Abstract
BackgroundPhenylalanine and tyrosine are precursor amino acids required for the synthesis of dopamine, the main neurotransmitter implicated in the neurobiology of schizophrenia. Inflammation, increasingly implicated in schizophrenia, can impair the function of the enzyme Phenylalanine hydroxylase (PAH; which catalyzes the conversion of phenylalanine to tyrosine) and thus lead to elevated phenylalanine levels and reduced tyrosine levels. This study aimed to compare phenylalanine, tyrosine, and their ratio (a proxy for PAH function) in a relatively large sample of schizophrenia patients and healthy controls.MethodsWe measured non-fasting plasma phenylalanine and tyrosine in 950 schizophrenia patients and 1000 healthy controls. We carried out multivariate analyses to compare log transformed phenylalanine, tyrosine, and phenylalanine:tyrosine ratio between patients and controls.ResultsCompared to controls, schizophrenia patients had higher phenylalanine (p<0.0001) and phenylalanine: tyrosine ratio (p<0.0001) but tyrosine did not differ between the two groups (p = 0.596).ConclusionsElevated phenylalanine and phenylalanine:tyrosine ratio in the blood of schizophrenia patients have to be replicated in longitudinal studies. The results may relate to an abnormal PAH function in schizophrenia that could become a target for novel preventative and interventional approaches.
Highlights
Dopamine (DA) is a major neurotransmitter implicated in both the neurobiology of schizophrenia and the underlying mechanism of action of antipsychotic medications [1]
The enzymes Phenylalanine hydroxylase (PAH), TH, and tryptophan-5-monoxygenase (TPH; which catalyzes the conversion of tryptophan to serotonin) require the cofactor 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) for optimal function and BH4 deficiency can lead to hyperphenylalaninemia [13]
BH4 is synthesized de novo from guanosine triphosphate (GTP) which is initially converted to 7,8dihydroneopterin triphosphate in a reaction catalyzed by GTP cyclohydrolase 1 (GTPCH-1); 6-pyruvoyltetrahydropterin synthase (PTPS) catalyzes the conversion of 7,8-dihydroneopterin triphosphate to 6-pyruvoyltetrahydropterin; the third and final step is the conversion of 6-pyruvoyltetrahydropterin to BH4, a reaction catalyzed by sepiapterin reductase (SR) [14]
Summary
Dopamine (DA) is a major neurotransmitter implicated in both the neurobiology of schizophrenia and the underlying mechanism of action of antipsychotic medications [1]. Phenylalanine hydroxylase (PAH) catalyzes the conversion of the essential amino acid phenylalanine (Phe) to tyrosine (Tyr). Tyr is converted in a two-step enzymatic reaction (catalyzed sequentially by tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (L-AAAD)) to DA. Phenylalanine and tyrosine are precursor amino acids required for the synthesis of dopamine, the main neurotransmitter implicated in the neurobiology of schizophrenia. Inflammation, increasingly implicated in schizophrenia, can impair the function of the enzyme Phenylalanine hydroxylase (PAH; which catalyzes the conversion of phenylalanine to tyrosine) and lead to elevated phenylalanine levels and reduced tyrosine levels. This study aimed to compare phenylalanine, tyrosine, and their ratio (a proxy for PAH function) in a relatively large sample of schizophrenia patients and healthy controls
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