Beyond phenylalanine to tyrosine: Mapping the comprehensive phenylalanine hydroxylase (PAH) pathway for systems biology

The phenylalanine hydroxylase (PAH) pathway is an enzymatic pathway focused primarily on the hydroxylation of the amino acid L-phenylalanine (Phe) to L-tyrosine (Tyr). However, the functioning of this pathway can also have significant impacts on other downstream metabolites. In addition, both common and rare genetic variants have been demonstrated to significantly impair PAH pathway function. However, to our knowledge, the comprehensive PAH pathway including influences on related downstream metabolic pathways has not been mapped in an integrative manner. As such, we conducted a narrative review of the literature to describe the comprehensive PAH pathway, including influences on downstream related metabolic pathways, while mapping a visual depiction of these integrative processes. In addition to the hydroxylation of Phe to Tyr, the comprehensive pathway narrative describes Phe metabolism and transport across the blood brain barrier including competition with other large neutral amino acids, Tyr catabolism, and others. Discussion of the importance of these metabolic processes in the context of PAH genetic variation are also provided. With an increased focus on conducting health research from a systems biology perspective, this work is critical to improving our understanding of the downstream effects of amino acid metabolism and their possible impacts on health outcomes.