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Electrostatic environment at the active site of prolyl oligopeptidase is highly influential during substrate binding.

Szeltner Z, Rea D, Renner V, Juliano L, Fülop V, Polgár L
J Biol Chem 278 48786-93 (2003)
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Cited: 19 times
EuropePMC logo PMID: 14514675

Abstract

The positive electrostatic environment of the active site of prolyl oligopeptidase was investigated by using substrates with glutamic acid at positions P2, P3, P4, and P5, respectively. The different substrates gave various pH rate profiles. The pKa values extracted from the curves are apparent parameters, presumably affected by the nearby charged residues, and do not reflect the ionization of a simple catalytic histidine as found in the classic serine peptidases like chymotrypsin and subtilisin. The temperature dependence of kcat/Km did not produce linear Arrhenius plots, indicating different changes in the individual rate constants with the increase in temperature. This rendered it possible to calculate these constants, i.e. the formation (k1) and decomposition (k-1) of the enzyme-substrate complex and the acylation constant (k2), as well as the corresponding activation energies. The results have revealed the relationship between the complex Michaelis parameters and the individual rate constants. Structure determination of the enzyme-substrate complexes has shown that the different substrates display a uniform binding mode. None of the glutamic acids interacts with a charged group. We conclude that the specific rate constant is controlled by k1 rather than k2 and that the charged residues from the substrate and the enzyme can markedly affect the formation but not the structure of the enzyme-substrate complexes.

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  1. Structural definition and substrate specificity of the S28 protease family: the crystal structure of human prolylcarboxypeptidase. Soisson SM, Patel SB, Abeywickrema PD, Byrne NJ, Diehl RE, Hall DL, Ford RE, Reid JC, Rickert KW, Shipman JM, Sharma S, Lumb KJ. BMC Struct Biol 10 16 (2010)


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  1. Low molecular weight inhibitors of Prolyl Oligopeptidase: a review of compounds patented from 2003 to 2010. López A, Tarragó T, Giralt E. Expert Opin Ther Pat 21 1023-1044 (2011)

