Structure of the human aldose reductase gene.

Graham, Alexander; Brown, LC; Hedge, Philip; Gammack, A.; Markham, Alexander F.

doi:10.1016/s0021-9258(20)89582-9

Cited by 72 publications

(5 citation statements)

References 28 publications

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“…The enzyme is a monomer (35.8 kDa) encoded by a single gene located on chromosome region 7q35. 2,3 It is expressed in various human tissues including retina, 4 muscle, 4 placenta, 1 and liver. 5 The enzyme utilizes NADPH cofactor to reduce carbonyl compounds such as sugars, 6 corticosteroid hormones 7 and aldehyde metabolites.…”

Section: Introductionmentioning

confidence: 99%

“…Human aldose reductase (ALR2, EC 1.1.1.21), a member of the aldo-keto oxidoreductase superfamily, catalyzes the reduction of a variety of carbonyl compounds to the corresponding alcohols. The enzyme is a monomer (35.8 kDa) encoded by a single gene located on chromosome region 7q35. , It is expressed in various human tissues including retina, muscle, placenta, and liver . The enzyme utilizes NADPH cofactor to reduce carbonyl compounds such as sugars, corticosteroid hormones 7 and aldehyde metabolites. , The physiological role of ALR2 spans from steroid and carbohydrate metabolism to detoxification. , The enzyme has received considerable attention due to its participation in the polyol pathway where it reduces glucose and galactose under hyperglycemic conditions …”

Section: Introductionmentioning

confidence: 99%

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Computer Simulation Studies of the Catalytic Mechanism of Human Aldose Reductase

and

Warshel

2000

J. Am. Chem. Soc.

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Aldose reductase, an NADPH dependent oxidoreductase, has received considerable attention due to its possible link to diabetic and galactosemic complications. It is known that the catalytic reaction involves a hydride shift from NADPH and a proton transfer from a suitable proton donor to the carbonyl group of the substrate. However, the details of the process are still unclear. The present work explores the catalytic mechanism of the enzyme by using the semi-microscopic protein dipoles Langevin dipoles (PDLD/S) and the empirical valence bond (EVB) methods. The pK a values of His-110 and Tyr-48 are evaluated to determine which of these two residues donates the proton in the reaction. It is found that the free energy of protonation of His-110 in its protein site is ∼9 kcal/mol and hence the pK a of this residue is abnormally low. Consequently, His-110 is not protonated in the active site of aldose reductase. On the other hand, it is found that the pK a of Tyr-48 is lowered to ∼8.5 in the active site due to the stabilization by the unique local environment of the phenol group. We conclude that Tyr-48 acts as the proton donor in the reduction of aldehydes by aldose reductase, while the neutral His-110 has a role in substrate binding during the catalysis. To obtain a quantitative picture of the energetics of different feasible catalytic mechanisms in the protein we follow the EVB philosophy and calibrate the potential surface of the catalytic reaction in a solvent cage by using the relevant energetics from experiments. It is found that a mechanism where a proton transfer precedes the hydride transfer is unfavorable in the solvent cage, relative to the alternative mechanism where the hydride transfer precedes protonation. Furthermore, our study of the reaction in the actual protein environment indicates that an initial proton transfer step would require prohibitively high energy. Thus, the most probable catalytic mechanism commences with the hydride shift, followed by a proton transfer from Tyr-48. The calculations show that in water the activation barrier for the hydride shift is ∼20 kcal/mol, which is far above the barrier of the subsequent proton transfer. The protein environment stabilizes the transition state of the hydride shift by ∼3 kcal/mol and destabilizes the intermediate state by ∼8 kcal/mol relative to the corresponding states in the water cage. This finding is consistent with the physiological role of the enzyme in detoxification where it catalyzes the reduction of a wide range of carbonyl-containing substrates without particular specificity. It is argued that it may be difficult for an enzyme to both satisfy this demand and catalyze the reaction beyond the simple role of bringing the proton and hydride donor groups to the proximity of the substrate.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Computer Simulation Studies of the Catalytic Mechanism of Human Aldose Reductase

and

Warshel

2000

J. Am. Chem. Soc.

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“…Additionally, an androgen-like response element (ALRE), three osmotic response elements (ORE), an activator protein 1 (Ap-1) binding site, and a thyroid receptor element (TRE) are located upstream of the gene. The AKR1B1 gene is translated to a monomeric protein containing 316 amino acid residues [ 26 , 36 ]. Fig.…”

