Introduction to Phenylketonuria

Phenylketonuria (PKU) is an inherited disorder caused by a mutation on the PAH gene on chromosome 12. Since the pattern of inheritance of this disorder is autosomal recessive, each of the 2 parents should carry one copy the mutated gene, for the child to inherit the disorder.

PAH structure

The PAH gene codes for Phenylalanine Hydroxylase (PAH) which is responsible for the catabolism of the amino acid Phenylalanine (Phe). The PAH exists as a tetramer.

The mutation of the PAH will result in the inability or reduced ability of the enzyme to convert Phenylalanine to Tyrosine (Tyr). The concentration of Phenylalanine will build up in the body and eventually this will poison the neurons as they are sensitive to Phenylalanine levels.

If still left untreated, Phenylalanine can build up to harmful levels in the body, causing intellectual disability and other severe health problems.

The Normal Situation 

Graphic representation of PKU

Studies have proven that another form of PKU exists due to inactive coenzymes. The main inactive coenzyme causing PKU is (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4). PAH together with BH4 catalyses the hydroxylation of L-Phe to L-Tyr.L- Tyr is then converted to Fumarate and then form CO2 and H2O. This metabolism mainly occurs in the liver.

Not much is known about cellular regulations of BH4 but several studies have shown that some patients suffering from PKU have decreased levels of tetrahydrobiopterin in their blood serum. Therefore, any mutation or change in structures of BH4 can lead to a rare form of Phenylketonuria. 

Structure of BH4

References

• Phenylketonuria - Genetics Home Reference. 2012. Phenylketonuria - Genetics Home Reference. [ONLINE] Available at: http://ghr.nlm.nih.gov/condition/phenylketonuria. [Accessed 28 December 2012].
• Phenylketonuria: What causes it? . 2012. Phenylketonuria: What causes it? . [ONLINE] Available at: http://www.yourgenesyourhealth.org/pku/cause.htm. [Accessed 28 December 2012].
• Basic PKU Biochem. 2012. Basic PKU Biochem. [ONLINE] Available at: http://www.uic.edu/classes/phar/phar332/Clinical_Cases/aa%20metab%20cases/  PKU%20Cases/PKU%20biochem%20intro.htm. [Accessed 28 December 2012].
• Neurowiki2012 - Phenylketonuria. 2013. Neurowiki2012 - Phenylketonuria. [ONLINE] Available at: https://neurowiki2012.wikispaces.com/Phenylketonuria#Ref12. [Accessed 13 January 2013].