EzCatDB: M00174
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DB codeM00174
RLCP classification1.13.30010.35 : Hydrolysis
CATH domainDomain 13.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1
Domain 23.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1
Domain 33.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1
Domain 43.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1
Domain 53.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1
Domain 63.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1
Domain 73.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1
Domain 83.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1
Domain 93.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1
Domain 103.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1
Domain 113.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1
Domain 123.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1
Domain 133.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1
Domain 143.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1
Domain 153.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1Catalytic domain
Domain 163.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1Catalytic domain
Domain 173.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1Catalytic domain
Domain 183.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1Catalytic domain
Domain 193.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1Catalytic domain
Domain 203.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1Catalytic domain
Domain 213.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1Catalytic domain
Domain 223.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1Catalytic domain
Domain 233.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1Catalytic domain
Domain 243.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1Catalytic domain
Domain 253.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1Catalytic domain
Domain 263.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1Catalytic domain
Domain 273.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1Catalytic domain
Domain 283.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1Catalytic domain
E.C.3.4.25.1
CSA1pma

CATH domainRelated DB codes (homologues)
3.60.20.10 : Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1T00201,M00123,D00300

Enzyme Name
UniProtKBKEGG

P25156P28061
Protein nameProteasome subunit alphaProteasome subunit betaproteasome endopeptidase complex
ingensin
macropain
multicatalytic endopeptidase complex
prosome
multicatalytic proteinase (complex)
MCP
proteasome
large multicatalytic protease
multicatalytic proteinase
proteasome organelle
alkaline protease
26S protease
tricorn proteinase
tricorn protease
SynonymsEC 3.4.25.1
Multicatalytic endopeptidase complex subunit alpha
EC 3.4.25.1
Multicatalytic endopeptidase complex subunit beta
RefSeqNP_394744.1 (Protein)
NC_002578.1 (DNA/RNA sequence)
NP_394085.1 (Protein)
NC_002578.1 (DNA/RNA sequence)
MEROPS
T01.002 (Threonine)
PfamPF00227 (Proteasome)
PF10584 (Proteasome_A_N)
[Graphical view]
PF00227 (Proteasome)
[Graphical view]


UniProtKB:Accession NumberP25156P28061
Entry namePSMA_THEACPSMB_THEAC
ActivityCleavage of peptide bonds with very broad specificity.Cleavage of peptide bonds with very broad specificity.
SubunitComposed of two subunits, alpha and beta. The complex is formed of four rings. The two outer rings are each composed of seven alpha subunits. The two inner rings are each composed of seven beta subunits.Composed of two subunits, alpha and beta. The complex is formed of four rings. The two outer rings are each composed of seven alpha subunits. The two inner rings are each composed of seven beta subunits.
Subcellular locationCytoplasm.Cytoplasm.
Cofactor


Compound table: links to PDB-related databases & PoSSuM

SubstratesProducts
KEGG-idC00017C00012C00001C00017C00012
CompoundProteinPeptideH2OProteinPeptide
Typepeptide/proteinpeptide/proteinH2Opeptide/proteinpeptide/protein
ChEBI

