Abstract |
Carbonic anhydrase II deficiency syndrome or Marble brain disease (MBD) is caused by autosomal recessive mutations in the human carbonic anhydrase II (HCA II) gene. Here we report a small-molecule stabilization study of the exceptionally destabilized HCA II mutant H107Y employing inhibitors based on p-aminobenzoylsulfonamide compounds and 1,3,4-thiadiazolylsulfonamides as well as amino acid activators. Protein stability assays showed a significant stabilization by the aromatic sulfonamide inhibitors when present at 10 microM concentration, providing shifts of the midpoint of thermal denaturation between 10 degrees C and 16 degrees C and increasing the free energies of denaturation 0.5-3.0 kcal/mol as deduced from GuHCl denaturation. This study could be used as a starting point for the design of small-molecule folding modulators and possibly autoactivatable molecules for suppression of misfolding of destabilized HCA II mutants.
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Authors | Karin Almstedt, Therese Rafstedt, Claudiu T Supuran, Uno Carlsson, Per Hammarström |
Journal | Biochemistry
(Biochemistry)
Vol. 48
Issue 23
Pg. 5358-64
(Jun 16 2009)
ISSN: 1520-4995 [Electronic] United States |
PMID | 19415900
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Carbonic Anhydrase Inhibitors
- Sulfonamides
- Carbonic Anhydrase II
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Topics |
- Brain Diseases, Metabolic, Inborn
(genetics)
- Carbonic Anhydrase II
(antagonists & inhibitors, chemistry, genetics)
- Carbonic Anhydrase Inhibitors
(pharmacology)
- Humans
- Kinetics
- Models, Molecular
- Protein Conformation
- Protein Denaturation
- Protein Folding
- Sulfonamides
(chemistry, pharmacology)
- Thermodynamics
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