Small-molecule suppression of misfolding of mutated human carbonic anhydrase II linked to marble brain disease.

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

Biochemistry

journal_title

Biochemistry

authors

Almstedt K,Rafstedt T,Supuran CT,Carlsson U,Hammarström P

doi

10.1021/bi900128e

subject

Has Abstract

pub_date

2009-06-16 00:00:00

pages

5358-64

issue

23

eissn

0006-2960

issn

1520-4995

journal_volume

48

pub_type

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