Phenylalanine-Free Protein Substitutes for Next-Generation PKU Diets: Amino-Acid Roles, Transport, Absorption, and Formulation

Phenylketonuria (PKU) requires lifelong control of blood phenylalanine (Phe), but reliance on specialized protein substitutes varies with dietary Phe tolerance and response to pharmacotherapy. Sapropterin may permit dietary liberalization in responsive individuals, whereas successful pegvaliase enzyme substitution therapy may substantially reduce or eliminate the need for Phe-free protein substitutes. Conventional free-amino-acid formulations are nutritionally effective but may produce rapid plasma amino-acid peaks, increased oxidation, gastrointestinal intolerance, and treatment fatigue. Alternative systems, including casein glycomacropeptide (CGMP), oligopeptides, engineered low-phenylalanine proteins and controlled-release amino acids, may improve physiological utilization, but their relative metabolic and technological advantages remain uncertain. This narrative review qualitatively discusses the cited literature on amino-acid metabolism, intestinal absorption, tissue utilization, large-neutral-amino-acid transport, blood–brain barrier competition, nitrogen retention, safety, and food-formulation performance. Building on previous reviews, this article connects amino-acid roles, delivery-system characteristics, and analytical and clinical validation needs in a formulation-oriented conceptual framework. Its contribution is an integrated basis for defining product-development questions and corresponding endpoints, rather than a new biological finding or a validated prioritization method. The established nutritional importance of tyrosine in phenylalanine hydroxylase (PAH) deficiency is distinguished from unvalidated hypotheses for selectively enriching tryptophan or branched-chain amino acids. These distinctions describe nutritional roles and research needs rather than a quantitatively derived ranking. All indispensable amino acids remain necessary for nutritional adequacy, and rapid absorption is not a sufficient indicator of superior utilization. Future substitutes should combine balanced composition, controlled delivery, sensory acceptability, and rigorous clinical validation.