Computer-aided Drug Design 2020Cancer is a well-known and well-studied disease. There are environmental as well as genetic factors that trigger cancer. All forms of cancer are associated with the...
BACKGROUND
Cancer is a well-known and well-studied disease. There are environmental as well as genetic factors that trigger cancer. All forms of cancer are associated with the deregulation of genes and proteins. Aldose reductase, Aldose Reductase like protein 1 and Aldehyde Reductase are homologous proteins that are overexpressed in different types of cancer. They are NADPHdependent oxidoreductases. The active site is conserved, thus there is very less substrate specificity among those proteins. In this study, novel molecules targeting the three proteins are designed.
METHODS
LigBuilder V2 software is used to design novel molecules. Molecular docking is performed to study the binding affinity of each ligand towards the targets. Molecular Dynamics Simulation was done to check the stability of protein-ligand complexes in an aqueous environment.
RESULTS
Six novel molecules have been designed. The six molecules studied are found to have better in silico affinity than tolrestat (known inhibitor). The designed molecules are predicted to be orally active. Finally, Molecular Dynamics Simulation showed that the protein-ligand complexes are stable in an aqueous environment.
CONCLUSION
New molecules targeting Aldose reductase, Aldose Reductase like protein 1 and Aldehyde Reductase have been designed.
Topics: Aldehyde Reductase; Aldo-Keto Reductase Family 1 member B10; Binding Sites; Computer Simulation; Enzyme Inhibitors; Kinetics; Ligands; Molecular Docking Simulation; Substrate Specificity
PubMed: 31749429
DOI: 10.2174/1573409915666191015111200 -
Journal of Enzyme Inhibition Dec 2001Aldose reductase ([EC1.1.1.21]: AR) acts on the first step of the polyol metabolic pathway to catalyze the reduction of glucose to sorbitol with NADPH as a coenzyme.... (Review)
Review
Aldose reductase ([EC1.1.1.21]: AR) acts on the first step of the polyol metabolic pathway to catalyze the reduction of glucose to sorbitol with NADPH as a coenzyme. Hyperactivity of the pathway in individuals with high blood glucose level is closely related to the onset or progression of diabetic complications. AR inhibitors have therefore been noted as possible pharmacotherapeutic agents for the treatment of diabetic complications. One AR inhibitor has been on the market in Japan, while some potent inhibitors are in clinical trials. Reviewed are the physiological roles of AR, the chemical structures of AR inhibitors, interactions of AR inhibitors with AR using X-ray studies, and the following potencies of AR inhibitors: in vitro activities for AR, in vitro selectivities between AR and aldehyde reductase, their pharmacological effects in vivo, and their effectiveness in clinical trials. Also discussed are directions for the design of future AR inhibitors.
Topics: Aldehyde Reductase; Binding Sites; Clinical Trials as Topic; Crystallography, X-Ray; Diabetic Neuropathies; Enzyme Inhibitors; Humans; Imidazoles; Imidazolidines; Naphthalenes; Quinazolines
PubMed: 12164386
DOI: 10.1080/14756360127568 -
Enzyme and Microbial Technology Sep 1992
Review
Topics: Alcohols; Aldehyde Reductase; Aldehydes; Animals; Carbohydrate Dehydrogenases; Diabetes Mellitus; Enzyme Activation; Humans; Kinetics; Oxidation-Reduction; Rats; Structure-Activity Relationship; Substrate Specificity; Sugar Alcohols; Swine
PubMed: 1368891
DOI: 10.1016/0141-0229(92)90107-y