[No authors listed]
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.
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