Abstract
Acylpeptide hydrolase (APEH) is a serine protease involved in the recycling of amino acids from acylated peptides. Beyond that, APEH participates in the metabolism of the antiepileptic drug valproic acid (2-propylpentanoic acid; VPA) by catalyzing the hydrolysis of the VPA metabolite valproylglucuronide (VPA-G) to its aglycon. It has been shown that the inhibition of APEH by carbapenem antibiotics decreases therapeutic VPA levels by enhancing the urinary elimination of VPA in form of VPA-G. As various sequence variants of the APEH gene (which encodes the APEH protein) are listed in databases, but have not been functionally characterized yet, we assume, that some APEH sequence variants may have pharmacogenetic relevance due to their impaired cleavage of VPA-G. APEH sequence variants predicted to affect enzyme activity were selected from databases, and overexpressed in HEK293 cells (stable transfection), a cell line derived from human embryonic kidney cells. APEH activity in cell homogenates was determined spectrophotometrically by monitoring the hydrolysis of the synthetic substrate N-acetyl-L-alanine-nitroanilide. APEH enzyme activity and protein expression of the sequence variants were compared with those of APEH with the reference sequence. Three out of five tested missense sequence variants resulted in a considerable decrease of enzyme activity assessed with the standard substrate N-acetyl-L-alanine-nitroanilide, suggesting an effect on pharmacokinetics of VPA. Our work underlines the need to consider the APEH genotype in investigations of altered VPA metabolism.
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Acknowledgments
Skilled technical assistance by Mrs. Annegret Flier is gratefully acknowledged. This research was supported by ‘Startförderung’ of Bonn-Rhein-Sieg University of Applied Sciences and Anna Feddersen-Wagner-Fonds of University of Zürich, both to J.O.S. He also gratefully acknowledges financial support by the programs FH-Struktur (‘FunForGen’, 322-08-03-04-02) and FH Zeit für Forschung (‘KETOplus’, 005-1703-0016) of the Ministry of Culture and Science of the German State of North Rhine-Westphalia.
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Tsortouktzidis, D., Grundke, K., Till, C. et al. Acylpeptide hydrolase (APEH) sequence variants with potential impact on the metabolism of the antiepileptic drug valproic acid. Metab Brain Dis 34, 1629–1634 (2019). https://doi.org/10.1007/s11011-019-00470-9
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DOI: https://doi.org/10.1007/s11011-019-00470-9