Phenylketonuria Synthesis

Abstract
Phenylketonuria (PKU) is an inherited genetic disease caused by mutations arising in the gene coding for Phenylalanine Hydroxylase (PAH) resulting in its changed conformation which prevents the hydrolysis of phenylalanine to tyrosine. This can lead to an increase of phenylalanine in the blood. Build-up of phenylalanine can be detrimental to a PKU sufferer because it means the individual is not synthesising enough tyrosine which acts as a precursor for catecholamine neurotransmitters like adrenaline and dopamine. Also phenylalanine competes with other large neutral amino acids (LNAA) to cross the blood brain barrier, leading to severe mental retardation. Because PKU is a metabolic disease, it can be regulated with a restricted phenylalanine …show more content…
It is thought that a missense mutation, also known as a point mutation where a single amino acid is substituted for another, is what gives rise to the incorrect structure of PAH thus resulting in the incorrect folding and conformation of PAH [10]. However it is difficult to pinpoint specifically which mutation affects PAH in regards to PKU, this is because over 100 mutations including missense, nonsense, deletion and insertion mutations have been found on the gene that codes for PAH and many severely limit its activity as a metabolic enzyme [1][9]. It is the slight adjustment of the conformation of the PAH enzyme that means phenylalanine is prevented from binding to its active site to be converted to tyrosine. However we must appreciate that because there are over 100 mutations on the gene coding for PAH, that there are many different effects on the form of PKU expressed by an individual, for example the mutation could disrupt the interaction between PAH the BH4 cofactor leading to reduced phenylalanine metabolism …show more content…
It is thought that the build-up of toxic phenylalanine derivative metabolites like phenylpyruvate, compete with tyrosine and tryptophan for entry into the brain by crossing the blood brain barrier [1][12]. It is also worth noting that without PAH there is a low level of tyrosine making it even more difficult for tyrosine to cross the blood brain barrier, so a reduction of tyrosine (the main precursor for the catecholamine neurotransmitters) and the blockage of tryptophan (the main precursor for serotonin) into the blood brain barrier has a detrimental effect on the PKU sufferer such as mental retardation, brain damage and dysfunction

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