15377


PubChem

962
22247451


             
1pmaAUnboundUnbound UnboundUnbound
1pmaCUnboundUnbound UnboundUnbound
1pmaDUnboundUnbound UnboundUnbound
1pmaEUnboundUnbound UnboundUnbound
1pmaFUnboundUnbound UnboundUnbound
1pmaGUnboundUnbound UnboundUnbound
1pmaHUnboundUnbound UnboundUnbound
1pmaIUnboundUnbound UnboundUnbound
1pmaJUnboundUnbound UnboundUnbound
1pmaKUnboundUnbound UnboundUnbound
1pmaLUnboundUnbound UnboundUnbound
1pmaMUnboundUnbound UnboundUnbound
1pmaNUnboundUnbound UnboundUnbound
1pmaOUnboundUnbound UnboundUnbound
1ya7AUnboundUnbound UnboundUnbound
1ya7BUnboundUnbound UnboundUnbound
1ya7CUnboundUnbound UnboundUnbound
1ya7DUnboundUnbound UnboundUnbound
1ya7EUnboundUnbound UnboundUnbound
1ya7FUnboundUnbound UnboundUnbound
1ya7GUnboundUnbound UnboundUnbound
1yarAUnboundUnbound UnboundUnbound
1yarBUnboundUnbound UnboundUnbound
1yarCUnboundUnbound UnboundUnbound
1yarDUnboundUnbound UnboundUnbound
1yarEUnboundUnbound UnboundUnbound
1yarFUnboundUnbound UnboundUnbound
1yarGUnboundUnbound UnboundUnbound
1yauAUnboundUnbound UnboundUnbound
1yauBUnboundUnbound UnboundUnbound
1yauCUnboundUnbound UnboundUnbound
1yauDUnboundUnbound UnboundUnbound
1yauEUnboundUnbound UnboundUnbound
1yauFUnboundUnbound UnboundUnbound
1yauGUnboundUnbound UnboundUnbound
1pmaBUnboundUnbound UnboundUnbound
1pmaPUnboundUnbound UnboundUnbound
1pmaQUnboundUnbound UnboundUnbound
1pmaRUnboundUnbound UnboundUnbound
1pmaSUnboundUnbound UnboundUnbound
1pmaTUnboundUnbound UnboundUnbound
1pmaUUnboundUnbound UnboundUnbound
1pmaVUnboundUnbound UnboundUnbound
1pmaWUnboundUnbound UnboundUnbound
1pmaXUnboundUnbound UnboundUnbound
1pmaYUnboundUnbound UnboundUnbound
1pmaZUnboundUnbound UnboundUnbound
1pma1UnboundUnbound UnboundUnbound
1pma2UnboundUnbound UnboundUnbound
1ya7HUnboundUnbound UnboundUnbound
1ya7IUnboundUnbound UnboundUnbound
1ya7JUnboundUnbound UnboundUnbound
1ya7KUnboundUnbound UnboundUnbound
1ya7LUnboundUnbound UnboundUnbound
1ya7MUnboundUnbound UnboundUnbound
1ya7NUnboundUnbound UnboundUnbound
1yarHUnboundUnbound UnboundUnbound
1yarIUnboundUnbound UnboundUnbound
1yarJUnboundUnbound UnboundUnbound
1yarKUnboundUnbound UnboundUnbound
1yarLUnboundUnbound UnboundUnbound
1yarMUnboundUnbound UnboundUnbound
1yarNUnboundUnbound UnboundUnbound
1yauHUnboundUnbound UnboundUnbound
1yauIUnboundUnbound UnboundUnbound
1yauJUnboundUnbound UnboundUnbound
1yauKUnboundUnbound UnboundUnbound
1yauLUnboundUnbound UnboundUnbound
1yauMUnboundUnbound UnboundUnbound
1yauNUnboundUnbound UnboundUnbound

Active-site residues
pdbCatalytic residuesMain-chain involved in catalysis
          
1pmaA 
 
1pmaC 
 
1pmaD 
 
1pmaE 
 
1pmaF 
 
1pmaG 
 
1pmaH 
 
1pmaI 
 
1pmaJ 
 
1pmaK 
 
1pmaL 
 
1pmaM 
 
1pmaN 
 
1pmaO 
 
1ya7A 
 
1ya7B 
 
1ya7C 
 
1ya7D 
 
1ya7E 
 
1ya7F 
 
1ya7G 
 
1yarA 
 
1yarB 
 
1yarC 
 
1yarD 
 
1yarE 
 
1yarF 
 
1yarG 
 
1yauA 
 
1yauB 
 
1yauC 
 
1yauD 
 
1yauE 
 
1yauF 
 
1yauG 
 
1pmaBTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1pmaPTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1pmaQTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1pmaRTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1pmaSTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1pmaTTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1pmaUTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1pmaVTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1pmaWTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1pmaXTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1pmaYTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1pmaZTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1pma1THR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1pma2THR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1ya7HTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1ya7ITHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1ya7JTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1ya7KTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1ya7LTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1ya7MTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1ya7NTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1yarHTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1yarITHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1yarJTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1yarKTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1yarLTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1yarMTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1yarNTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1yauHTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1yauITHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1yauJTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1yauKTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1yauLTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1yauMTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47
1yauNTHR 1;GLU 17;LYS 33;ASP 166
THR 1;GLY 47

