Function follows form –
Proteins need to fold into a specific three-dimensional structure to fulfil their functions. If this error-prone process is disturbed the consequences can be fatal. Misfolded proteins can aggregate and then cause Alzheimer’s or Parkinson’s disease. “In other cases faulty proteins lose their function,” explains Muntau. “If this type of deficiency occurs in enzymes a variety of diseases can occur of which phenylketonuria is but one example. We know now that misfolded proteins are the cause of a surprising number of hereditary conditions. Even so, the mechanism and importance of protein misfolding with loss of function have been investigated only recently.”
If the enzyme phenylalanine hydroxylase loses its function, the amino acid phenylalanine, a building block of proteins, cannot be metabolized. The disease is usually detected early because newborns are tested for phenylketonuria and other hereditary disorders. A lifelong diet without phenylalanine will then prevent the severe symptoms to occur. In a previous study Muntau and her colleagues found proof that up to 60 percent of all patients can even tolerate a regular diet if they are treated with PAH’s natural cofactor tetrahydrobiopterin – which is already available in the US as an approved medication for phenylketonuria.
It has been speculated that tetrahydrobiopterin’s therapeutic effect is due to its correction of PAH misfolding. Muntau and her team were now able to show for the first time that even small genetic changes can have reverberations on the enzyme’s three-dimensional structure. In these cases only one amino acid is substituted by another. “We were surprised to find how many functions of the enzyme can be affected by this,” says Muntau. “Our results have opened up new perspectives on the function – and failure – of phenylalanine hyroxylase and probably also on other enzymes.”
A new project will now show how the cofactor actually works on the process of protein folding. It is possible that tetrahydrobiopterin acts the part of a molecular chaperone that stabilizes the three-dimensional structure of proteins. For the treatment of phenylketonuria it will be important to find out what kind of genetic changes the cofactor can neutralize, so that individualized therapies can be developed.
“We might even be able to create derivates of tetrahydrobiopterin which are tailored to specific genetic changes,” says Muntau. “These therapeutic molecules would then be used in different variants of phenylketonuria and probably in other diseases as well since tetrahydrobiopterin is a cofactor to other enzymes besides PAH. Our novel approach to counter the misfolding of enzymes with the help of their natural cofactors could in the end prove useful in a variety of conditions.”
“Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability”,
Soeren W. Gersting, Kristina F. Kemter, Michael Staudigl, Dunja D. Messing, Marta K. Danecka, Florian B. Lagler, Christian B. Sommerhoff, Adelbert A. Roscher, and Ania C. Muntau,
American Journal of Human Genetics, online June 5, 2008
Professor Dr. Ania C. Muntau
Dr. von Hauner Children’s Hospital at LMU Munich
Tel.: ++49-89 / 5160-2746