Phenylalanine 4-mono-oxygenase

Fig. 25.8 (a) Normal metabolism, in which phenylalanine is converted by phenylalanine 4-mono-oxygenase to tyrosine, (b) Phenylketonuria, in which there is a transamination reaction between phenylalanine and a-ketoglutaric acid. Phenylalanine 4-mono-oxygenase is absent in about 1 in every 10000 human beings because of a recessive mutant gene. 

Phenylketonuria (PKU) is an inborn error of metabolism by which the body is unable to convert surplus phenylalanine (PA) to tyrosine for use in the biosynthesis of, for example, thyroxine, adrenaline and noradrenaline. This results from a deficiency in the liver enzyme phenylalanine 4-mono-oxygenase (phenylalanine hydroxylase). A secondary metabolic pathway comes into play in which there is a transamination reaction between PA and a-keto-glutaric acid to produce phenylpyruvic acid (PPVA), a ketone and glutamic acid. Overall, PKU may be defined as a genetic defect in PA metabolism such that there are elevated levels of both PA and PPVA in blood and excessive excretion of PPVA (Fig. 25.7). 

The specific electron donor utilized in these reactions varies from one enzyme to another. Reduced pyridine nucleotides, tetrahydropteri-dines, and ascorbate have all been shown to function as electron-donating cofactors with different mono-oxygenases. These cofactor requirements are usually specific. Phenylalanine hydroxylase, for example, utilizes a... 

The levels of monoenoic lipids in brain are reduced in phenylketonuric patients, and it has been postulated that the absence of phenylalanine hydroxylase is associated with reduced levels of fatty acid desaturase. The desaturase is truly a mono-oxygenase, but there is no indication that mono-oxygenases are generally depressed in phenylketonuria. 

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