DB code: D00210

RLCP classification 1.13.30000.13 : Hydrolysis
CATH domain 3.40.50.1820 : Rossmann fold Catalytic domain
2.130.10.120 : Methylamine Dehydrogenase; Chain H
E.C. 3.4.21.26
CSA 1qfm
M-CSA 1qfm
MACiE

CATH domain Related DB codes (homologues)
3.40.50.1820 : Rossmann fold S00544 S00344 S00517 S00525 S00526 S00720 S00723 S00724 S00725 S00919 S00057 S00374 S00345 S00347 S00348 S00346 S00350 S00352 S00353 S00355 S00356 S00358 D00189 D00539 T00253

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq MEROPS Pfam
P23687 Prolyl endopeptidase
PE
EC 3.4.21.26
Post-proline cleaving enzyme
NP_001004050.1 (Protein)
NM_001004050.1 (DNA/RNA sequence)
S09.001 (Serine)
PF00326 (Peptidase_S9)
PF02897 (Peptidase_S9_N)
[Graphical View]

KEGG enzyme name
prolyl oligopeptidase
post-proline cleaving enzyme
proline-specific endopeptidase
post-proline endopeptidase
proline endopeptidase
endoprolylpeptidase
prolyl endopeptidase

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P23687 PPCE_PIG Hydrolysis of Pro-|-Xaa >> Ala-|-Xaa in oligopeptides. Cytoplasm.

KEGG Pathways
Map code Pathways E.C.

Compound table
Substrates Products Intermediates
KEGG-id C00001 C00012 C00746 C00840 C00012 C00098 I00087 I00085 I00086
E.C.
Compound H2O Peptide Oxytocin Vasopressin Peptide Oligopeptide Peptidyl-tetrahedral intermediate Acyl-enzyme Tetrahedral intermediate
Type H2O peptide/protein amide group,amine group,aromatic ring (only carbon atom),disulfide bond,peptide/protein amide group,amine group,aromatic ring (only carbon atom),carbohydrate,disulfide bond,lipid,peptide/protein peptide/protein amine group,carboxyl group,peptide/protein
ChEBI 15377
7872
PubChem 22247451
962
439302
1e5tA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Intermediate-analogue:GOL
1e8mA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Analogue:PHQ-GLY-PRO (chain I) Unbound Unbound Unbound
1e8nA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:GLY-PHE-GLY-PRO-PHE-GLY (chain I) Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1qfmA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Intermediate-analogue:SGL
1qfsA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Intermediate-analogue:ZPR
1e5tA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1e8mA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1e8nA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1qfmA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1qfsA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
Swiss-prot;P23687 & literature [17], [22], [29], [32] & [33]

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1e5tA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain TYR 473;SER 554;ASP 641;HIS 680 ASN 555
1e8mA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain TYR 473;;ASP 641;HIS 680 ASN 555 mutant S554A
1e8nA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain TYR 473;;ASP 641;HIS 680 ASN 555 mutant S554A
1qfmA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain TYR 473;SER 554;ASP 641;HIS 680 ASN 555
1qfsA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain TYR 473;SER 554;ASP 641;HIS 680 ASN 555
1e5tA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1e8mA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1e8nA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1qfmA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1qfsA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[9]
[14]
Scheme 1
[17]
p.165
[22]
[29]
p.354

