Numerous severe human diseases are caused by protein mutations as a result of inherited gene variations rendering proteins prone to misfolding. Phenylketonuria represents a paradigm of such diseases. It is related to mental retardation if left untreated, and is caused by mutations in the enzyme phenylalanine hydroxylase, which impair proper function of the enzyme.
Protein function is intimately linked to their three-dimensional structure, which is uniquely encoded in their amino acid sequence. Any substitution of amino acids in the protein sequence can potentially alter the protein stability, fold, and/or function. A number of diseases are in fact caused by mutations in important enzymes and other proteins. Typical examples include several rare metabolic diseases, inherited forms of Parkinson’s disease, cystic fibrosis, Huntington’s disease as well as other neurodegenerative disorders.
Phenylketonuria - a paradigm of misfolding diseases
Følling's disease, or phenylketonuria (PKU), has been addressed to specific mutations in phenylalanine hydroxylase (PAH) which alters the conformational stability of the enzyme. Consequently, the hydroxylation of phenylalanine is impaired leaving toxic levels of phenylalanine. Conventional PKU treatment relates to restricted phenylalanine.
The Biorecognition group is exploring new therapeutic options for the treatment of such misfolding diseases, with a special focus on PKU. The development of pharmacological chaperones – small molecule compounds that bind to and rescue protein function – represents an important contribution.