We take up amino acids with our food. They play a key role in almost all life processes in the human body. But what happens when the molecular machinery in the cells is no longer able to correctly process the amino acids? It was only about six years ago that Prof. Dr. Jörn Oliver Saß and his colleagues at the Freiburg University Medical Centre discovered a new metabolic disorder characterised by the defective degradation of a N-acetylated amino acids. Their research showed that this defect had similarities to Canavan disease, an inherited neurodegenerative disease. It is possible that other diseases are also associated with this defect. The Freiburg researchers are now investigating the underlying molecular relationships.
It turned out that the researchers had discovered a completely new metabolic disorder as up to that point it had not been known that other N-acetylated amino acids could not be degraded either. In collaboration with a research group led by Prof. Heymut Omran, Saß and his team found that the metabolic disease was associated with a defect in the gene coding for the enzyme aminoacylase 1 (ACY1), which is a close relative of aminoacylase 2. However, ACY1 is not as specific as ACY2; it is able to metabolise a broad range of different amino acids and it ensures that the amino acids are recycled in the kidneys. ACY1 therefore plays a key role in the complex metabolic network.Saß and his team subsequently found in different human body cells that the lack of ACY1 affects the metabolism of acetylated amino acids. The lack of ACY1 coincides with a range of disease symptoms, including cramps, brain malformation, amyosthenia and other genetic metabolic disorders. A group of researchers from Berlin carried out investigations on mice that provided evidence for the hypothesis that the enzyme has an effect on the development of different neurodegenerative diseases.
"We do not yet know whether the deficiency of the enzyme leads to a specific disease," said Saß. "Maybe it is only one of several risk factors or maybe it is potentially also an advantage to the organism. We do not know." The enzyme is also known to convert a range of compounds into toxic intermediary products. One thing that has become clear after examining many patients is that a defect in the ACY1 gene occurs quite frequently. It is therefore important for clinical laboratories to pay greater attention to the presence of N-acetylated amino acids in patients' urine.
Known disease in a new focus
In addition, the parallel with the ACY2 deficiency that leads to Canavan disease is very striking. An investigation of these correlations might potentially lead to a better understanding of Canavan disease as well. A doctoral student in Prof. Saß' group is to investigate the molecular processes in cells that are defective as a result of ACY1 deficiency. The doctoral student will carry out expression analyses, which involves introducing different mutations into the gene coding for the ACY1 enzyme and subsequently introducing the modified gene into cultured cells. She will subsequently assess the characteristics of the altered enzyme molecules and investigate how they interact with other molecules. Slowly but surely, this might generate comprehensive knowledge about the entire molecular network of which ACY1 is part. Maybe this will also enable the researchers to associate the defects with known metabolic disorders.
The Freiburg researchers are also beginning to focus intensively on Canavan disease. Knowing about the molecular relationships in the metabolism of N-acetylated amino acid can only be the basis for further insights. It would be interesting to find out how many people suffer from this disease and whether the effects of the disease vary from case to case. However, insufficient data are currently available to clarify these questions. There is evidence that some Canavan disease sufferers even reach adult age. “We are now carrying out a systematic study on people suffering from Canavan disease in German-speaking countries in order to get a comprehensive overview,” said Saß. In addition to their research into the metabolism of N-acetylated amino acids, Saß and his team of researchers also deal with disorders in the metabolism of branched-chain and sulphur-containing amino acids, which also play a key role in the cellular “construction sites”. Disorders in the metabolism of these amino acids might also be the cause of metabolic diseases.