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PDBsum entry 1apy

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Hydrolase PDB id
1apy
Jmol
Contents
Protein chains
161 a.a. *
141 a.a. *
Ligands
NAG ×3
NAG-NAG-BMA
Waters ×237
* Residue conservation analysis
PDB id:
1apy
Name: Hydrolase
Title: Human aspartylglucosaminidase
Structure: Aspartylglucosaminidase. Chain: a, c. Synonym: aga, glycosylasparaginase. Aspartylglucosaminidase. Chain: b, d. Synonym: aga, glycosylasparaginase. Ec: 3.5.1.26
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell: leukocyte. Cell: leukocyte
Biol. unit: Tetramer (from PQS)
Resolution:
2.00Å     R-factor:   0.169     R-free:   0.224
Authors: J.Rouvinen,C.Oinonen
Key ref: C.Oinonen et al. (1995). Three-dimensional structure of human lysosomal aspartylglucosaminidase. Nat Struct Biol, 2, 1102-1108. PubMed id: 8846222
Date:
14-Jun-95     Release date:   23-Dec-96    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P20933  (ASPG_HUMAN) -  N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase
Seq:
Struc:
346 a.a.
161 a.a.*
Protein chains
Pfam   ArchSchema ?
P20933  (ASPG_HUMAN) -  N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase
Seq:
Struc:
346 a.a.
141 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chains A, B, C, D: E.C.3.5.1.26  - N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: N4-(beta-N-acetyl-D-glucosaminyl)-L-asparagine + H2O = N-acetyl-beta- D-glucosaminylamine + L-aspartate
N(4)-(beta-N-acetyl-D-glucosaminyl)-L-asparagine
+ H(2)O
=
N-acetyl-beta- D-glucosaminylamine
Bound ligand (Het Group name = NAG)
matches with 93.33% similarity
+ L-aspartate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biochemical function     hydrolase activity     1 term  

 

 
    reference    
 
 
Nat Struct Biol 2:1102-1108 (1995)
PubMed id: 8846222  
 
 
Three-dimensional structure of human lysosomal aspartylglucosaminidase.
C.Oinonen, R.Tikkanen, J.Rouvinen, L.Peltonen.
 
