University researchers discovered that tannic acid used in the wine industry andEGCG found in green tea prevent the formation of toxic amyloid structures in metabolic diseases
"Inborn metabolic diseases are genetic diseases in which the body does not produce a certain enzyme," explains Shira Shaham-Niv. "As a result, metabolites accumulate in the body (substances that are, among other things, building blocks of the proteins and DNA in our body), which the same enzyme was supposed to break down or convert into other metabolites. Such uncontrolled accumulation can be toxic and cause various damages, and severe metabolic diseases can lead to severe developmental delay and mental retardation. One example, relatively common, is the disease PKU, which causes the accumulation of the metabolite phenylalanine. To avoid its damage, PKU patients are required, from the day they are born, to adhere to a strict diet that does not contain phenylalanine. This is a difficult task, especially for young children, because phenylalanine is found in many foods that most of us consume on a regular basis. Today, in the absence of a cure for the disease, avoidance is the only way. We were looking for a new approach, which would enable the development of drugs for congenital metabolic diseases."
According to her, "It is important to note that despite the fact that PKU is considered a rare disease (a definition given to diseases whose prevalence is 1:100,000 in the population), its prevalence is very high and varies geographically. In Israel the prevalence is 1:13,000 and in Turkey it is even higher and reaches 1:2,600. This makes PKU an attractive disease for pharmaceutical companies due to its inherent commercial potential. Another interesting fact is that the overall prevalence of congenital metabolic diseases constitutes a central part of all genetic diseases in children."
The new study, recently published in the journal Communications Chemistry, is based on two previous studies from Prof. Gazit's laboratory: in the first study it was shown that phenylalanine is capable of undergoing a process of self-assembly, and creating an amyloid structure - similar to the amyloid clusters that cause the destruction of cells in the brains of Alzheimer's, Parkinson's and other neurodegenerative diseases. The difference between the two types of accumulation is in the building blocks: phenylalanine is a single amino acid, while the amyloid structures known from neurodegenerative diseases are composed of proteins or peptides - molecules made of dozens of amino acids. In the second study, it was found that other metabolites, such as adenine and tyrosine, which accumulate in other congenital metabolic diseases (besides PKU) can undergo self-assembly processes, creating toxic amyloid clusters. Both studies led to an innovative change of perception in the world of congenital metabolic diseases.
"In the current study, we decided to test whether molecules known from research on Alzheimer's and other amyloid diseases, and which are known to inhibit the production of amyloid deposits, can also help against the deposits characteristic of congenital metabolic diseases," says Shaham-Niv. "We hoped that such molecules could form a basis for the development of future drugs for metabolic diseases."
The researchers focused on two available molecules that inhibit amyloid production: the antioxidant EGCG found in green tea, and tannic acid used in the wine industry (both from the polyphenol group). Both substances were tested on three metabolites (amino acids and a basic acid) associated with three congenital metabolic diseases: adenine that accumulates in the disease APRT adenine (phosphoribosyltransferase deficiency), tyrosine that accumulates in tyrosinemia patients and phenylalanine that accumulates in PKU. The results were promising: both the tannic acid and the EGCG showed the ability to stop the formation of the amyloid structures, and also reduce their level of toxicity. Later, the researchers used computational simulations in order to deeply understand the mechanism of action of the tested molecules - in order to find in the future other molecules with a similar mode of action, as a basis for the development of drugs that change the course of the disease.
"We are entering a new era when it comes to understanding the role and importance of metabolites in various diseases, including metabolic diseases, neurodegenerative diseases and even cancer," concludes Shira Shaham-Niv. "The tools we are developing today are groundbreaking, and have tremendous potential to help a wide variety of patients in the future."