References
[1]
Resource
Comments ACTIVE SITE HIS-680.
Medline ID 91291146
PubMed ID 2064618
Journal Biochem J
Year 1991
Volume 276
Pages 837-40
Authors Stone SR, Rennex D, Wikstrom P, Shaw E, Hofsteenge J
Title Inactivation of prolyl endopeptidase by a peptidylchloromethane. Kinetics of inactivation and identification of sites of modification.
Related PDB
Related UniProtKB P23687
[2]
Resource
Comments
Medline ID
PubMed ID 1900195
Journal Biochemistry
Year 1991
Volume 30
Pages 2195-203
Authors Rennex D, Hemmings BA, Hofsteenge J, Stone SR
Title cDNA cloning of porcine brain prolyl endopeptidase and identification of the active-site seryl residue.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 2026166
Journal Eur J Biochem
Year 1991
Volume 197
Pages 441-7
Authors Polgar L
Title pH-dependent mechanism in the catalysis of prolyl endopeptidase from pig muscle.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 1590752
Journal Biochem J
Year 1992
Volume 283
Pages 647-8
Authors Polgar L
Title Prolyl endopeptidase catalysis. A physical rather than a chemical step is rate-limiting.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 1590775
Journal Biochem J
Year 1992
Volume 283
Pages 871-6
Authors Stone SR, Rennex D, Wikstrom P, Shaw E, Hofsteenge J
Title Peptidyldiazomethanes. A novel mechanism of interaction with prolyl endopeptidase.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 1510958
Journal Biochemistry
Year 1992
Volume 31
Pages 7729-35
Authors Polgar L
Title Unusual secondary specificity of prolyl oligopeptidase and the different reactivities of its two forms toward charged substrates.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 1420194
Journal Biochemistry
Year 1992
Volume 31
Pages 10769-73
Authors Polgar L, Patthy A
Title Cleavage of the Lys196-Ser197 bond of prolyl oligopeptidase: enhanced catalytic activity for one of the two active enzyme forms.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 1569074
Journal J Biol Chem
Year 1992
Volume 267
Pages 8192-9
Authors Chevallier S, Goeltz P, Thibault P, Banville D, Gagnon J
Title Characterization of a prolyl endopeptidase from Flavobacterium meningosepticum. Complete sequence and localization of the active-site serine.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 8486154
Journal FEBS Lett
Year 1993
Volume 322
Pages 227-30
Authors Polgar L, Kollt E, Hollosi M
Title Prolyl oligopeptidase catalysis. Reactions with thiono substrates reveal substrate-induced conformational change to be the rate-limiting step.
Related PDB
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID 8027988
Journal J Med Chem
Year 1994
Volume 37
Pages 2071-8
Authors Tanaka Y, Niwa S, Nishioka H, Yamanaka T, Torizuka M, Yoshinaga K, Kobayashi N, Ikeda Y, Arai H
Title New potent prolyl endopeptidase inhibitors: synthesis and structure-activity relationships of indan and tetralin derivatives and their analogues.
Related PDB
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 7932578
Journal J Med Chem
Year 1994
Volume 37
Pages 3492-502
Authors Tsutsumi S, Okonogi T, Shibahara S, Ohuchi S, Hatsushiba E, Patchett AA, Christensen BG
Title Synthesis and structure-activity relationships of peptidyl alpha-keto heterocycles as novel inhibitors of prolyl endopeptidase.
Related PDB
Related UniProtKB
[12]
Resource
Comments
Medline ID
PubMed ID 9148758
Journal Biochem J
Year 1997
Volume 322
Pages 839-43
Authors Kahyaoglu A, Haghjoo K, Kraicsovits F, Jordan F, Polgar L
Title Benzyloxycarbonylprolylprolinal, a transition-state analogue for prolyl oligopeptidase, forms a tetrahedral adduct with catalytic serine, not a reactive cysteine.
Related PDB
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID 9151967
Journal Eur J Biochem
Year 1997
Volume 245
Pages 381-5
Authors Schutkowski M, Jakob M, Landgraf G, Born I, Neubert K, Fischer G