  ABSTRACT  
 
The high resolution crystal structure of human lysosomal aspartylglucosaminidase (AGA) has been determined. This lysosomal enzyme is synthesized as a single polypeptide precursor, which is immediately post-translationally cleaved into alpha- and beta-subunits. Two alpha- and beta-chains are found to pack together forming the final heterotetrameric structure. The catalytically essential residue, the N-terminal threonine of the beta-chain is situated in the deep pocket of the funnel-shaped active site. On the basis of the structure of the enzyme-product complex we present a catalytic mechanism for this lysosomal enzyme with an exceptionally high pH optimum. The three-dimensional structure also allows the prediction of the structural consequences of human mutations resulting in aspartylglucosaminuria (AGU), a lysosomal storage disease.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20088880 K.Wada, M.Irie, H.Suzuki, and K.Fukuyama (2010).
Crystal structure of the halotolerant gamma-glutamyltranspeptidase from Bacillus subtilis in complex with glutamate reveals a unique architecture of the solvent-exposed catalytic pocket.
  FEBS J, 277, 1000-1009.
PDB code: 3a75
19476497 D.Zhiryakova, I.Ivanov, S.Ilieva, M.Guncheva, B.Galunsky, and N.Stambolieva (2009).
Do N-terminal nucleophile hydrolases indeed have a single amino acid catalytic center?
  FEBS J, 276, 2589-2598.  
19839645 J.R.Cantor, E.M.Stone, L.Chantranupong, and G.Georgiou (2009).
The human asparaginase-like protein 1 hASRGL1 is an Ntn hydrolase with beta-aspartyl peptidase activity.
  Biochemistry, 48, 11026-11031.  
19706171 K.Lakomek, A.Dickmanns, M.Kettwig, H.Urlaub, R.Ficner, and T.Lübke (2009).
Initial insight into the function of the lysosomal 66.3 kDa protein from mouse by means of X-ray crystallography.
  BMC Struct Biol, 9, 56.
PDB codes: 3fgr 3fgt 3fgw
18334484 K.Michalska, A.Hernandez-Santoyo, and M.Jaskolski (2008).
The mechanism of autocatalytic activation of plant-type L-asparaginases.
  J Biol Chem, 283, 13388-13397.
PDB code: 3c17
18323626 K.Michalska, D.Borek, A.Hernández-Santoyo, and M.Jaskolski (2008).
Crystal packing of plant-type L-asparaginase from Escherichia coli.
  Acta Crystallogr D Biol Crystallogr, 64, 309-320.
PDB codes: 1jn9 1k2x 2zak
17565660 A.Lyly, C.von Schantz, T.Salonen, O.Kopra, J.Saarela, M.Jauhiainen, A.Kyttälä, and A.Jalanko (2007).
Glycosylation, transport, and complex formation of palmitoyl protein thioesterase 1 (PPT1)--distinct characteristics in neurons.
  BMC Cell Biol, 8, 22.  
17107958 G.Boanca, A.Sand, T.Okada, H.Suzuki, H.Kumagai, K.Fukuyama, and J.J.Barycki (2007).
Autoprocessing of Helicobacter pylori gamma-glutamyltranspeptidase leads to the formation of a threonine-threonine catalytic dyad.
  J Biol Chem, 282, 534-541.
PDB code: 2nqo
17620333 J.Q.Davies, G.W.Chang, S.Yona, S.Gordon, M.Stacey, and H.H.Lin (2007).
The role of receptor oligomerization in modulating the expression and function of leukocyte adhesion-G protein-coupled receptors.
  J Biol Chem, 282, 27343-27353.  
17157318 Y.Wang, and H.C.Guo (2007).
Crystallographic snapshot of a productive glycosylasparaginase-substrate complex.
  J Mol Biol, 366, 82-92.
PDB code: 2gl9
17008720 J.Wang, and E.R.Kantrowitz (2006).
Trapping the tetrahedral intermediate in the alkaline phosphatase reaction by substitution of the active site serine with threonine.
  Protein Sci, 15, 2395-2401.
PDB codes: 2g9y 2ga3
16756505 N.G.Richards, and M.S.Kilberg (2006).
Asparagine synthetase chemotherapy.
  Annu Rev Biochem, 75, 629-654.  
16618936 T.Okada, H.Suzuki, K.Wada, H.Kumagai, and K.Fukuyama (2006).
Crystal structures of gamma-glutamyltranspeptidase from Escherichia coli, a key enzyme in glutathione metabolism, and its reaction intermediate.
