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Researchers are understanding the most common congenital metabolic disease

Posted on 05/24/2019 13:20:53PST


An international team with the participation of scientists from the Spanish National Research Council (CSIC) has defined the atomic structure of phenylalanine hydroxylase, a human enzyme whose failures are responsible for the inherent error of the most common metabolism: phenylketonuria.

Phenylketonuria (PKU) is a congenital disease that, according to the researchers, affects one in 10,000 newborns. Children affected by PKU suffer from metabolic disorders, because the body is unable to adequately metabolize the amino acid, phenylalanine, which in large amounts is toxic to the central nervous system. Affected children experience serious problems with neurological and psychosocial development that cause poor quality of life and a high social burden.

"We knew that this disease was the result of a mutation in the phenylalanine hydroxylase gene or PAH, a liver enzyme that eliminates the excess phenylalanine we consume in the diet, but its structure has not yet been determined. it gives us clues about its catalytic mechanism, "explains CSIC researcher Juan Antonio Hermoso of the Rocasolano Institute of Physical Chemistry, who conducted research together with scientists from the University of Bergen (Norway).

The PAH enzyme requires a "complicated mechanism" of regulation: it must be very active during meals to eliminate the excess phenylalanine, but very little active between meals, when the elimination of the amino acid is not needed. "To do this, the PAH enzyme binds to BH4, a molecule necessary for the enzymatic reaction to occur, but also stabilizes the complex enzyme structure and reduces its activity when it does not require amino acid elimination", in detail,

"Too many amino acids cause brain damage and very little interfere with the production of proteins, that's why the BH4 molecule is one of the sophisticated ways in which the body regulates PAH activity," says Hermoso, whose work was published in the journal Proceedings of the National Academy of Sciences .

How this regulation occurs at the molecular level is what the scientific community has been trying to determine for decades. The molecular foundations of this mechanism have now been discovered. "Thanks to X-ray crystallography and electron microscopy we obtained three-dimensional structures of the PAH enzyme itself and the BH4 complex, which allowed us to analyze the mechanism by which this enzyme regulates its activity in response to phenylalanine levels," adds the CSIC researcher.

The resulting structures are the first full structures of the human enzyme, as well as the first full PAH associated with BH4. Most mutations associated with PKU (over 950 according to available statistics on diseases of children's neurotransmitters) lead to dysfunctional and less stable PAH conformations, more susceptible to degradation.

"The stabilizing property of the BH4 molecule has been used clinically and is currently the only available PKU treatment option that helps about 25 percent of patients." The structural and functional analysis presented today is important both for understanding the normal functioning of the enzyme and for developing new, more effective treatments phenylketonuria – summarizes Hermoso.

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