title: Mechanism of inhibition of arginine kinase by flavonoids consistent with thermodynamics of docking simulation.
abstract: Arginine kinase plays a vital role in invertebrate homeostasis by buffering ATP concentrations. Arginine kinase might serve as a target for environmentally friendly insect-selective pesticides, because it differs notably from its counterpart in vertebrates, creatine kinase. In this study, two members of the flavonoid family, quercetin (QU) and luteolin (LU), were identified as novel noncompetitive inhibitors of locust arginine kinase. They were found to have inhibition parameters (K(i)) of 11.2 and 23.9 μM, respectively. By comparing changes in the activity and intrinsic fluorescence of AK, the inhibition mechanisms of these flavonoids were found to involve binding to Trp residues in the active site. This was determined by examination of the static quenching parameter K(sv). The main binding forces between flavonoids and AK were found to be hydrophobic based on the thermodynamic parameters of changes in enthalpy (ΔH), entropy (ΔS), and free energy (ΔG) and on docking simulation results. Molecular docking analyses also suggested that flavonoids could bind to the active site of AK and were close to the Trp 221 in active site. Molecular simulation results mimic the experimental results, indicated that QU had a lower binding energy and a stronger inhibitory effect on AK than LU, suggesting that the extra hydroxyl group in QU might increase binding ability.
authors: College of Life Science, Shandong Agricultural University, Shandong, Taian 271018, People's Republic of China.
authors: Hua-Rong
authors: HR
authors: Wang
authors: Wen-Jing
authors: WJ
authors: Zhu
authors: Xiao-yun
authors: XY
authors: Wang
mesh_terms: D000818:Animals; D001122:Arginine Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D002942:Circular Dichroism; D003402:Creatine Kinase / Q000737:chemistry / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D006110:Grasshoppers / Q000187:drug effects* / Q000201:enzymology; D057927:Hydrophobic and Hydrophilic Interactions; D007300:Insect Control / Q000379:methods*; D019476:Insect Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D007306:Insecticides; D007448:Invertebrates; D007700:Kinetics; D047311:Luteolin / Q000494:pharmacology; D056004:Molecular Dynamics Simulation; D011485:Protein Binding / Q000187:drug effects; D011794:Quercetin / Q000494:pharmacology*; D012996:Solutions; D013050:Spectrometry, Fluorescence; D013816:Thermodynamics; D014364:Tryptophan / Q000378:metabolism; D014714:Vertebrates
chemical_list: D005419:Flavonoids; D019476:Insect Proteins; D007306:Insecticides; D012996:Solutions; D014364:Tryptophan; D011794:Quercetin; D003402:Creatine Kinase; D001122:Arginine Kinase; D047311:Luteolin