  Proc Natl Acad Sci U S A, 103, 6471-6476.
PDB codes: 2dbu 2dbw 2dbx 2dg5
15987679 F.Levitin, O.Stern, M.Weiss, C.Gil-Henn, R.Ziv, Z.Prokocimer, N.I.Smorodinsky, D.B.Rubinstein, and D.H.Wreschner (2005).
The MUC1 SEA module is a self-cleaving domain.
  J Biol Chem, 280, 33374-33386.  
15946951 K.Michalska, K.Brzezinski, and M.Jaskolski (2005).
Crystal structure of isoaspartyl aminopeptidase in complex with L-aspartate.
  J Biol Chem, 280, 28484-28491.
PDB codes: 1seo 2zal
15159592 A.Prahl, M.Pazgier, M.Hejazi, W.Lockau, and J.Lubkowski (2004).
Structure of the isoaspartyl peptidase with L-asparaginase activity from Escherichia coli.
  Acta Crystallogr D Biol Crystallogr, 60, 1173-1176.
PDB code: 1t3m
15265041 D.Borek, K.Michalska, K.Brzezinski, A.Kisiel, J.Podkowinski, D.T.Bonthron, D.Krowarsch, J.Otlewski, and M.Jaskolski (2004).
Expression, purification and catalytic activity of Lupinus luteus asparagine beta-amidohydrolase and its Escherichia coli homolog.
  Eur J Biochem, 271, 3215-3226.  
15150276 H.H.Lin, G.W.Chang, J.Q.Davies, M.Stacey, J.Harris, and S.Gordon (2004).
Autocatalytic cleavage of the EMR2 receptor occurs at a conserved G protein-coupled receptor proteolytic site motif.
  J Biol Chem, 279, 31823-31832.  
14633979 F.Schmitzberger, M.L.Kilkenny, C.M.Lobley, M.E.Webb, M.Vinkovic, D.Matak-Vinkovic, M.Witty, D.Y.Chirgadze, A.G.Smith, C.Abell, and T.L.Blundell (2003).
Structural constraints on protein self-processing in L-aspartate-alpha-decarboxylase.
  EMBO J, 22, 6193-6204.
PDB codes: 1ppy 1pqe 1pqf 1pqh 1pt0 1pt1 1pyq 1pyu
12717035 J.Pei, and N.V.Grishin (2003).
Peptidase family U34 belongs to the superfamily of N-terminal nucleophile hydrolases.
  Protein Sci, 12, 1131-1135.  
12672453 M.Groll, and R.Huber (2003).
Substrate access and processing by the 20S proteasome core particle.
  Int J Biochem Cell Biol, 35, 606-616.  
12797112 S.Harkke, M.Laine, and A.Jalanko (2003).
Aspartylglucosaminidase (AGA) is efficiently produced and endocytosed by glial cells: implication for the therapy of a lysosomal storage disorder.
  J Gene Med, 5, 472-482.  
12433919 Y.Wang, and H.C.Guo (2003).
Two-step dimerization for autoproteolysis to activate glycosylasparaginase.
  J Biol Chem, 278, 3210-3219.  
11984834 L.A.Bush, J.C.Herr, M.Wolkowicz, N.E.Sherman, A.Shore, and C.J.Flickinger (2002).
A novel asparaginase-like protein is a sperm autoantigen in rats.
  Mol Reprod Dev, 62, 233-247.  
11410931 J.Myung, K.B.Kim, and C.M.Crews (2001).
The ubiquitin-proteasome pathway and proteasome inhibitors.
  Med Res Rev, 21, 245-273.  
11179218 M.S.Kang, B.K.Lim, I.S.Seong, J.H.Seol, N.Tanahashi, K.Tanaka, and C.H.Chung (2001).
The ATP-dependent CodWX (HslVU) protease in Bacillus subtilis is an N-terminal serine protease.
  EMBO J, 20, 734-742.  
11325937 R.A.Larsen, T.M.Knox, and C.G.Miller (2001).
Aspartic peptide hydrolases in Salmonella enterica serovar typhimurium.
  J Bacteriol, 183, 3089-3097.  
10809725 A.F.Kisselev, Z.Songyang, and A.L.Goldberg (2000).
Why does threonine, and not serine, function as the active site nucleophile in proteasomes?
  J Biol Chem, 275, 14831-14837.  
  11206054 C.Oinonen, and J.Rouvinen (2000).
Structural comparison of Ntn-hydrolases.
  Protein Sci, 9, 2329-2337.  
10869181 M.Inoue, J.Hiratake, H.Suzuki, H.Kumagai, and K.Sakata (2000).
Identification of catalytic nucleophile of Escherichia coli gamma-glutamyltranspeptidase by gamma-monofluorophosphono derivative of glutamic acid: N-terminal thr-391 in small subunit is the nucleophile.
  Biochemistry, 39, 7764-7771.  
10410804 M.Bochtler, L.Ditzel, M.Groll, C.Hartmann, and R.Huber (1999).
The proteasome.
