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Identification of a novel polyfluorinated compound as a lead to inhibit the human enzymes aldose reductase and AKR1B10: structure determination of both ternary complexes and implications for drug design.

Cousido-Siah A, Ruiz FX, Mitschler A, Porté S, de Lera ÁR, Martín MJ, Manzanaro S, de la Fuente JA, Terwesten F, Betz M, Klebe G, Farrés J, Parés X, Podjarny A
Acta Crystallogr D Biol Crystallogr 70 889-903 (2014)
Cited: 17 times
EuropePMC logo PMID: 24598757

Abstract

Aldo-keto reductases (AKRs) are mostly monomeric enzymes which fold into a highly conserved (α/β)8 barrel, while their substrate specificity and inhibitor selectivity are determined by interaction with residues located in three highly variable external loops. The closely related human enzymes aldose reductase (AR or AKR1B1) and AKR1B10 are of biomedical interest because of their involvement in secondary diabetic complications (AR) and in cancer, e.g. hepatocellular carcinoma and smoking-related lung cancer (AKR1B10). After characterization of the IC50 values of both AKRs with a series of polyhalogenated compounds, 2,2',3,3',5,5',6,6'-octafluoro-4,4'-biphenyldiol (JF0064) was identified as a lead inhibitor of both enzymes with a new scaffold (a 1,1'-biphenyl-4,4'-diol). An ultrahigh-resolution X-ray structure of the AR-NADP(+)-JF0064 complex has been determined at 0.85 Å resolution, allowing it to be observed that JF0064 interacts with the catalytic residue Tyr48 through a negatively charged hydroxyl group (i.e. the acidic phenol). The non-competitive inhibition pattern observed for JF0064 with both enzymes suggests that this acidic hydroxyl group is also present in the case of AKR1B10. Moreover, the combination of surface lysine methylation and the introduction of K125R and V301L mutations enabled the determination of the X-ray crystallographic structure of the corresponding AKR1B10-NADP(+)-JF0064 complex. Comparison of the two structures has unveiled some important hints for subsequent structure-based drug-design efforts.

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  1. Aldose Reductase Differential Inhibitors in Green Tea. Balestri F, Poli G, Pineschi C, Moschini R, Cappiello M, Mura U, Tuccinardi T, Del Corso A. Biomolecules 10 E1003 (2020)
  2. Vitamin K1 prevents diabetic cataract by inhibiting lens aldose reductase 2 (ALR2) activity. Thiagarajan R, Varsha MKNS, Srinivasan V, Ravichandran R, Saraboji K. Sci Rep 9 14684 (2019)
  3. Nature-Inspired O-Benzyl Oxime-Based Derivatives as New Dual-Acting Agents Targeting Aldose Reductase and Oxidative Stress. Ciccone L, Petrarolo G, Barsuglia F, Fruchart-Gaillard C, Cassar Lajeunesse E, Adewumi AT, Soliman MES, La Motta C, Orlandini E, Nencetti S. Biomolecules 12 448 (2022)
  4. The oxygen-oxygen distance of water in crystallographic data sets. Palese LL. Data Brief 28 105076 (2020)


Reviews citing this publication (2)

  1. Aldo-Keto Reductase Family 1 Member B10 Inhibitors: Potential Drugs for Cancer Treatment. Huang L, He R, Luo W, Zhu YS, Li J, Tan T, Zhang X, Hu Z, Luo D. Recent Pat Anticancer Drug Discov 11 184-196 (2016)
  2. Perspective on the Structural Basis for Human Aldo-Keto Reductase 1B10 Inhibition. Ruiz FX, Parés X, Farrés J. Metabolites 11 865 (2021)

Articles citing this publication (11)

  1. Metabolomics reveals that aldose reductase activity due to AKR1B10 is upregulated in hepatitis C virus infection. Semmo N, Weber T, Idle JR, Beyoğlu D. J Viral Hepat 22 617-624 (2015)
  2. Structural analysis of sulindac as an inhibitor of aldose reductase and AKR1B10. Cousido-Siah A, Ruiz FX, Crespo I, Porté S, Mitschler A, Parés X, Podjarny A, Farrés J. Chem Biol Interact 234 290-296 (2015)
  3. Structural Determinants of the Selectivity of 3-Benzyluracil-1-acetic Acids toward Human Enzymes Aldose Reductase and AKR1B10. Ruiz FX, Cousido-Siah A, Porté S, Domínguez M, Crespo I, Rechlin C, Mitschler A, de Lera ÁR, Martín MJ, de la Fuente JÁ, Klebe G, Parés X, Farrés J, Podjarny A. ChemMedChem 10 1989-2003 (2015)
  4. Substrate Specificity, Inhibitor Selectivity and Structure-Function Relationships of Aldo-Keto Reductase 1B15: A Novel Human Retinaldehyde Reductase. Giménez-Dejoz J, Kolář MH, Ruiz FX, Crespo I, Cousido-Siah A, Podjarny A, Barski OA, Fanfrlík J, Parés X, Farrés J, Porté S. PLoS One 10 e0134506 (2015)
  5. Potential of AKR1B10 as a Biomarker and Therapeutic Target in Type 2 Leprosy Reaction. Soares CT, Fachin LRV, Trombone APF, Rosa PS, Ghidella CC, Belone AFF. Front Med (Lausanne) 5 263 (2018)
  6. The expression and significance of AKR1B10 in laryngeal squamous cell carcinoma. Liu J, Ban H, Liu Y, Ni J. Sci Rep 11 18228 (2021)
  7. Dietary flavonoids inhibit the glycation of lens proteins: implications in the management of diabetic cataract. Patil KK, Meshram RJ, Barage SH, Gacche RN. 3 Biotech 9 47 (2019)
  8. Effect of monohydroxylated flavonoids on glycation-induced lens opacity and protein aggregation. Patil KK, Meshram RJ, Gacche RN. J Enzyme Inhib Med Chem 31 148-156 (2016)
  9. Green fluorescent protein chromophore derivatives as a new class of aldose reductase inhibitors. Saito R, Hoshi M, Kato A, Ishikawa C, Komatsu T. Eur J Med Chem 125 965-974 (2017)
  10. Synthesis and Functional Evaluation of Novel Aldose Reductase Inhibitors Bearing a Spirobenzopyran Scaffold. Digiacomo M, Sartini S, Nesi G, Sestito S, Coviello V, La Motta C, Rapposelli S. Open Med Chem J 11 9-23 (2017)
  11. Synthesis and Aldose Reductase Inhibitory Activity of Botryllazine A Derivatives. Saito R, Ishibashi K, Noumi M, Uno S, Higashi S, Goto M, Kuwahara S, Komatsu T. Chem Pharm Bull (Tokyo) 67 556-565 (2019)


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