Section: Structurementioning

confidence: 99%

Aldo-keto reductases: Role in cancer development and theranostics

NAGINI,

KALLAMADI,

TANAGALA

et al. 2024

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Aldo-keto reductases (AKRs) are a superfamily of enzymes that play crucial roles in various cellular processes, including the metabolism of xenobiotics, steroids, and carbohydrates. A growing body of evidence has unveiled the involvement of AKRs in the development and progression of various cancers. AKRs are aberrantly expressed in a wide range of malignant tumors. Dysregulated expression of AKRs enables the acquisition of hallmark traits of cancer by activating oncogenic signaling pathways and contributing to chemoresistance. AKRs have emerged as promising oncotherapeutic targets given their pivotal role in cancer development and progression. Inhibition of aldose reductase (AR), either alone or in combination with chemotherapeutic drugs, has evolved as a pragmatic therapeutic option for cancer. Several classes of synthetic aldo-keto reductase (AKR) inhibitors have been developed as potential anticancer agents, some of which have shown promise in clinical trials. Many AKR inhibitors from natural sources also exhibit anticancer effects. Small molecule inhibitors targeting specific AKR isoforms have shown promise in preclinical studies. These inhibitors disrupt the activation of oncogenic signaling by modulating transcription factors and kinases and sensitizing cancer cells to chemotherapy. In this review, we discuss the physiological functions of human AKRs, the aberrant expression of AKRs in malignancies, the involvement of AKRs in the acquisition of cancer hallmarks, and the role of AKRs in oncogenic signaling, and drug resistance. Finally, the potential of aldose reductase inhibitors (ARIs) as anticancer drugs is summarized.

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“…Its mRNA transcript is 1,384 nucleotides long and codes a 316‐amino acid protein 6 . In addition to a TATA (TATTTA) box at −37 and a CCAAT box at −104 in the promoter, the AKR1B1 gene contains two Alu repeats in intron 1 and two Alu repeats in intron 4 and 9, respectively 7 . An androgen‐like response element is also located at 396 to 382 nucleotides upstream of the gene 6,8 .…”

Section: Introductionmentioning

confidence: 99%

“…−37 and a CCAAT box at −104 in the promoter, the AKR1B1 gene contains two Alu repeats in intron 1 and two Alu repeats in intron 4 and 9, respectively. 7 An androgen-like response element is also located at 396 to 382 nucleotides upstream of the gene. 6,8 Three osmotic response elements (OreA, OreB and OreC) are found at approximately 1 kb upstream of the transcription start site in a 132 bp region.…”

mentioning

confidence: 99%

Role of aldo‐keto reductase family 1 member B1 (AKR1B1) in the cancer process and its therapeutic potential

Khayami

Hashemi

Kerachian

2020

J Cellular Molecular Medi

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The role of aldo‐keto reductase family 1 member B1 (AKR1B1) in cancer is not totally clear but growing evidence is suggesting to have a great impact on cancer progression. AKR1B1 could participate in a complicated network of signalling pathways, proteins and miRNAs such as mir‐21 mediating mechanisms like inflammatory responses, cell cycle, epithelial to mesenchymal transition, cell survival and apoptosis. AKR1B1 has been shown to be mostly overexpressed in cancer. This overexpression has been associated with inflammatory mediators including nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFκB), cell cycle mediators such as cyclins and cyclin‐dependent kinases (CDKs), survival proteins and pathways like mammalian target of rapamycin (mTOR) and protein kinase B (PKB) or AKT, and other regulatory factors in response to reactive oxygen species (ROS) and prostaglandin synthesis. In addition, inhibition of AKR1B1 has been shown to mostly have anti‐cancer effects. Several studies have also suggested that AKR1B1 inhibition as an adjuvant therapy could render tumour cells more sensitive to anti‐cancer therapy or alleviate the adverse effects of therapy. AKR1B1 could also be considered as a potential cancer diagnostic biomarker since its promoter has shown high levels of methylation. Although pre‐clinical investigations on the role of AKR1B1 in cancer and the application of its inhibitors have shown promising results, the lack of clinical studies on AKR1B1 inhibitors has hampered the use of these drugs to treat cancer. Thus, there is a need to conduct more clinical studies on the application of AKR1B1 inhibitors as adjuvant therapy on different cancers.

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Structure of the human aldose reductase gene.

Cited by 72 publications

References 28 publications

Computer Simulation Studies of the Catalytic Mechanism of Human Aldose Reductase

Computer Simulation Studies of the Catalytic Mechanism of Human Aldose Reductase

Aldo-keto reductases: Role in cancer development and theranostics

Role of aldo‐keto reductase family 1 member B1 (AKR1B1) in the cancer process and its therapeutic potential

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