Phenylketonuria (Pku) Disease

INTRODUCTION 

Chemistry plays a major role in medicine, such as diagnosis, and treatments of several diseases, better understanding of disease mechanisms, etc. One of the most interesting and serious diseases that relies mainly on the concept of Chemistry is PKU disease. This disease is genetically inherited and more common in Caucasians and Americans. It is caused by the lack of the function of phenylalanine hydroxylase enzyme.

What is the PKU Disease? 

PKU (Phenylketonuria) is a genetic mutation leading to the concept of one gene-one protein. Even though it is rare, it is a serious disease, and also one of the causes of mental retardation. But fortunately, it is an autosomal recessive inherited disease. That means one can suffer from PKU with only the presence of 2 copies of mutated genes. This disease was discovered by Dr. Asbjorn Folling in 1934 because of his awareness of mental disorders in two children who came from the same family. His curious mind led him to test the urine of those two children with ferric chloride, which is used to test the phenol groups. To his surprise, the urine turned dark green, and later, he found out that is because of the presence of phenylpyruvic acid. That describes that there is excess phenylalanine. This test is later known as the phenylalanine deamination test.

Phenylalanine Deamination Test

 

What is Phenylalanine?

Phenylalanine, which has a formula of  is an essential α- amino acid for the body. Among the three forms of phenylalanine, only L – phenylalanine is essential for the body. It is mainly converted to tyrosine which is further converted to L-DOPA, a precursor of dopamine.

Types of PKU Disease

There are generally 3 types of PKU:

(1) HPA (Hyperphenylalaninemia) [120 – 600 µM of blood phenylalanine]

(2) Mild PKU [360 – 1200 µM of blood phenylalanine]

(3) Classic PKU [over 1200 µM of blood phenylalanine]

 

The main cause of PKU Disease

The mechanism of Phe to Tyr

In the liver, phenylalanine is converted to tyrosine with the presence of an enzyme called phenylalanine hydroxylase (PAH). The monomeric form of PAH contains 3 domains – (1) the Catalytic domain, (2) Self – association domain, and (3) the Regulatory domain. Tetramer (Active form of PAH) is formed by the interaction of 4 identical subunits via the self-association domain. PAH has 2 binding sites for phenylalanine (one is on the regulatory domain and the other is on the catalytic domain).

In addition to PAH, (Tetrahydrobiopterin) is also required as a cofactor. Actually,  has 2 functions. It is not just a cofactor. It also acts as PAH specific chaperone by binding to the regulatory domain and stabilizes the inactive form of PAH to partially achieve the function of PAH. Another enzyme called PKA kinase can also activate PAH by phosphorylation. 

 

Hydroxylation of Phenylalanine to Tyrosine

As mentioned above, phenylalanine from dietary and tissue protein needs the PAH enzyme to be converted into tyrosine, which is essential for the nervous system. Normally, the amount of active native folded PAH should be more than the inactive misfolded PAH. Therefore, the inactivation of PAH blocks the conversion of phenylalanine to tyrosine, causing PKU. The mutations in PAH are mainly in the catalytic domain, which is around 73% of mutations. About 60% of patients who do not respond to  tests are mostly because of the mutation in DHPR and PCD enzymes.

Treatments of PKU Disease

Unfortunately, there is still no cure for PKU. The only primary treatment that can minimize the symptoms of PKU is the PKU diet. The PKU patient must avoid any protein-rich food (meat, beans, dairy products, etc.) since proteins may contain phenylalanine. But other amino acid supplements (Tyrosine and Tryptophan) should be provided to the PKU patients. GMP (Glycomacropeptide) which is a kind of protein derived from the residual liquid left after curd formation, is also good for PKU patients since GMP contains low phenylalanine and is rich in valine, isoleucine, and tyrosine.

But for those who are positive to PKU test but are responsive to  can use a drug named Kuvan (sapropterin dihydrochloride) which is a synthetic form of . The daily dose of 5 to 20mg of  per 1 kg of body weight is administered.

Diagnosis of PKU Disease

Early screening of PKU is very important. Hence, the “Heel stick” test should be performed in 36–70-hour old newborns. PKU can also be tested with ferric chloride through the phenylalanine deamination test.

 

Consequences of PKU Disease

Excess phenylalanine can lead to the deficiency of other amino acids (like tyrosine, tryptophan) and that can further cause oxidative stress, decrease in neurotransmitter synthesis because of the low tyrosine which leads to the reduction of Catecholamines and Serotonin, dopamine deficit, developing of Parkinson like symptoms, Anhedonia (inability to feel the pleasure), mental retardation, depression, OCD – like symptoms, uncontrolled impulsivity, seizures, severe eczema, microcephaly, problems in lipid metabolism which can even lead to the damage of myelin sheath, difficulty in controlling movements and balance, bioenergy deficiency which can result the decrease of ATP synthesis in brain, anemia and excess of intracellular Calcium ions (Ca2+ ).

Conclusion

Resulting in several neurological problems is the main reason why PKU disease has remained untreated. A lot of researchers are also trying to find a cure for PKU. Even so, a better understanding of the structure of the PAH enzyme and the chemical mechanism of phenylalanine in the human body may answer the solution to PKU disease. And that is expected to bring down about $200,000, the annual cost for each untreated PKU patient.