Top

Published in:

01-12-2019 | Antiepileptic Drugs | Original Article

Acylpeptide hydrolase (APEH) sequence variants with potential impact on the metabolism of the antiepileptic drug valproic acid

Authors: Despina Tsortouktzidis, Kathleen Grundke, Claudia Till, Anne Korwitz-Reichelt, Jörn Oliver Sass

Published in: Metabolic Brain Disease | Issue 6/2019

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.

De Turck BJ, Diltoer MW, Cornelis PJ, Maes V, Spapen HD, Camu F, Huyghens LP (1998) Lowering of plasma valproic acid concentrations during concomitant therapy with meropenem and amikacin. J Antimicrob Chemother 42(4):563–564CrossRefPubMed

Fujino T, Watanabe K, Beppu M, Kikugawa K, Yasuda H (2000) Identification of oxidized protein hydrolase of human erythrocytes as acylpeptide hydrolase. Biochim Biophys Acta 1478(1):102–112CrossRefPubMed

Ishikawa T, Otaki H, Mizuta S, Kuriyama M, Onomura O, Higuchi N, Nakashima MN, Nakashima M, Ohyama K (2017) Computational study of the competitive binding of valproic acid glucuronide and carbapenem antibiotics to acylpeptide hydrolase. Drug Metab Pharmacokinet 32(4):201–207CrossRefPubMed

Kobayashi K, Smith JA (1987) Acyl-peptide hydrolase from rat liver: characterization of enzyme reaction. J Biol Chem 262(24):11435–11445PubMed

Lineweaver H, Burk D (1934) The determination of enzyme dissociation constant. J Am Chem Soc 56(3):658–666CrossRef

Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275PubMed

Miranda Herrero MC, Alcaraz RAJ, Escudero VV, Fernández LSN, Fernández-Llamazares CM, Barredo VE, Vásquez LM, de Castro P (2015) Pharmacological interaction between valproic acid and carbapenem: what about levels in pediatrics? Eur J Paediatr Neurol 19(2):155–161CrossRefPubMed

Nagai K, Shimizu T, Togo A, Takeya M, Yokomizo Y, Sakata Y, Matsuishi T, Kato H (1997) Decrease in serum levels of valproic acid during treatment with a new carbapenem, panipenem/betamipron. J Antimicrob Chemother 39(2):295–296CrossRefPubMed

Palmieri G, Cocca E, Gogliettino M, Valentino R, Ruvo M, Cristofano G, Angiolillo A, Balestrieri M, Rossi M, Di Costanzo A (2017) Low erythrocyte levels of proteasome and acyl-peptide hydrolase (APEH) activities in Alzheimer's disease: A sign of defective Proteostasis? J Alzheimers Dis 60(3):1097–1106CrossRefPubMed

Palumbo R, Gogliettino M, Cocca E, Iannitti R, Sandomenico A, Ruvo M, Balestrieri M, Rossi M, Palmieri G (2016) APEH inhibition affects osteosarcoma cell viability via downregulation of the proteasome. Int J Mol Sci 17(10) pii: E1614 https://doi.org/10.3390/ijms17101614

Perrier J, Giardina T, Durand A, Puigserver A (2002) Specific enhancement of acylase I and acylpeptide hydrolase activities by the corresponding N-acetylated substrates in primary rat hepatocyte cultures. Biol Cell 94(1):45–54CrossRefPubMed

Perrier J, Durand A, Giardina T, Puigserver A (2005) Catabolism of intracellular N-terminal acetylated proteins: involvement of acylpeptide hydrolase and acylase. Biochimie 87(8):673–685CrossRefPubMed

Raphel V, Giardina T, Guevel L, Perrier J, Dupuis L, Guo XJ, Puigserver A (1999) Cloning, sequencing and further characterization of acylpeptide hydrolase from porcine intestinal mucosa. Biochim Biophys Acta 1432(2):371–381CrossRefPubMed

Sass JO, Mohr V, Olbrich H, Engelke U, Horvath J, Fliegauf M, Loges NT, Schweitzer-Krantz S, Moebus R, Weiler P, Kispert A, Superti-Furga A, Wevers RA, Omran H (2006) Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism. Am J Hum Genet 78(3):401–409CrossRefPubMedPubMedCentral

Sass JO, Vaithilingam J, Gemperle-Britschgi C, Delnooz CC, Kluijtmans LA, van de Warrenburg BP, Wevers RA (2016) Expanding the phenotype in aminoacylase 1 (ACY1) deficiency: characterization of the molecular defect in a 63-year-old woman with generalized dystonia. Metab Brain Dis 31(3):587–592CrossRefPubMed

