By: Anurag Jakkula


Phenylketonuria (PKU) is a rare inherited disease that may lead to cognitive disability and other problems with the central nervous system if not treated properly. The disease is the result of accumulated phenylalanine, an amino acid, in an affected individual’s blood. PKU can cause damage quite quickly if left untreated. Therefore, it is important to gain a deep understanding of the cause of the disease on a molecular level all the way to the disease’s resulting impact on the functioning human organ systems in order to make sure individuals with phenylketonuria live a long and healthy life.

What is Phenylalanine?

In order to gain an in-depth understanding of phenylketonuria, it is extremely important to understand the amino acid which causes this disease, phenylalanine. Phenylalanine is an essential amino acid, meaning that it is obtained through diet (Tinsley). As it is an amino acid, it is needed in order to make proteins during the translation process of protein synthesis. As an amino acid, it is essential for the folding, and therefore, functioning of proteins. Proteins are essential for all organ systems in the human body, such as the nervous system and digestive system.

In addition to serving as an amino acid during protein synthesis, phenylalanine is also essential for the creation of other molecules that have various functions in the human body. Four of these various molecules are tyrosine, epinephrine, norepinephrine, and dopamine.

Tyrosine is another amino acid. The amount of phenylalanine converted to tyrosine is dictated by the amount of tyrosine the human receives through diet. If the human doesn’t receive any significant amount of tyrosine through the diet, as much as around fifty percent of the phenylalanine can be converted to tyrosine (Litwack). An inability to convert phenylalanine to tyrosine is the cause of PKU (Tinsley). Undoubtedly, the large amount of phenylalanine normally converted to tyrosine, which is not able to occur in an individual with PKU, is the reason why PKU’s effects on organ system functions are so large.

The molecules epinephrine and norepinephrine are the molecules that are responsible for the “fight or flight” reaction to stress. Both are neurotransmitters, and are part of the nervous system. Dopamine, a molecule involved with feelings of pleasure, the ability to learn, and memories, is also part of the nervous system (Tinsley).

-phenylalanine molecule

What is The Process of Phenylalanine Breaking Down into Tyrosine in healthy people without PKU?

As mentioned earlier, the inability to break down phenylalanine into tyrosine is what causes PKU. Therefore, it is imperative to gain in depth knowledge of the process of breaking down phenylalanine into tyrosine in order to fully understand PKU. The process occurs in the circulatory system, specifically the liver. An enzyme called phenylalanine hydroxylase works with the molecule tetrahydrobiopterin in order to create a chemical reaction with phenylalanine. A product of this chemical reaction is the amino acid tyrosine. Not all phenylalanine is converted to tyrosine, as some of it is used as an amino acid during the translation of protein synthesis, with the rest being used for the creation of other molecules (Litwack).

What DNA Segments Code For This Process?

Phenylalanine hydroxylase is what drives the chemical reaction in the process of converting phenylalanine into tyrosine. Therefore, it is the DNA that codes for this enzyme which codes for the whole process. It is referred to as the PAH gene. This gene is located in the long arm of chromosome 12 and mutations in this gene are the root cause of phenylketonuria (NIH).

What Kind of Mutations in the PAH Gene Causes PKU?

Mutations in the PAH gene are indeed the root cause of PKU (NIH). However, it is important to understand that mutations are completely random. Therefore, it is extremely unlikely that the parents of a person with PKU or a person with PKU developed the mutation within themselves. Rather, the mutations occurred in their ancestors, causing the recessive alleles that express PKU to be passed down. Therefore, even though mutations are the cause PKU, PKU is obtained from inheritance.

The mutations that are the most common cause of PKU are point mutations (NIH). These are mutations that occurred during DNA replication. During the process, DNA polymerase attaches an incorrect nucleotide, instead of the correct nucleotide complementa