6-Formyl Umbelliferone, a Furanocoumarin from Angelica decursiva L., Inhibits Key Diabetes-Related Enzymes and Advanced Glycation End-Product Formation
Abstract
:1. Introduction
2. Results and Discussion
2.1. Inhibitory Activity of 6-FU against PTP1B, α-Glucosidase, HRAR, and AGE Formation
2.2. Kinetic Parameters of 6-FU against PTP1B, α-Glucosidase, and HRAR
2.3. Molecular Docking Analysis of 6-FU Interactions with PTP1B
2.4. Molecular Docking Analysis of 6-FU Interactions with α-Glucosidase
2.5. Molecular Docking Analysis of 6-FU Interactions with HRAR
2.6. Molecular Docking Analysis of 6-FU Interactions with HAS
2.7. Effect of 6-FU on Glucose Uptake and PTP1B Expression in Insulin-Resistant C2C12 Skeletal Muscle Cells
2.8. Effect of 6-FU on Fluorescent AGE Formation
3. Materials and Methods
3.1. Chemicals and Reagents
3.2. Isolation of 6-FU from A. decursiva
3.3. Assay for PTP1B Inhibition
3.4. α-Glucosidase Inhibitory Assay
3.5. HRAR Inhibition Assay
3.6. In Vitro Glycation of HSA
3.7. Inhibition of AGE Formation
3.8. Determination of the Kinetic Parameters of PTP1B, α-Glucosidase, and HRAR Inhibition via Lineweaver-Burk and Dixon Plots
3.9. Molecular Docking Studies
3.10. Cell Culture and Cell Viability Assay
3.11. Muscle Cell Differentiation and Glucose Uptake Assay
3.12. Preparation of Protein Lysates and Western Blot Analysis
3.13. Statistical Analysis
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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IC50 (µM) a | ||||
---|---|---|---|---|
Test Sample | PTP1B | α-Glucosidase | HRAR | AGE |
6-FU | 1.13 ± 0.12 *** | 58.36 ± 1.02 *** | 5.11 ± 0.21 ** | 2.15 ± 0.13 *** |
Kib | 1.72 | 49.52 | 4.87 | |
Inhibition type c | Competitive | Mixed | Mixed | |
Ursolic acid d | 4.28 ± 0.32 ** | |||
Acarbose e | 123.88 ± 0.87 ** | |||
Quercetin f | 3.14 ± 0.17 ** | |||
Aminoguanidine g | 527.43 ± 4.55 * | |||
Zenarestat h | 0.63 ± 0.01 *** |
Target Enzymes | PDB ID | Ligands | Binding Energies (Kcal/mol) | Hydrogen Bonds, Interacting Residues, and Bonding Distance | Hydrophobic Interactions |
---|---|---|---|---|---|
Protein tyrosine phosphatase 1B (PTP1B) | 1NNY | 6-formyl umbelliferone (6-FU) | −8.1 | Gly218 (2.89 Å), Gly220 (1.97Å), Ile219 (2.10 Å), Ser216 (2.75 Å), Arg221 (2.58 Å), Lys116 (2.29 Å) | Ala217 (π-alkyl, 4.50 Å), Cys215 (π-alkyl, 4.84 Å) |
Compound 23 | −8.6 | Asp48 (2.82 and 2.64 Å), Arg254 (2.86 Å), Arg221(2.80 and 3.05 Å), Ser216 (3.14 Å), Gly220 (2.72 Å), Gly218 (3.39 Å), Ile219 (3.01 Å), Ala217 (2.69 Å) | Ala27 (π-alkyl, 5.09 Å), Ala217 (π-alkyl, 5.36 Å), Met258 (π-sulfur, 5.59 and 5.91 Å), Tyr46 (π-sigma, 3.57 Å), Ala217 (π-sigma, 3.87 Å), Tyr46 (π-π stacked 5.21 Å), Tyr46 (carbon hydrogen bond, 3.94 Å), Gly220 (π-donor-hydrogen bond, 3.88 Å) | ||