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[3]Fig.4, p.517-519
[4]Fig.5A, p.529-530
[11]p.418
[13]p.381-382
[16]p.275-276
[18]Fig.2, p.4-5
[19]p.840-841
[20]Fig.2

references
[1]
PubMed ID7697124
JournalEnzyme Protein
Year1993
Volume47
Pages252-73
AuthorsLupas A, Koster AJ, Baumeister W
TitleStructural features of 26S and 20S proteasomes.
[2]
PubMed ID7697123
JournalEnzyme Protein
Year1993
Volume47
Pages241-51
AuthorsTanahashi N, Tsurumi C, Tamura T, Tanaka K
TitleMolecular structure of 20S and 26S proteasomes.
[3]
PubMed ID8824424
JournalCold Spring Harb Symp Quant Biol
Year1995
Volume60
Pages515-24
AuthorsLupas A, Zwickl P, Wenzel T, Seemuller E, Baumeister W
TitleStructure and function of the 20S proteasome and of its regulatory complexes.
[4]
PubMed ID8824425
JournalCold Spring Harb Symp Quant Biol
Year1995
Volume60
Pages525-32
AuthorsStock D, Ditzel L, Baumeister W, Huber R, Lowe J
TitleCatalytic mechanism of the 20S proteasome of Thermoplasma acidophilum revealed by X-ray crystallography.
[5]
PubMed ID7867793
JournalFEBS Lett
Year1995
Volume359
Pages173-8
AuthorsSeemuller E, Lupas A, Zuhl F, Zwickl P, Baumeister W
TitleThe proteasome from Thermoplasma acidophilum is neither a cysteine nor a serine protease.
[6]
PubMed ID7565658
JournalMol Biol Rep
Year1995
Volume21
Pages11-20
AuthorsKoster AJ, Walz J, Lupas A, Baumeister W
TitleStructural features of archaebacterial and eukaryotic proteasomes.
[7]
PubMed ID7477383
JournalNature
Year1995
Volume378
Pages416-9
AuthorsBrannigan JA, Dodson G, Duggleby HJ, Moody PC, Smith JL, Tomchick DR, Murzin AG
TitleA protein catalytic framework with an N-terminal nucleophile is capable of self-activation.
[8]
PubMed ID7725095
JournalScience
Year1995
Volume268
Pages522-3
AuthorsGoldberg AL
TitleFunctions of the proteasome: the lysis at the end of the tunnel.
[9]
PubMed ID7725097
JournalScience
Year1995
Volume268
Pages533-9
AuthorsLowe J, Stock D, Jap B, Zwickl P, Baumeister W, Huber R
TitleCrystal structure of the 20S proteasome from the archaeon T. acidophilum at 3.4 A resolution.
Related PDB1pma
[10]
PubMed ID7725107
JournalScience
Year1995
Volume268
Pages579-82
AuthorsSeemuller E, Lupas A, Stock D, Lowe J, Huber R, Baumeister W
TitleProteasome from Thermoplasma acidophilum: a threonine protease.
[11]
PubMed ID7663937
JournalStructure
Year1995
Volume3
Pages417-20
AuthorsWlodawer A
TitleProteasome: a complex protease with a new fold and a distinct mechanism.
[12]
PubMed ID8811196
JournalAnnu Rev Biochem
Year1996
Volume65
Pages801-47
AuthorsCoux O, Tanaka K, Goldberg AL
TitleStructure and functions of the 20S and 26S proteasomes.
[13]
PubMed ID8768894
JournalCurr Opin Biotechnol
Year1996
Volume7
Pages376-85
AuthorsStock D, Nederlof PM, Seemuller E, Baumeister W, Huber R, Lowe J
TitleProteasome: from structure to function.
[14]
PubMed ID8684489
JournalNature
Year1996
Volume382
Pages468-71
AuthorsSeemuller E, Lupas A, Baumeister W
TitleAutocatalytic processing of the 20S proteasome.
[15]
PubMed ID9377486
JournalBiol Chem
Year1997
Volume378
Pages893-8
AuthorsEscherich A, Ditzel L, Musiol HJ, Groll M, Huber R, Moroder L
TitleSynthesis, kinetic characterization and X-ray analysis of peptide aldehydes as inhibitors of the 20S proteasomes from Thermoplasma acidophilum and Saccharomyces cerevisiae.
[16]
PubMed ID9094332
JournalCurr Opin Struct Biol
Year1997
Volume7
Pages273-8
AuthorsBaumeister W, Lupas A
TitleThe proteasome.
[17]
PubMed ID9334174
JournalJ Biol Chem
Year1997
Volume272
Pages26103-9
AuthorsMc Cormack T, Baumeister W, Grenier L, Moomaw C, Plamondon L, Pramanik B, Slaughter C, Soucy F, Stein R, Zuhl F, Dick L
TitleActive site-directed inhibitors of Rhodococcus 20 S proteasome. Kinetics and mechanism.
[18]
PubMed ID11097171
JournalArch Biochem Biophys
Year2000
Volume383
Pages1-16
AuthorsOrlowski M, Wilk S
TitleCatalytic activities of the 20 S proteasome, a multicatalytic proteinase complex.
[19]
PubMed ID10966872
JournalFront Biosci
Year2000
Volume5
PagesD837-65
AuthorsMaupin-Furlow JA, Wilson HL, Kaczowka SJ, Ou MS
TitleProteasomes in the archaea: from structure to function.
[20]
PubMed ID10809725
JournalJ Biol Chem
Year2000
Volume275
Pages14831-7
AuthorsKisselev AF, Songyang Z, Goldberg AL
TitleWhy does threonine, and not serine, function as the active site nucleophile in proteasomes?
[21]
PubMed ID10843865
JournalJ Mol Biol
Year2000
Volume299
Pages1147-54
AuthorsGille C, Goede A, Preissner R, Rother K, Frommel C
TitleConservation of substructures in proteins: interfaces of secondary structural elements in proteasomal subunits.
[22]
PubMed ID12083009
JournalCurr Top Microbiol Immunol
Year2002
Volume268
Pages73-89
AuthorsHill CP, Masters EI, Whitby FG
TitleThe 11S regulators of 20S proteasome activity.
[23]
PubMed ID12083007
JournalCurr Top Microbiol Immunol
Year2002
Volume268
Pages23-41
AuthorsZwickl P
TitleThe 20S proteasome.
[24]
PubMed ID12354607
JournalFEBS Lett
Year2002
Volume529
Pages22-6
AuthorsDantuma NP, Masucci MG
TitleStabilization signals: a novel regulatory mechanism in the ubiquitin/proteasome system.
[25]
PubMed ID12941688
JournalEMBO J
Year2003
Volume22
Pages4356-64
AuthorsForster A, Whitby FG, Hill CP
TitleThe pore of activated 20S proteasomes has an ordered 7-fold symmetric conformation.
[26]
PubMed ID12614609
JournalJ Mol Biol
Year2003
Volume327
Pages75-83
AuthorsGroll M, Brandstetter H, Bartunik H, Bourenkow G, Huber R
TitleInvestigations on the maturation and regulation of archaebacterial proteasomes.
[27]
PubMed ID15916965
JournalMol Cell
Year2005
Volume18
Pages589-99
AuthorsForster A, Masters EI, Whitby FG, Robinson H, Hill CP
TitleThe 1.9 A structure of a proteasome-11S activator complex and implications for proteasome-PAN/PA700 interactions.
Related PDB1ya7,1yar,1yau