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  1. Flexibility of prolyl oligopeptidase: molecular dynamics and molecular framework analysis of the potential substrate pathways. Fuxreiter M, Magyar C, Juhász T, Szeltner Z, Polgár L, Simon I. Proteins 60 504-512 (2005)
  2. Search for substrates for prolyl oligopeptidase in porcine brain. Brandt I, De Vriendt K, Devreese B, Van Beeumen J, Van Dongen W, Augustyns K, De Meester I, Scharpé S, Lambeir AM. Peptides 26 2536-2546 (2005)
  3. Discrimination of esterase and peptidase activities of acylaminoacyl peptidase from hyperthermophilic Aeropyrum pernix K1 by a single mutation. Wang Q, Yang G, Liu Y, Feng Y. J Biol Chem 281 18618-18625 (2006)
  4. The acylaminoacyl peptidase from Aeropyrum pernix K1 thought to be an exopeptidase displays endopeptidase activity. Kiss AL, Hornung B, Rádi K, Gengeliczki Z, Sztáray B, Juhász T, Szeltner Z, Harmat V, Polgár L. J Mol Biol 368 509-520 (2007)
  5. The loops facing the active site of prolyl oligopeptidase are crucial components in substrate gating and specificity. Szeltner Z, Juhász T, Szamosi I, Rea D, Fülöp V, Módos K, Juliano L, Polgár L. Biochim Biophys Acta 1834 98-111 (2013)
  6. Selective Homogeneous Assay for Circulating Endopeptidase Fibroblast Activation Protein (FAP). Bainbridge TW, Dunshee DR, Kljavin NM, Skelton NJ, Sonoda J, Ernst JA. Sci Rep 7 12524 (2017)
  7. Swapping the substrate specificities of the neuropeptidases neurolysin and thimet oligopeptidase. Lim EJ, Sampath S, Coll-Rodriguez J, Schmidt J, Ray K, Rodgers DW. J Biol Chem 282 9722-9732 (2007)
  8. Primary structure, recombinant expression and homology modelling of human brain prolyl oligopeptidase, an important therapeutic target in the treatment of neuropsychiatric diseases. Tarragó T, Sabidó E, Kogan MJ, de Oliveira E, Giralt E. J Pept Sci 11 283-287 (2005)
  9. Mechanism of Action of Prolyl Oligopeptidase (PREP) in Degenerative Brain Diseases: Has Peptidase Activity Only a Modulatory Role on the Interactions of PREP with Proteins? Männistö PT, García-Horsman JA. Front Aging Neurosci 9 27 (2017)
  10. Properties of the prolyl oligopeptidase homologue from Pyrococcus furiosus. Juhász T, Szeltner Z, Polgár L. FEBS Lett 580 3493-3497 (2006)
  11. A link between hinge-bending domain motions and the temperature dependence of catalysis in 3-isopropylmalate dehydrogenase. Hajdú I, Szilágyi A, Kardos J, Závodszky P. Biophys J 96 5003-5012 (2009)
  12. Kinetic Landscape of a Peptide Bond-Forming Prolyl Oligopeptidase. Czekster CM, Naismith JH. Biochemistry 56 2086-2095 (2017)
  13. Dynamics and ligand-induced conformational changes in human prolyl oligopeptidase analyzed by hydrogen/deuterium exchange mass spectrometry. Tsirigotaki A, Elzen RV, Veken PV, Lambeir AM, Economou A. Sci Rep 7 2456 (2017)
  14. Carboxypeptidase in prolyl oligopeptidase family: Unique enzyme activation and substrate-screening mechanisms. Yadav P, Goyal VD, Gaur NK, Kumar A, Gokhale SM, Jamdar SN, Makde RD. J Biol Chem 294 89-100 (2019)
  15. Molecular dynamics study of prolyl oligopeptidase with inhibitor in binding cavity. Kaszuba K, Rog T, St Pierre JF, Mannisto PT, Karttunen M, Bunker A. SAR QSAR Environ Res 20 595-609 (2009)
  16. Exploration of the chlorpyrifos escape pathway from acylpeptide hydrolases using steered molecular dynamics simulations. Wang D, Jin H, Wang J, Guan S, Zhang Z, Han W. J Biomol Struct Dyn 34 749-761 (2016)
  17. Ligand-induced conformational changes in prolyl oligopeptidase: a kinetic approach. Van Elzen R, Schoenmakers E, Brandt I, Van Der Veken P, Lambeir AM. Protein Eng Des Sel 30 217-224 (2017)


Related citations provided by authors (5)

  1. Electrostatic effects and binding determinants in the catalysis of prolyl oligopeptidase. Site specific mutagenesis at the oxyanion binding site.. Szeltner Z, Rea D, Renner V, Fulop V, Polgar L J Biol Chem 277 42613-22 (2002)
  2. Substrate-dependent competency of the catalytic triad of prolyl oligopeptidase.. Szeltner Z, Rea D, Juhász T, Renner V, Mucsi Z, Orosz G, Fülöp V, Polgár L J Biol Chem 277 44597-605 (2002)
  3. Structures of prolyl oligopeptidase substrate/inhibitor complexes. Use of inhibitor binding for titration of the catalytic histidine residue.. Fülöp V, Szeltner Z, Renner V, Polgár L J Biol Chem 276 1262-6 (2001)
  4. Catalysis of serine oligopeptidases is controlled by a gating filter mechanism.. Fülöp V, Szeltner Z, Polgár L EMBO Rep 1 277-81 (2000)
  5. Prolyl oligopeptidase: an unusual beta-propeller domain regulates proteolysis.. Fülöp V, Böcskei Z, Polgár L Cell 94 161-70 (1998)

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