Small-Molecule Suppression of Misfolding of Mutated Human Carbonic Anhydrase II Linked to Marble Brain Disease

On the day of the defence date tha status of this articel was In Manuscript.
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-aminobenzoyisulfonamide 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 mu M 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.

Rafstedt, ThereseLinköpings universitet,Institutionen för fysik, kemi och biologi,Tekniska högskolan (författare)
Supuran, Claudiu TUniversity of Florence (författare)
Carlsson, UnoLinköpings universitet,Biokemi,Tekniska högskolan(Swepub:liu)unoca34 (författare)
Hammarström, PerLinköpings universitet,Biokemi,Tekniska högskolan(Swepub:liu)perha81 (författare)
Linköpings universitetBiokemi (creator_code:org_t)

Ingår i:Biochemistry: American Chemical Society (ACS)48:23, s. 5358-53640006-29601520-4995

Av författaren/redakt...: Almstedt, Karin; Rafstedt, Theres ...; Supuran, Claudiu ...; Carlsson, Uno; Hammarström, Per

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