α-Glucosidase | 3A4A | 6-formyl umbelliferone (6-FU) | −7.9 | Asn235 (1.83 Å), Asn317 (2.17 Å), Gly161 (2.05 Å), Lys156 (3.08 Å) | Ala418 (π-alkyl, 4.69 Å), Ile419 (π-alkyl, 5.24 Å), His423 (π-π T-shaped 5.10 Å), Lys156 (π-cation, 4.01 Å), Lys156 (carbon hydrogen bond, 3.38 Å) |
Acarbose | −8.2 | Asp352 (2.38 Å), Asp215 (2.90 Å), Arg442 (2.31 Å), Gln279 (3.02 Å), Pro312 (3.08 Å), Ser240 (2.90 Å), Tyr158 (2.73 Å) | Pro312 (carbon hydrogen bond, 2.68 Å), His280 (π-sigma, 3.93 Å), Glu411 (unfavorable accepter-accepter, 2.93 Å) | ||
Alpha-D-glucose | −6.8 | Asp69 (2.63 Å), Arg442 (2.78 Å), Arg213 (2.89 Å), Asp352 (2.67 and 2.52Å), Asp (2.88 Å), Glu277 (2.75 Å), His112 (2.77 Å), His351 (3.01 and 3.01 Å) | Tyr72 (π-donor hydrogen bond 3.93 Å), Asp69 (carbon hydrogen bond, 3.41 Å) | ||
Human recombinant aldose reductase (HRAR) | 1IEI | 6-formyl umbelliferone (6-FU) | −7.8 | Cys298 (2.19 Å), Tyr309 (2.10 Å) | Leu300 (π-sigma, 3.64 Å), Leu300 (π-alkyl, 4.48 Å), Cys303 (π-alkyl, 5.02 Å), Trp111 (π-π stacked, 4.57 and 4.21 Å) |
Zenarestat | −8.0 | Cys298 (2.45 Å), Lys21 (2.29 Å), Tyr48 (2.91 Å), Trp111(2.98 Å), Trp20 (2.78 Å) | Trp20 (π-alkyl, 4.83 Å), Pro218 (π-alkyl, 4.83 Å), Lys21 (π-alkyl, 5.23 Å), Val47 (alkyl, 4.48 Å), Nap350 (π-alkyl, 4.44 Å), Trp20 (π-π stacked, 5.56 Å) | ||
Quercetin | −8.2 | Arg217 (2.32 and 4.09 Å), Gly213 (2.59 Å), Leu227 (2.64 Å), Ser226 (2.66 Å) | Pro215 (π-alkyl, 5.07 and 3.99 Å), Asp224 (unfavorable donor-donor, 3.68 Å), Pro222 (carbon hydrogen bond, 3.49 Å) | ||
Human serum albumin (HSA) | 1AO6 | 6-formyl umbelliferone (Site-I) | −6.9 | Arg257 (3.46 Å) | Leu260 (π-alkyl, 5.29 Å), Ala291(π-alkyl, 4.64 and 4.28 Å), Leu238 (π-alkyl, 5.31Å), Ile290 (π-alkyl, 5.26 Å), Leu238 (π-sigma, 4.77 Å), Arg222 (π-cation, 4.32 Å) |
6-formyl umbelliferone (Site-II) | −6.6 | Asn405 (2.38 Å) | Ala406 (π-alkyl, 4.84 Å), Leu529 (π-alkyl, 4.95 Å), Lys545 (π-alkyl, 4.08 and 3.98 Å), Val406 (π-alkyl, 5.17 Å), Met548 (π-sulfur, 5.71 Å), Val409 (π-sigma, 3.91 Å), Leu544 (amide-π stacked, 4.33 Å), Asn403 (amide-π stacked, 4.54 and 4.59 Å) |
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Ali, M.Y.; Zamponi, G.W.; Seong, S.H.; Jung, H.A.; Choi, J.S. 6-Formyl Umbelliferone, a Furanocoumarin from Angelica decursiva L., Inhibits Key Diabetes-Related Enzymes and Advanced Glycation End-Product Formation. Molecules 2022, 27, 5720. https://doi.org/10.3390/molecules27175720
Ali MY, Zamponi GW, Seong SH, Jung HA, Choi JS. 6-Formyl Umbelliferone, a Furanocoumarin from Angelica decursiva L., Inhibits Key Diabetes-Related Enzymes and Advanced Glycation End-Product Formation. Molecules. 2022; 27(17):5720. https://doi.org/10.3390/molecules27175720
Chicago/Turabian StyleAli, Md Yousof, Gerald W. Zamponi, Su Hui Seong, Hyun Ah Jung, and Jae Sue Choi. 2022. "6-Formyl Umbelliferone, a Furanocoumarin from Angelica decursiva L., Inhibits Key Diabetes-Related Enzymes and Advanced Glycation End-Product Formation" Molecules 27, no. 17: 5720. https://doi.org/10.3390/molecules27175720