Molecular mechanisms underlying the flavonoid-induced inhibition of alpha-synuclein fibrillation.
The molecular mechanism underlying the flavonoid-induced inhibition of alpha-synuclein fibrillation was thoroughly examined by various biochemical and biophysical approaches. The noncovalent binding of the inhibitory flavonoids to alpha-synuclein and the covalent modification by the flavonoid quinone led to the restriction of the conformational changes in this natively unfolded protein and to the stabilization of soluble flavonoid-modified species of alpha-synuclein (monomers and oligomers). All of these factors rather than a single one contribute to the inhibition of WT alpha-synuclein fibrillation induced by the flavonoid. The structural requirements that appear necessary to provide a flavonoid the ability to inhibit alpha-synuclein fibrillation were determined to be vicinal dihydroxyphenyl moieties, irrespective of the ring position where they are located. Flavonoids with three vicinal hydroxyl groups exhibited enhanced inhibitory effects on alpha-synuclein fibrillation. The antioxidant activities of flavonoids were generally correlated with their in vitro inhibitory effects on alpha-synuclein fibrillation. The flavonoids inhibiting alpha-synuclein fibrillation and stabilizing the protein monomeric conformation can serve as a model for the development of therapeutic drugs in combating Parkinson's disease.
Meng
Xiaoyun
X
Department of Chemistry, University of California at Santa Cruz, Santa Cruz, California 95064, USA.
Munishkina
Larissa A
LA
Fink
Anthony L
AL
Uversky
Vladimir N
VN
D000818:Animals; D001665:Binding Sites; D002374:Catalase / Q000494:pharmacology; D002417:Cattle; D003497:Cyclic N-Oxides / Q000494:pharmacology; D044950:Flavanones / Q000494:pharmacology; D005419:Flavonoids / Q000378:metabolism / Q000494:pharmacology*; D005609:Free Radicals / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007525:Isoelectric Focusing; D013058:Mass Spectrometry; D009154:Mutation; D010084:Oxidation-Reduction; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D003497:Cyclic N-Oxides; D044950:Flavanones; D005419:Flavonoids; D005609:Free Radicals; D051844:alpha-Synuclein; D014443:Tyrosine; C006680:baicalein; C017245:5,5-dimethyl-1-pyrroline-1-oxide; D006861:Hydrogen Peroxide; C007543:dityrosine; D002374:Catalase