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.

Structural Changes of Sarco/Endoplasmic Reticulum Ca2+-ATPase Induced by Rutin Arachidonate: A Molecular Dynamics Study

“…In agreement with our previous results [33], the starting structure of RA complex with SERCA1a was based on the crystal structure of E2 state free from exogenous inhibitors, ATP and calcium ions (Toyoshima et al, 2013, Protein Data Bank (PDB); http://www.rcsb.org; PDB ID 3w5c). The PDB model of E2 state was chosen based on partial structural similarity with the compounds identified as SERCA1a E2 state inhibitors (thapsigargine and nonylphenol) [16], as well as according to the long lipophilic chain of RA.…”

“…As the experimentally tested rutin derivatives brought new structural features (e.g., long fatty acid chain) into the diversity of SERCA inhibitors as described above, we reasoned to perform a molecular dynamics simulation study to elucidate the mechanism of action of the most effective inhibitor of the series, rutin arachidonate [33] (see Figure 1). Our results predicted that the binding of rutin arachidonate towards SERCA1a occurs in the vicinity of the binding site of calcium ions (transmembrane region) and near the location of the well-known inhibitor thapsigargin.…”

“…The rutin arachidonate ligand had previously been docked against SERCA1a using YASARA (www.yasara.org) [42]. As a result, a complex model of SERCA1a-RA was built and used as a starting structure to construct the binary system [33]. We generated the binary system model with pure 1-palmitoyl-2-oleoyl-sn glycero-3-PC (POPC).…”

Biocatalytic Synthesis of Flavonoid Esters by Lipases and Their Biological Benefits

“…The posttranslational modifications of SERCA1 by rutin esters include a significant loss of free sufhydryl groups, the protection of the enzyme from protein carbonyl formation, and the prevention of SERCA from tyrosinase (except R20:4 and R22:1). The inhibitory activity of the rutin esters is probably due to the interaction of these compounds with Glu771, a residue involved in Ca 2+ binding [132].…”

Quantification of rutin in rat’s brain by UHPLC/ESI-Q-TOF-MS/MS after intranasal administration of rutin loaded chitosan nanoparticles

“…Recently, the research studies on rutin revealed the effectiveness of this drug in treating cerebral ischemia (Annapurna et al, 2013[6]; Zhang et al, 2013[25]; Jang et al, 2014[13]; Rodrigues et al, 2013[18]; Khan et al, 2009[14]; Raza et al, 2011[17]), however a major problem of low water solubility hence low bioavailability still exist with rutin (Park et al, 2013[16]; Veselova et al, 2012[21]; Sasikala et al, 2013[19]). In addition, literature studies report rutin, a drug with lipophilic property (Baldisserotto et al, 2015[7]; Viskupicová et al, 2015[22]) and thus it is a well-known fact that oral delivery of lipophilic drugs including rutin encounters different problems such as i) permeability complications leading to poor bioavailability ii) more prone to chemical and enzymatic degradation in the gastrointestinal tract, and iii) extensive hepatic first-pass metabolism. The complications aforementioned necessitate effective solution in the form of intranasal drug administration for targeted therapy in brain with numerous advantages, i.e.…”