comments
This enzyme was transferred from E.C. 3.4.99.46 to E.C. 3.4.25.1.
The structure of this enzyme is cylindrical with four layers of seven subunits, composed of two different subunits, alpha and beta. All the alpha subunits are enzymatically inactive, whereas the beta-subunits exhibit proteolytic activity. Alpha- and beta-subunits belong to peptidase family-T1A and -T1B, respectively.
According to the literature [18], this enzyme has got a similar mechanism to that of its counterpart in yeast (M00123 in EzCatDB).
(1) Alpha-amino group of Thr1 acts as a general base to activate the nucleophile, sidechain of Thr1, through a water molecule (NUK). At the same time, Lys33, which is modulated by Glu17, might modulate or stabilize the nucleophilicity of Thr1.
(2) Thr1 makes a nucleophilic attack on the carbonyl carbon of the target peptide bond, forming a tetrahedral (hemiacetal) transition-state.
(3) The alpha-amino group of Thr1 acts as a general acid to protonate the leaving group, giving a carbonyl intermediate through a water. The intermediate might be stabilized by an oxyanion hole, composed of the sidechain of Lys33 and mainchain amide of Gly47.
(4) Alpha-amino group of Thr1 acts as a general base to activate the NUK water, through another water, which completes hydrolysis.
###
Autocatalysis, in which Thr1 acts as a nucleophile and Ser129 forms an oxyanion hole, activates the catalytic site of this enzyme (see [14]).

createdupdated
2002-07-012010-02-03


Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
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