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Inhibition of transthyretin amyloid fibril formation by 2,4-dinitrophenol through tetramer stabilization.
- Source :
-
Archives of biochemistry and biophysics [Arch Biochem Biophys] 2002 Apr 01; Vol. 400 (1), pp. 43-7. - Publication Year :
- 2002
-
Abstract
- Transthyretin (TTR), a homotetrameric thyroxine transport protein found in the plasma and cerebrospinal fluid, circulates normally as a innocuous soluble protein. In some individuals, TTR polymerizes to form insoluble amyloid fibrils. TTR amyloid fibril formation and deposition have been associated with several diseases like familial amyloid polyneuropathy and senile systemic amyloidosis. Inhibition of the fibril formation is considered a potential strategy for the therapeutic intervention. The effect of small water-soluble, hydrophobic ligand 2,4-dinitrophenol (2,4-DNP) on TTR amyloid formation has been tested. 2,4-DNP binds to TTR both at acidic and physiological pH, as shown by the quenching of TTR intrinsic fluorescence. Interestingly, 2,4-DNP not only binds to TTR at acidic pH but also inhibits amyloid fibril formation as shown by the light scattering and Congo red-binding assay. Inhibition of fibril formation by 2,4-DNP appears to be through the stabilization of TTR tetramer upon binding to the protein, which includes active site. These findings may have implications for the development of mechanism based small molecular weight compounds as therapeutic agents for the prevention/inhibition of the amyloid diseases.
- Subjects :
- Binding Sites
Coloring Agents pharmacology
Congo Red pharmacology
Dimerization
Dose-Response Relationship, Drug
Electrophoresis, Polyacrylamide Gel
Glutaral pharmacology
Humans
Hydrogen-Ion Concentration
Light
Protein Binding
Scattering, Radiation
Spectrometry, Fluorescence
Uncoupling Agents pharmacology
2,4-Dinitrophenol pharmacology
Amyloid biosynthesis
Amyloid chemistry
Prealbumin biosynthesis
Prealbumin chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 0003-9861
- Volume :
- 400
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Archives of biochemistry and biophysics
- Publication Type :
- Academic Journal
- Accession number :
- 11913969
- Full Text :
- https://doi.org/10.1006/abbi.2002.2779