  Annu Rev Biophys Biomol Struct, 28, 295-317.  
10571008 N.N.Aronson (1999).
Aspartylglycosaminuria: biochemistry and molecular biology.
  Biochim Biophys Acta, 1455, 139-154.  
10490104 Q.Xu, D.Buckley, C.Guan, and H.C.Guo (1999).
Structural insights into the mechanism of intramolecular proteolysis.
  Cell, 98, 651-661.
PDB codes: 9gaa 9gac 9gaf
  10049369 S.Li, J.L.Smith, and H.Zalkin (1999).
Mutational analysis of Bacillus subtilis glutamine phosphoribosylpyrophosphate amidotransferase propeptide processing.
  J Bacteriol, 181, 1403-1408.  
10411632 Y.Li, J.Chen, W.Jiang, X.Mao, G.Zhao, and E.Wang (1999).
In vivo post-translational processing and subunit reconstitution of cephalosporin acylase from Pseudomonas sp. 130.
  Eur J Biochem, 262, 713-719.  
9545304 C.Guan, Y.Liu, Y.Shao, T.Cui, W.Liao, A.Ewel, R.Whitaker, and H.Paulus (1998).
Characterization and functional analysis of the cis-autoproteolysis active center of glycosylasparaginase.
  J Biol Chem, 273, 9695-9702.  
9685368 H.C.Guo, Q.Xu, D.Buckley, and C.Guan (1998).
Crystal structures of Flavobacterium glycosylasparaginase. An N-terminal nucleophile hydrolase activated by intramolecular proteolysis.
  J Biol Chem, 273, 20205-20212.
PDB codes: 2gac 2gaw
9914248 J.L.Smith (1998).
Glutamine PRPP amidotransferase: snapshots of an enzyme in action.
  Curr Opin Struct Biol, 8, 686-694.  
9737998 J.Saarela, M.Laine, R.Tikkanen, C.Oinonen, A.Jalanko, J.Rouvinen, and L.Peltonen (1998).
Activation and oligomerization of aspartylglucosaminidase.
  J Biol Chem, 273, 25320-25328.  
  9541410 J.Xuan, A.L.Tarentino, B.G.Grimwood, T.H.Plummer, T.Cui, C.Guan, and P.Van Roey (1998).
Crystal structure of glycosylasparaginase from Flavobacterium meningosepticum.
  Protein Sci, 7, 774-781.
PDB code: 1ayy
9437427 T.Klabunde, S.Sharma, A.Telenti, W.R.Jacobs, and J.C.Sacchettini (1998).
Crystal structure of GyrA intein from Mycobacterium xenopi reveals structural basis of protein splicing.
  Nat Struct Biol, 5, 31-36.
PDB code: 1am2
9756857 T.Noronkoski, I.B.Stoineva, I.P.Ivanov, D.D.Petkov, and I.Mononen (1998).
Glycosylasparaginase-catalyzed synthesis and hydrolysis of beta-aspartyl peptides.
  J Biol Chem, 273, 26295-26297.  
  9562523 L.Peltonen (1997).
Molecular background of the Finnish disease heritage.
  Ann Med, 29, 553-556.  
9362483 R.Tikkanen, M.Peltola, C.Oinonen, J.Rouvinen, and L.Peltonen (1997).
Several cooperating binding sites mediate the interaction of a lysosomal enzyme with phosphotransferase.
  EMBO J, 16, 6684-6693.  
9094332 W.Baumeister, and A.Lupas (1997).
The proteasome.
  Curr Opin Struct Biol, 7, 273-278.  
9115411 Y.Shao, and S.B.Kent (1997).
Protein splicing: occurrence, mechanisms and related phenomena.
  Chem Biol, 4, 187-194.  
8804825 A.G.Murzin (1996).
Structural classification of proteins: new superfamilies.
  Curr Opin Struct Biol, 6, 386-394.  
8702913 A.Riikonen, J.Rouvinen, R.Tikkanen, I.Julkunen, L.Peltonen, and A.Jalanko (1996).
Primary folding of aspartylglucosaminidase. Significance of disulfide bridges and evidence of early multimerization.
  J Biol Chem, 271, 21340-21344.  
8663035 J.H.Kim, J.M.Krahn, D.R.Tomchick, J.L.Smith, and H.Zalkin (1996).
Structure and function of the glutamine phosphoribosylpyrophosphate amidotransferase glutamine site and communication with the phosphoribosylpyrophosphate site.
  J Biol Chem, 271, 15549-15557.
PDB code: 1ecg
  8670796 R.Tikkanen, A.Riikonen, C.Oinonen, R.Rouvinen, and L.Peltonen (1996).
Functional analyses of active site residues of human lysosomal aspartylglucosaminidase: implications for catalytic mechanism and autocatalytic activation.
  EMBO J, 15, 2954-2960.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.