Title Probing substrate backbone function in prolyl oligopeptidase catalysis--large positional effects of peptide bond monothioxylation.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 9325271
Journal J Biol Chem
Year 1997
Volume 272
Pages 25547-54
Authors Kahyaoglu A, Haghjoo K, Guo F, Jordan F, Kettner C, Felfoldi F, Polgar L
Title Low barrier hydrogen bond is absent in the catalytic triads in the ground state but Is present in a transition-state complex in the prolyl oligopeptidase family of serine proteases.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 9128099
Journal J Pept Res
Year 1997
Volume 49
Pages 46-51
Authors Noula C, Kokotos G, Barth T, Tzougraki C
Title New fluorogenic substrates for the study of secondary specificity of prolyl oligopeptidase.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 9839007
Journal Bioorg Med Chem
Year 1998
Volume 6
Pages 1775-80
Authors Bordusa F, Jakubke HD
Title The specificity of prolyl endopeptidase from Flavobacterium meningoseptum: mapping the S' subsites by positional scanning via acyl transfer.
Related PDB
Related UniProtKB
[17]
Resource
Comments X-RAY CRYSTALLOGRAPHY (1.4 ANGSTROMS).
Medline ID 98359116
PubMed ID 9695945
Journal Cell
Year 1998
Volume 94
Pages 161-70
Authors Fulop V, Bocskei Z, Polgar L
Title Prolyl oligopeptidase: an unusual beta-propeller domain regulates proteolysis.
Related PDB 1qfm 1qfs
Related UniProtKB P23687
[18]
Resource
Comments
Medline ID
PubMed ID 9427736
Journal EMBO J
Year 1998
Volume 17
Pages 1-9
Authors Medrano FJ, Alonso J, Garcia JL, Romero A, Bode W, Gomis-Ruth FX
Title Structure of proline iminopeptidase from Xanthomonas campestris pv. citri: a prototype for the prolyl oligopeptidase family.
Related PDB
Related UniProtKB
[19]
Resource
Comments
Medline ID
PubMed ID 9440697
Journal Nature
Year 1998
Volume 391
Pages 301-4
Authors Quemeneur E, Moutiez M, Charbonnier JB, Menez A
Title Engineering cyclophilin into a proline-specific endopeptidase.
Related PDB
Related UniProtKB
[20]
Resource
Comments X-ray crystallography
Medline ID
PubMed ID 11256612
Journal EMBO Rep
Year 2000
Volume 1
Pages 277-81
Authors Fulop V, Szeltner Z, Polgar L
Title Catalysis of serine oligopeptidases is controlled by a gating filter mechanism.
Related PDB 1e5t
Related UniProtKB
[21]
Resource
Comments
Medline ID
PubMed ID 10747969
Journal J Biol Chem
Year 2000
Volume 275
Pages 15000-5
Authors Szeltner Z, Renner V, Polgar L
Title The noncatalytic beta-propeller domain of prolyl oligopeptidase enhances the catalytic capability of the peptidase domain.
Related PDB
Related UniProtKB
[22]
Resource
Comments
Medline ID
PubMed ID 10716187
Journal Protein Sci
Year 2000
Volume 9
Pages 353-60
Authors Szeltner Z, Renner V, Polgar L
Title Substrate- and pH-dependent contribution of oxyanion binding site to the catalysis of prolyl oligopeptidase, a paradigm of the serine oligopeptidase family.
Related PDB
Related UniProtKB
[23]
Resource
Comments
Medline ID
PubMed ID 11310664
Journal Chem Pharm Bull (Tokyo)
Year 2001
Volume 49
Pages 396-401
Authors Fan W, Tezuka Y, Ni KM, Kadota S
Title Prolyl endopeptidase inhibitors from the underground part of Rhodiola sachalinensis.
Related PDB
Related UniProtKB
[24]
Resource
Comments X-ray crystallography
Medline ID
PubMed ID 11031266
Journal J Biol Chem
Year 2001
Volume 276
Pages 1262-6
Authors Fulop V, Szeltner Z, Renner V, Polgar L
Title Structures of prolyl oligopeptidase substrate/inhibitor complexes. Use of inhibitor binding for titration of the catalytic histidine residue.
Related PDB 1e8m 1e8n
Related UniProtKB
[25]
Resource
Comments
Medline ID
PubMed ID 11598112
Journal J Biol Chem
Year 2001
Volume 276
Pages 47078-86
Authors Grellier P, Vendeville S, Joyeau R, Bastos IM, Drobecq H, Frappier F, Teixeira AR, Schrevel J, Davioud-Charvet E, Sergheraert C, Santana JM
Title Trypanosoma cruzi prolyl oligopeptidase Tc80 is involved in nonphagocytic mammalian cell invasion by trypomastigotes.
