Acylpeptide hydrolase

Acylpeptide hydrolase (APH) removes an acylated amino acid residue from the N-terminus of oligopeptides. The enzyme is linked with diverse carcinomas and is also a potential target for cognitive enhancing drugs. We solved the structure of APH from Aeropyrum pernix K1 (ApAPH) in complex with small molecules, which could be products of the enzyme reaction. We characterized the substrate binding region of the enzyme (S1-S3 sites). Analysis of the structures together with the results of solution kinetics studies revealed that in contrast to its mammalian orthologues ApAPH were an endopeptidase. In order to clarify the role of conserved His367 in enzyme activity we solved the crystal strucutre of the ApAAP H367A variant and characterized it in solution. We showed that His367 not involved directly in the catalytic apparatus stabilizes the conformation of the oxyanion site in APH enzymes.

Structure of acylpeptide hydrolase

Former collaboration:

Polgár group, Institute of Enzymology,  Budapest

Structures determined (PDB codes):

2HU5, 2HU7, 2HU8, 2QR5, 4RE5, 4RE6, 4HXE, 4HXF, 4HXG, 3O4G, 3O4H, 3O4I, 3O4J, 3EQ7, 3EQ8, 3EQ9

Kapcsolódó publikációk

  • Veronika Harmat , Klarissza Domokos , Dóra K. Menyhárd , Anna Palló , Zoltán Szeltner , Ilona Szamosi , Tamás Beke , Gábor Náray-Szabó , László Polgár
    Structure and catalysis of acylamonoacyl peptidase: closed and open subunits of a dimer oligopeptidase
    Journal of Biological Chemistry 286:1987-1998. PMID: 21084296 | DOI: 10.1074/jbc.M110.169862 (2011) Kivonat
  • Zoltán Szeltner , András L. Kiss , Klarissza Domokos , Veronika Harmat , Gábor Náray-Szabó , László Polgár
    Characterization of a novel acylaminoacyl peptidase with hexameric structure and endopeptidase activity
    Biochem. Biophys. Acta 1794:1204-1210 (2009) Kivonat
  • András L. Kiss , Balázs Hornung , Krisztina Rádi , Zsolt Gengeliczki , Bálint Sztáray , Tünde Juhász , Zoltán Szeltner , Veronika Harmat , László Polgár
    The acylaminoacyl peptidase from Aeropyrum pernix K1 thought to be an exopeptidase displays endopeptidase activity
    J. Mol. Biol. 368: 509-520. (2007) Kivonat
  • Dóra K. Menyhárd , Anna Kiss-Szemán , Éva Tichy-Rács , Balázs Hornung , Krisztina Rádi , Zoltán Szeltner , Klarissza Domokos , Ilona Szamosi , Gábor Náray-Szabó , László Polgár , Veronika Harmat
    A self-compartmentalizing hexamer serine protease from Pyrococcus horikoshii: substrate selection achieved through multimerization
    J Biol Chem 288(24):17884-17894. | DOI: 10.1074/jbc.M113.451534 | PMID: 23632025 (2013) Kivonat
  • Károly Kánai , Péter Arányi , Zsolt Böcskei , György Ferenczy , Veronika Harmat , Kálmán Simon , Sándor Bátori , Gábor Náray-Szabó , István Hermecz
    Prolyl oligopeptidase inhibition by N-acyl-pro-pyrrolidine-type molecules
    J Med Chem. 51(23):7514-7522. | DOI: 10.1021/jm800944x | PMID: 19006380 (2008) Kivonat
  • András L. Kiss , Anna Palló , Gábor Náray-Szabó , Veronika Harmat , László Polgár
    Structural and kinetic contributions of the oxyanion binding site to the catalytic activity of acylaminoacyl peptidase
    J Struct Biol. 162(2):312-323. | DOI: 10.1016/j.jsb.2008.01.012 | PMID: (2008) Kivonat
  • Dóra K. Menyhárd , Zoltán Orgován , Zoltán Szeltner , Ilona Szamosi , Veronika Harmat
    Catalytically distinct states captured in a crystal lattice: the substrate-bound and scavenger states of acylaminoacyl peptidase and their implications for functionality
    Acta Crystallogr D Biol Crystallogr. 71(Pt 3):461-472. | DOI: 10.1107/S1399004714026819 | PMID: 25760596 (2015) Kivonat