TY - JOUR T1 - Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA<sub>1</sub> and Clinically Used Prostaglandins JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.115.100693 SP - mol.115.100693 AU - Beatriz Diez-Dacal AU - Francisco J Sanchez-Gomez AU - Pedro A Sanchez-Murcia AU - Ivana Milackova AU - Tahl Zimmerman AU - Jana Ballekova AU - Elena Garcia-Martin AU - Jose A.G. Agundez AU - Severine Gharbi AU - Federico Gago AU - Milan Stefek AU - Dolores Perez-Sala Y1 - 2015/01/01 UR - http://molpharm.aspetjournals.org/content/early/2015/10/20/mol.115.100693.abstract N2 - Aldose reductase (AKR1B1) is a critical drug target due to 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 the 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 MALDI-TOF MS 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 PG, including non-electrophilic PGE1 and PGE2, currently used in the clinical practice, inhibited the enzyme. Moreover, both PGA1 and PGE1 reduced the formation of sorbitol in an ex-vivo model of diabetic cataract to extents comparable to those attained by the known AKR inhibitor epalrestat. Taken together, these results highlight the role of PG as AKR1B1 inhibitors and the interest of PG-related molecules as leads for the development of novel pharmacological tools. ER -