Related PDB
Related UniProtKB
[26]
Resource
Comments
Medline ID
PubMed ID 11278687
Journal J Biol Chem
Year 2001
Volume 276
Pages 19310-7
Authors Harris MN, Madura JD, Ming LJ, Harwood VJ
Title Kinetic and mechanistic studies of prolyl oligopeptidase from the hyperthermophile Pyrococcus furiosus.
Related PDB
Related UniProtKB
[27]
Resource
Comments
Medline ID
PubMed ID 12147298
Journal Biochem Pharmacol
Year 2002
Volume 64
Pages 463-71
Authors Venalainen JI, Juvonen RO, Forsberg MM, Garcia-Horsman A, Poso A, Wallen EA, Gynther J, Mannisto PT
Title Substrate-dependent, non-hyperbolic kinetics of pig brain prolyl oligopeptidase and its tight binding inhibition by JTP-4819.
Related PDB
Related UniProtKB
[28]
Resource
Comments
Medline ID
PubMed ID 11983517
Journal Bioorg Med Chem
Year 2002
Volume 10
Pages 2199-206
Authors Wallen EA, Christiaans JA, Saario SM, Forsberg MM, Venalainen JI, Paso HM, Mannisto PT, Gynther J
Title 4-Phenylbutanoyl-2(S)-acylpyrrolidines and 4-phenylbutanoyl-L-prolyl-2(S)-acylpyrrolidines as prolyl oligopeptidase inhibitors.
Related PDB
Related UniProtKB
[29]
Resource
Comments
Medline ID
PubMed ID 11915948
Journal Cell Mol Life Sci
Year 2002
Volume 59
Pages 349-62
Authors Polgar L
Title The prolyl oligopeptidase family.
Related PDB
Related UniProtKB
[30]
Resource
Comments
Medline ID
PubMed ID 11964000
Journal Chem Pharm Bull (Tokyo)
Year 2002
Volume 50
Pages 515-8
Authors Anis I, Ahmed S, Malik A, Yasin A, Choudary MI
Title Enzyme inhibitory constituents from Duranta repens.
Related PDB
Related UniProtKB
[31]
Resource
Comments
Medline ID
PubMed ID 12029050
Journal J Bacteriol
Year 2002
Volume 184
Pages 3329-37
Authors Morty RE, Fulop V, Andrews NW
Title Substrate recognition properties of oligopeptidase B from Salmonella enterica serovar Typhimurium.
Related PDB
Related UniProtKB
[32]
Resource
Comments
Medline ID
PubMed ID 12202494
Journal J Biol Chem
Year 2002
Volume 277
Pages 42613-22
Authors Szeltner Z, Rea D, Renner V, Fulop V, Polgar L
Title Electrostatic effects and binding determinants in the catalysis of prolyl oligopeptidase. Site specific mutagenesis at the oxyanion binding site.
Related PDB
Related UniProtKB
[33]
Resource
Comments
Medline ID
PubMed ID 12228249
Journal J Biol Chem
Year 2002
Volume 277
Pages 44597-605
Authors Szeltner Z, Rea D, Juhasz T, Renner V, Mucsi Z, Orosz G, Fulop V, Polgar L
Title Substrate-dependent competency of the catalytic triad of prolyl oligopeptidase.
Related PDB
Related UniProtKB
[34]
Resource
Comments
Medline ID
PubMed ID 11809072
Journal J Nat Prod
Year 2002
Volume 65
Pages 76-8
Authors Song KS, Raskin I
Title A prolyl endopeptidase-inhibiting benzofuran dimer from Polyozellus multiflex.
Related PDB
Related UniProtKB
[35]
Resource
Comments
Medline ID
PubMed ID 14514675
Journal J Biol Chem
Year 2003
Volume 278
Pages 48786-93
Authors Szeltner Z, Rea D, Renner V, Juliano L, Fulop V, Polgar L
Title Electrostatic environment at the active site of prolyl oligopeptidase is highly influential during substrate binding.
Related PDB
Related UniProtKB
[36]
Resource
Comments
Medline ID
PubMed ID 15210359
Journal J Mol Biol
Year 2004
Volume 340
Pages 627-37
Authors Szeltner Z, Rea D, Juhasz T, Renner V, Fulop V, Polgar L
Title Concerted structural changes in the peptidase and the propeller domains of prolyl oligopeptidase are required for substrate binding.
Related PDB
Related UniProtKB

Comments
This enzyme belongs to the peptidase family-S9A.
According to the literature [22] & [29], this enzyme has got a catalytic triad (Ser554, Asp641, His680) as in the classical serine proteases such as trypsin.
However, the oxyanion hole, which stabilizes the tetrahedral intermediate, is composed of the hydroxyl group of Tyr473 and mainchain amide group of Asn555 (see [29]).

Created Updated
2004-08-20 2011-02-18