Approximately one in 10,000 babies is born with a congenital metabolic disease called. phenylketonuria or PKU which prevents your body from properly metabolizing the phenylalanine an amino acid that if it accumulates in large amounts is toxic to the central nervous system, so that children who suffer from it have problems in their neurological and psychosocial development, which impairs their quality of life and is a major social burden.
A new study in which scientists have participated from the. Consejo Superior de Investigaciones Científicas (CSIC)and which has been published in Proceedings of the National Academy of Sciences (PNAS).has made it possible to describe the atomic structure of phenylalanine hydroxyl a or PAH, an enzyme in the liver that is responsible for removing excess phenylalanine from the diet, and whose dysfunction is the cause of phenylketonuria.
Phenylalanine regulation, a complex process.
The regulation of the PAH enzyme requires a complex mechanism, as its activity needs to increase during food intake to eliminate excess phenylalanine, while between meals it has to remain underactive because the amino acid does not need to be eliminated at those times. To achieve this, PAH binds to BH4, which is a molecule that is essential for the enzymatic reaction but also stabilizes the complex structure of the enzyme and reduces its activity when it is not necessary to remove the amino acid.
If too much phenylalanine accumulates brain damage occurs, but if the levels of this amino acid are too low the body has difficulty producing proteins
The international team of researchers has now discovered the molecular basis of this regulatory mechanism. As Juan Antonio Hermoso, from the Institute of Physical Chemistry Rocasolano, who has led the work together with scientists from the University of Bergen (Norway), has stated, if too much amino acid accumulates it causes brain damage, but if there is too little the body has difficulty producing proteins.
The scientist explained that using X-ray crystallography and electron microscopy they obtained the three-dimensional structures of the PAH enzyme alone and in complex with BH4, and were able to discover the mechanism by which this enzyme regulates its activity depending on phenylalanine levels.
Until now, adds the expert, the stabilizing capacity of the BH4 molecule is the only one alternative of treatment for phenylketonuria and is effective in about 25% of those affected, but the structural and functional analysis of PKU achieved in the study will help to understand the normal functioning of this enzyme and contribute to the development of new and more effective treatments for the disease.