Structure–Function Relationships in the Aromatic Amino Acid Hydroxylases Enzyme Family: Evolutionary Insights

Abstract The nonheme iron and tetrahydrobiopterin dependent aromatic amino acid hydroxylases (AAAHs) comprise a family of enzymes that catalyse the hydroxylation of l ‐Phe, l ‐Tyr and l ‐Trp. These reactions are of central physiological importance. Consequently, dysfunction of the AAAHs is associated with serious disorders, that is, the genetic metabolic disease phenylketonuria for phenylalanine hydroxylase (PAH), and neurological and neuropsychiatric disorders for tyrosine hydroxylase (TH) and tryptophan hydroxylase 1 and 2 (TPH1, TPH2). Mammalian AAAHs are tetrameric proteins that present a three‐domain structure with a remarkable high similarity, in particularly for the catalytic domains. Structural analyses have provided valuable insights on the effect of disease‐associated mutations, mechanism of catalysis, the determinants for substrate specificity and regulation of enzymatic activity. The best characterised AAAH is PAH, which also seems to be the precursor of the family. The AAAHs have developed sophisticated regulatory mechanisms during evolution to control substrate l ‐Phe (PAH), catecholamine (TH), serotonin and melatonin (TPHs) levels. Key Concepts: The aromatic amino acid hydroxylases (AAAHs) are tetrahydrobiopterin (BH 4 ) dependent enzymes that use dioxygen as additional substrate. The AAAHs are involved in serious inborn errors of metabolism with neuronal impact. The AAAHs are highly homologous, contain a catalytic mononuclear nonheme iron coordinated by a 2‐His‐1‐carboxylate facial triad and show similar reaction mechanism. Metazoans have at least three AAAH genes: phenylalanine hydroxylase ( PAH ), tyrosine hydroxylase ( TH ) and tryptophan hydroxylase(s) ( TPH (s)), where PAH appears as the precursor of the family. Mammalian PAH, TH, TPH1 and TPH2 are tetrameric, with a three‐domain subunit structure; substrate specificity is provided by the catalytic domain. The AAAHs are highly regulated by mechanisms at the transcriptional, translational, posttranslational and allosteric levels. Evolutionary adaptation of the enzymes is most evident at the regulatory mechanisms, along the complexity of the organisms, especially of the central nervous system (CNS).