title: Inhibition of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA1) by rutin derivatives.
abstract: The effect of lipophilic rutin derivatives (acylated with fatty acid chain length of 16-22) on sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA1 isoform) compared to the parent molecule rutin was evaluated. Rutin derivatives caused concentration dependent decrease of SERCA1 activity (IC50 ~ 23-64 µM) and significant conformational alterations in the transmembrane region of the enzyme. Upon treatment by peroxynitrite, rutin derivatives exerted a hormetic effect, i.e. prevented enzyme activity decrease at low concentrations, while additionally inhibited at high concentrations. Concerning the posttranslational modifications of SERCA1, rutin esters: (i) induced a significant loss of free sulfhydryl groups, (ii) protected the enzyme from protein carbonyl formation, and (iii) prevented SERCA from tyrosine nitration (except R20:4 and R22:1). In silico study revealed a strong affinity of the derivative R20:4 to the transmembrane region of SERCA1, stabilized via hydrogen bonds with Glu90, Glu771, Thr778 and Thr848 residues. Interaction of rutin derivatives with Glu771, a residue involved in Ca(2+) binding, is likely to be responsible for the inhibitory effect of the esters.
authors.affiliation: Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dubravska cesta 9, 841 04, Bratislava, Slovakia, janaviskupicova@gmail.com.
authors.forename: Jana
authors.initials: J
authors.lastname: Viskupicova
authors.forename: Magdalena
authors.initials: M
authors.lastname: Majekova
authors.forename: Lubica
authors.initials: L
authors.lastname: Horakova
mesh_terms: D000818:Animals; D006860:Hydrogen Bonding; D030421:Peroxynitrous Acid / Q000737:chemistry; D011817:Rabbits; D012431:Rutin / Q000031:analogs & derivatives* / Q000737:chemistry*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D030421:Peroxynitrous Acid; D012431:Rutin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases