Çocuk Sağlığı ve Hastalıkları Dergisi
2010 , Vol 53 , Num 3
Sfingolipit depo hastalıklarında enzim inhibitörlerinin tedavide kullanımları
Hacettepe Üniversitesi Tıp Fakültesi Tıbbi Biyokimya Yardımcı Doçenti
Sphingolipidoses are a group of inherited metabolic diseases caused by a genetic
defect in the catabolism of sphingosine-containing lipids. Glycosphingolipids
accumulate in the lysosome due to a mutation in genes that encode their
catabolic enzymes or activator proteins. They are fatal disorders and significant
for some populations. Sphingolipidoses are relatively common and represent
an important health problem in Turkey due to the ‘founder effect’ created
by consanguineous marriages. Only a low level of residual enzyme activity is
apparently needed to prevent or reverse substrate (glycosphingolipids) storage
in these diseases, mostly in juvenile and adult forms. Low molecular weight
pharmacological chaperones have newly appeared as enzyme enhancement
therapy agents in sphingolipidoses resulting from enzyme protein misfolding
or mistracking due to certain missense mutations and some small inframe
deletions. Pharmacological chaperones can stabilize the conformation of
a mutant protein, allowing it to pass the quality control system of the
endoplasmic reticulum. To date, all successful pharmacological chaperones
have also been competitive inhibitors of the enzyme proteins. They assist
the proper folding of mutant proteins in the endoplasmic reticulum, increase
stability, avoid aggregation, and thus increase the activity at their target sites
by allowing passage of the mutant protein from the endoplasmic reticulum
quality control system. These agents, are attracting considerable interest in the
enhancement of quality of life and clinical improvement in the juvenile and
adult forms of sphingolipidoses which have residual enzymatic activity. In this
review, we describe the actions and usage area of pharmacological chaperones
in sphingolipidoses, together with their advantages and disadvantages and
recent developments.
Anahtar Kelimeler :
sfingolipidozlar, enzim inhibitörleri, farmakolojik şaperonlar,
protein katlanma bozukluğu, yanlış anlamlı mutasyonlar.