<P> Prokaryotic PAH is monomeric, whereas eukaryotic PAH exists in an equilibrium between homotetrameric and homodimeric forms . The dimerization interface is composed of symmetry - related loops that link identical monomers, while the overlapping C - terminal tetramerization domain mediates the association of conformationally distinct dimers that are characterized by a different relative orientation of the catalytic and tetramerization domains (Flatmark, Erlandsen). The resulting distortion of the tetramer symmetry is evident in the differential surface area of the dimerization interfaces and distinguishes PAH from the tetramerically symmetrical tyrosine hydroxylase . A domain - swapping mechanism has been proposed to mediate formation of the tetramer from dimers, in which C - terminal alpha - helixes mutually alter their conformation around a flexible C - terminal five - residue hinge region to form a coiled - coil structure, shifting equilibrium toward the tetrameric form . Although both the homodimeric and homotetrameric forms of PAH are catalytically active, the two exhibit differential kinetics and regulation . In addition to reduced catalytic efficiency, the dimer does not display positive cooperativity toward L - Phe (which at high concentrations activates the enzyme), suggesting that L - Phe allosterically regulates PAH by influencing dimer - dimer interaction . </P> <P> PAH is a critical enzyme in phenylalanine metabolism and catalyzes the rate - limiting step in its complete catabolism to carbon dioxide and water . Regulation of flux through phenylalanine - associated pathways is critical in mammalian metabolism, as evidenced by the toxicity of high plasma levels of this amino acid observed in phenylketonuria (see below). The principal source of phenylalanine is ingested proteins, but relatively little of this pool is used for protein synthesis . Instead, the majority of ingested phenylalanine is catabolized through PAH to form tyrosine; addition of the hydroxyl group allows for the benzene ring to be broken in subsequent catabolic steps . Transamination to phenylpyruvate, whose metabolites are excreted in the urine, represents another pathway of phenylalanine turnover, but catabolism through PAH predominates . </P> <P> In humans, this enzyme is expressed both in the liver and the kidney, and there is some indication that it may be differentially regulated in these tissues . PAH is unusual among the aromatic amino acid hydroxylases for its involvement in catabolism; tyrosine and tryptophan hydroxylases, on the other hand, are primarily expressed in the central nervous system and catalyze rate - limiting steps in neurotransmitter / hormone biosynthesis . </P> <P> Deficiency in PAH activity due to mutations in the PAH gene causes hyperphenylalaninemia (HPA), and when blood phenylalanine levels increase above 20 times the normal concentration, the metabolic disease phenylketonuria (PKU) results . PKU is both genotypically and phenotypically heterogeneous: Over 300 distinct pathological mutants have been identified, the majority of which correspond to missense mutations that map to the catalytic domain . When a cohort of identified PAH mutants were expressed in recombinant systems, the enzymes displayed altered kinetic behavior and / or reduced stability, consistent with structural mapping of these mutations to both the catalytic and tetramerization domains of the enzyme . BH4 has been administered as a pharmacological treatment and has been shown to reduce blood levels of phenylalanine for a segment of PKU patients whose genotypes lead to some residual PAH activity but have no defect in BH4 synthesis or regeneration . Follow - up studies suggest that in the case of certain PAH mutants, excess BH4 acts as a pharmacological chaperone to stabilize mutant enzymes with disrupted tetramer assembly and increased sensitivity to proteolytic cleavage and aggregation . Mutations that have been identified in the PAH locus are documented at the Phenylalanine Hydroxylase Locus Knowledgbase (PAHdb, http://www.pahdb.mcgill.ca/). </P>

Where is phenylalanine hydroxylase found in the body