DB code: D00210

RLCP classification	1.13.30000.13 : Hydrolysis
CATH domain	3.40.50.1820 : Rossmann fold	Catalytic domain
CATH 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 15377		7872 7872
PubChem	22247451 962 22247451 962		439302 439302

1e5tA01		Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Intermediate-analogue:GOL
1e8mA01		Unbound	Unbound	Unbound	Unbound	Analogue:PHQ-GLY-PRO (chain I)	Unbound	Unbound	Unbound
1e8nA01		Bound:GLY-PHE-GLY-PRO-PHE-GLY (chain I)	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound
1qfmA01		Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Intermediate-analogue:SGL
1qfsA01		Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Intermediate-analogue:ZPR
1e5tA02		Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound
1e8mA02		Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound
1e8nA02		Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound
1qfmA02		Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound	Unbound
1qfsA02		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	TYR 473;SER 554;ASP 641;HIS 680			ASN 555
1e8mA01	TYR 473;;ASP 641;HIS 680			ASN 555	mutant S554A
1e8nA01	TYR 473;;ASP 641;HIS 680			ASN 555	mutant S554A
1qfmA01	TYR 473;SER 554;ASP 641;HIS 680			ASN 555
1qfsA01	TYR 473;SER 554;ASP 641;HIS 680			ASN 555
1e5tA02
1e8mA02
1e8nA02
1qfmA02
1qfsA02

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