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.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Almstedt K,Rafstedt T,Supuran CT,Carlsson U,Hammarström Pdoi
10.1021/bi900128esubject
Has Abstractpub_date
2009-06-16 00:00:00pages
5358-64issue
23eissn
0006-2960issn
1520-4995journal_volume
48pub_type
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