Biochemistry behind Phenylketonuria

Someone suffering from PKU is incapable of metabolizing Phenylalanine which can lead to great toxicity for neuronal cells. There are two main pathways in which Phenylalanine can be metabolized. First is the most common path whereby Phenylalanine (Phe) is oxidized to Tyrosine (Tyr). The second or the minor pathway is Phe transamination to phenylpyruvate and subsequent further metabolism to Phenylacetylglutamate, O-Hydroxyphenylacetate and Phenyl Lactate. The metabolites in the minor pathway will be released into the bloodstream and brought to the brain.

Diagram depicting metabolism pathways of Phenylalanine

When the PAH is mutated and unable to convert Phenylalanine to Tyrosine resulting in Phe levels buiding up, the minor pathway takes over the major pathway. The minor pathway leads to a rise in levels of Phenylacetylglutamate which is known to be substance that is very toxic and on its own, can lead to alteration in mental status and cognitive impairments when accumulated. In addition, studies have shown that other substances created in the minor pathway including Phenyl lactate, can also lead to growth retardations by causing deficit of myelin in the cerebral hemispheres and the cerebellum and therefore, it has been directly linked to the mental retardations in PKU.

A mutation in the cofactor of PAH tetrahydropterin (BH4) can also cause PKU. This is called malignant PKU. This can also be caused by defective synthesis of the BH4. This deterioration cannot be removed by limiting the phenylalanine dietary intake. Consequence of such problem is defection in neurotransmission.

Reference

• Neurowiki2012 - Phenylketonuria. 2013. Neurowiki2012 - Phenylketonuria. [ONLINE] Available at: https://neurowiki2012.wikispaces.com/Phenylketonuria. [Accessed 13 January 2013].
• Malignant phenylketonuria due to defective syn... [Isr J Med Sci. 1985] - PubMed - NCBI. 2013.  [ONLINE] Available at: http://www.ncbi.nlm.nih.gov/pubmed/3874852. [Accessed 25 January 2013].