Revisiting phenylketonuria: Do high brain glycine levels caused by chronic hyperphenylalanemia contribute to brain dysfunction by modulating D-serine levels and NMDA receptor activity?

Abstract

Phenylketonuria (PKU) is an inborn error of metabolism owing to deficits in phenylalanine hydroxylase (PAH) activity. PKU children acquire irreversible brain damage if newborns are not identified and treated with a phenylalanine-restricted diet. In spite of decades of research, the mechanisms underlying PKU brain dysfunction are not adequately understood. Competition of phenylalanine with large neutral amino acids (LNAAs) for carrier-mediated uptake into brain, causing lower brain LNAA levels and reduced neurotransmitter synthesis from tyrosine and tryptophan, is a long-favored mechanism for brain dysfunction. Here, glycine is hypothesized to contribute to phenylalanine-evoked brain disorders. All PKU animal models exhibit elevated brain glycine levels similar to mouse models of nonketotic hyperglycinemia. Glycine is synthesized from l-serine; it is a co-agonist of N-methyl-d-aspartate receptors (NMDARs) and an inhibitory neurotransmitter. l-Serine is synthesized from glucose in astrocytes, exported to neurons, and converted by serine racemase to d-serine, an NMDAR co-agonist. Increased glycine level enhances its inhibition of serine racemase and reduces levels of d-serine. l-Serine-glycine-d-serine interactions can be linked to PAH deficits because elevated brain phenylalanine concentration causes its metabolism by minor pathways to generate phenyllactate. If phenyllactate and l-serine synthesis are coupled via transaminase and redox reactions, the stoichiometry is 1:1. These findings support the following hypothesis: (i) phenylalanine disrupts glycine and d-serine homeostasis during brain maturation, irreversibly altering neuronal development and circuit formation, and (ii) high glycine and low d-serine levels in PKU adults contribute to cognitive and behavioral dysfunction. Suggested new directions for future studies of PKU focus on glycine neurotoxicity.