Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA1 and Clinically Used Prostaglandins
| Autor: | Jana Ballekova, Dolores Pérez-Sala, José A. G. Agúndez, Ivana Milackova, Beatriz Díez-Dacal, Tahl Zimmerman, Milan Stefek, Elena García-Martín, Severine Gharbi, Pedro A. Sánchez-Murcia, Francisco J. Sánchez-Gómez, Federico Gago |
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| Rok vydání: | 2015 |
| Předmět: |
Male
0301 basic medicine Pharmacology 03 medical and health sciences chemistry.chemical_compound Aldehyde Reductase Animals Humans Enzyme Inhibitors Rats Wistar Prostaglandin a Cyclopentenone prostaglandins Epalrestat chemistry.chemical_classification Prostaglandins A Aldose reductase Dose-Response Relationship Drug Glutathione Rats 030104 developmental biology Enzyme Biochemistry chemistry Biotinylation Prostaglandins Molecular Medicine Protein Binding |
| Zdroj: | Molecular Pharmacology. 89:42-52 |
| ISSN: | 1521-0111 0026-895X |
| Popis: | Aldose reductase (AKR1B1) is a critical drug target because of its involvement in diabetic complications, inflammation, and tumorigenesis. However, to date, development of clinically useful inhibitors has been largely unsuccessful. Cyclopentenone prostaglandins (cyPGs) are reactive lipid mediators that bind covalently to proteins and exert anti-inflammatory and antiproliferative effects in numerous settings. By pursuing targets for modification by cyPGs we have found that the cyPG PGA1 binds to and inactivates AKR1B1. A PGA1-AKR1B1 adduct was observed, both by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and by SDS-PAGE using biotinylated PGA1 (PGA1-B). Insight into the molecular interactions between AKR1B1 and PGA1 was advanced by molecular modeling. This anticipated the addition of PGA1 to active site Cys298 and the potential reversibility of the adduct, which was supported experimentally. Indeed, loss of biotin label from the AKR1B1-PGA1-B adduct was favored by glutathione, indicating a retro-Michael reaction, which unveils new implications of cyPG-protein interaction. PGA1 elicited only marginal inhibition of aldehyde reductase (AKR1A1), considered responsible for the severe adverse effects of many AKR1B1 inhibitors. Interestingly, other prostaglandins (PGs) inhibited the enzyme, including non-electrophilic PGE1 and PGE2, currently used in clinical practice. Moreover, both PGA1 and PGE1 reduced the formation of sorbitol in an ex-vivo model of diabetic cataract to an extent comparable to that attained by the known AKR inhibitor epalrestat. Taken together, these results highlight the role of PGs as AKR1B1 inhibitors and the interest in PG-related molecules as leads for the development of novel pharmacological tools. |
| Databáze: | OpenAIRE |
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