Scaloni A, Jones W, Pospischil M, Sassa S, Schneewind O, Popowicz AM, Bossa F, Graziano SL, Manning JM (1992) Deficiency of acylpeptide hydrolase in small-cell lung carcinoma cell lines. J Lab Clin Med 120(4):546–552PubMed

Scaloni A, Ingallinella P, Andolfo A Jones W, Marino G, Manning JM (1999) Structural investigations on human erythrocyte acylpeptide hydrolase by mass spectrometric procedures. J Protein Chem 18(3):349–360CrossRefPubMed

Shimizu K, Kiuchi Y, Ando K, Hayakawa M, Kikugawa K (2004) Coordination of oxidized protein hydrolase and the proteasome in the clearance of cytotoxic denatured proteins. Biochem Biophys Res Commun 324(1):140–146CrossRefPubMed

Sommer A, Christensen E, Schwenger S, Seul R, Haas D, Olbrich H, Omran H, Sass JO (2011) The molecular basis of aminoacylase 1 deficiency. Biochim Biophys Acta 1812(6):685–690CrossRefPubMed

Suzuki E, Naotoshi Y, Ogura Y, Nakai D, Kazuishi K, Nobuhiro K, S-i M, Okazaki O (2010) Identification of valproic acid glucuronide hydrolase as a key enzyme for the interaction of valproic acid with carbapenem antibiotics. Drug Metab Dispos 38(9):1538–1544CrossRefPubMed

Suzuki E, Nakai D, Yamamura N, Kobayashi N, Okazaki O, Izumi T (2011) Inhibition mechanism of carbapenem antibiotics on acylpeptide hydrolase, a key enzyme in the interaction with valproic acid. Xenobiotica 41(11):958–963CrossRefPubMed

Suzuki E, Nakai D, Ikenaga H, Fusegawa K, Goda R, Kobayashi N, Kuga H, Izumi T (2016) In vivo inhibition of acylpeptide hydrolase by carbapenem antibiotics causes the decrease of plasma concentration of valproic acid in dogs. Xenobiotica 46(2):126–131CrossRefPubMed

Wen ZP, Fan SS, Du C, Yin T, Zhou BT, Peng ZF, Xie YY, Zhang W, Chen Y, Tang J, Xiao J, Chen XP (2016) Influence of acylpeptide hydrolase polymorphisms on valproic acid level in Chinese epilepsy patients. Pharmacogenomics 17(11):1219–1225CrossRefPubMed

Yamin R, Bagchi S, Hildebrant R, Scaloni A, Widom RL, Abraham CR (2007) Acyl peptide hydrolase, a serine proteinase isolated from conditioned medium of neuroblastoma cells, degrades the amyloid-beta peptide. J Neurochem 100(2):458–467CrossRefPubMed

Yamin R, Zhao C, O'Connor PB, McKee AC, Abraham CR (2009) Acyl peptide hydrolase degrades monomeric and oligomeric amyloid-beta peptide. Mol Neurodegener 4:33. https://doi.org/10.1186/1750-1326-4-33

Zeng Z, Rulten SL, Breslin C, Zlatanou A, Coulthard V, Caldecott KW (2017) Acylpeptide hydrolase is a component of the cellular response to DNA damage. DNA Repair 58:52–61CrossRefPubMed

Title: Acylpeptide hydrolase (APEH) sequence variants with potential impact on the metabolism of the antiepileptic drug valproic acid
Authors: Despina Tsortouktzidis
Kathleen Grundke
Claudia Till
Anne Korwitz-Reichelt
Jörn Oliver Sass
Publication date: 01-12-2019
Publisher: Springer US
Keywords: Antiepileptic Drugs
Carbapenem Antibiotic
Antiepileptic Drugs
Valproate
Published in: Metabolic Brain Disease / Issue 6/2019
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-019-00470-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Acylpeptide hydrolase (APEH) sequence variants with potential impact on the metabolism of the antiepileptic drug valproic acid

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2019

Rare Angiogenin and Ribonuclease 4 variants associated with amyotrophic lateral sclerosis exhibit loss-of-function: a comprehensive in silico study

Safranal, an active ingredient of saffron, attenuates cognitive deficits in amyloid β-induced rat model of Alzheimer’s disease: underlying mechanisms

Metabolomic profiling on rat brain of prenatal malnutrition: implicated for oxidative stress and schizophrenia

Vitamin D supplementation ameliorates severity of generalized anxiety disorder (GAD)

Creatine plus pyruvate supplementation prevents oxidative stress and phosphotransfer network disturbances in the brain of rats subjected to chemically-induced phenylketonuria

Methyl jasmonate ameliorates rotenone-induced motor deficits in rats through its neuroprotective activity and increased expression of tyrosine hydroxylase immunopositive cells