M00314
type: Enzyme
rlcp: p482
cath: 7-stranded beta/alpha barrel
cath: http://ezcatdb.cbrc.jp/EzCatDB/cath/1.-.-.-
cath: Immunoglobulin-like
cath: Beta-galactosidase; Chain A, domain 5
ec: https://purl.uniprot.org/enzyme/3.2.1.24
uniprot: Q99YP5
uniprot: Q29451
kegg enzyme: Alpha-mannosidase
kegg enzyme: Alpha-D-mannosidase
kegg enzyme: p-Nitrophenyl-alpha-mannosidase
kegg enzyme: Alpha-D-mannopyranosidase
kegg enzyme: 1,2-Alpha-mannosidase
kegg enzyme: 1,2-Alpha-D-mannosidase
kegg enzyme: Exo-alpha-mannosidase
kegg pathway: N-Glycan degradation
kegg cofactor: Zinc
kegg substrate: alpha-D-Mannoside
kegg substrate: H2O
kegg product: alpha-D-Mannoside
kegg product: alpha-D-Mannose
pdb: 2wyhA01
pdb: 2wyhB01
pdb: 2wyiA01
pdb: 2wyiB01
pdb: 1o7dA
pdb: 1o7dB
pdb: 2wyhA02
pdb: 2wyhB02
pdb: 2wyiA02
pdb: 2wyiB02
pdb: 1o7dC01
pdb: 2wyhA03
pdb: 2wyhB03
pdb: 2wyiA03
pdb: 2wyiB03
pdb: 1o7dC02
pdb: 2wyhA04
pdb: 2wyhB04
pdb: 2wyiA04
pdb: 2wyiB04
pdb: 1o7dD
pdb: 2wyhA05
pdb: 2wyhB05
pdb: 2wyiA05
pdb: 2wyiB05
pdb: 1o7dE
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 2wyhA01
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 2wyhB01
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 2wyiA01
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 2wyiB01
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 1o7dA
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 1o7dB
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 2wyhA02
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 2wyhB02
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 2wyiA02
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 2wyiB02
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 1o7dC01
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 2wyhA03
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 2wyhB03
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 2wyiA03
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 2wyiB03
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 1o7dC02
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 2wyhA04
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 2wyhB04
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 2wyiA04
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 2wyiB04
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 1o7dD
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 2wyhA05
pdb bound state: Unbound
  compound: alpha-D-Mannoside
  pdb: 2wyhB05
active site residues resources: Structure and kinetic investigation of Streptococcus pyogenes family GH38 alpha-mannosidase.
active site residues resources: http://ezcatdb.cbrc.jp/EzCatDB/reference/M00314#5
active site residues resources: Q29451
references: Human lysosomal and jack bean alpha-mannosidases are retaining glycosidases.
references: Identification of Asp197 as the catalytic nucleophile in the family 38 alpha-mannosidase from bovine kidney lysosomes.
references: The structure of bovine lysosomal alpha-mannosidase suggests a novel mechanism for low-pH activation.
references: Structure and kinetic investigation of Streptococcus pyogenes family GH38 alpha-mannosidase.
comment: This enzyme belongs to glycosyl hydrolase family-38. Although the nucleophilic residue, Asp125 (of 2wyh), is bound to zinc ion in the apo enzyme, it does not seem to be bound to the zinc ion while the substrate/product is bound to the active site on this enzyme. During the reaction, the zinc ion is bound to the hydroxyl groups of the mannoside, as well as to His13 and Asp15. Thus, the reaction of this enzyme proceeds as follows (see [3] & [4]): (0) Arg149 and Tyr192 modulate the activity of the nucleophilic residue, Asp125, by interacting with it. (1) Asp232 acts as a general acid to protonate the oxygen atom of the leaving group, leading to the formation of oxocarbenium-ion like transition-state (in a 1S5 skew-boat conformation). Here, the skew-boat conformation of the transition-state seems to be stabilized by the zinc ion, which is bound to His13 and Asp15. (2) Asp125 makes a nucleophilic attack on the C1 atom of the alpha-mannoside in the oxocarbenium-ion like transition-state, forming a covalent glycosyl-enzyme intermediate. (This nucleophilic substitution seems to be SN1-like raction.) (3) Asp232 now acts as a general base to activate a water molecule. The activated water makes a nucleophilic attack on the glycosyl-enzyme intermediate, leading to the formation of oxocarbenium-ion like transition-state. The transition-state is also stabilized by the zinc ion. (4) Finally, the bond between the alpha-mannose and Asp125 is cleaved, while the bond between the alpha-mannose and the activated water is formed, to complete the reaction.

7-stranded beta/alpha barrel
type: Cath
references: http://www.cathdb.info/version/latest/superfamily/3.20.110.10
catalytic domain: index.html

Immunoglobulin-like
type: Cath
references: http://www.cathdb.info/version/latest/superfamily/2.60.40.1180

Beta-galactosidase; Chain A, domain 5
type: Cath
references: http://www.cathdb.info/version/latest/superfamily/2.70.98.30

Immunoglobulin-like
type: Cath
references: http://www.cathdb.info/version/latest/superfamily/2.60.40.1360

N-Glycan degradation
type: KeggPathway
references: KEGG:MAP00511

Zinc
type: KeggCofactor
references: KEGG:C00038
compound type: heavy metal
references: CHEBI:29105
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

alpha-D-Mannoside
type: KeggSubstrate
references: KEGG:C02603
compound type: carbohydrate
type: KeggProduct

H2O
type: KeggSubstrate
references: KEGG:C00001
compound type: H2O
references: CHEBI:15377
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

alpha-D-Mannose
type: KeggProduct
references: KEGG:C00936
compound type: carbohydrate
references: CHEBI:28729
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

2wyhA01
type: Pdb
references: 2wyh
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2wyh
catalytic residue: ASP 125;ARG 149;TYR 192;ASP 232
cofactor binding residue: HIS 13;ASP 15;ASP 125(Zinc binding)

2wyhB01
type: Pdb
references: 2wyh
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2wyh
catalytic residue: ASP 125;ARG 149;TYR 192;ASP 232
cofactor binding residue: HIS 13;ASP 15;ASP 125(Zinc binding)

2wyiA01
type: Pdb
references: 2wyi
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2wyi
catalytic residue: ASP 125;ARG 149;TYR 192;ASP 232
cofactor binding residue: HIS 13;ASP 15;ASP 125(Zinc binding)

2wyiB01
type: Pdb
references: 2wyi
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2wyi
catalytic residue: ASP 125;ARG 149;TYR 192;ASP 232
cofactor binding residue: HIS 13;ASP 15;ASP 125(Zinc binding)

1o7dA
type: Pdb
references: 1o7d
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1o7d
catalytic residue: ASP 196;ARG 220;TYR 261;ASP 319
cofactor binding residue: HIS 72;ASP 74;ASP 196(Zinc binding)

2wyhA02
type: Pdb
references: 2wyh
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2wyh
cofactor binding residue: HIS 351(Zinc binding)

2wyhB02
type: Pdb
references: 2wyh
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2wyh
cofactor binding residue: HIS 351(Zinc binding)

2wyiA02
type: Pdb
references: 2wyi
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2wyi
cofactor binding residue: HIS 351(Zinc binding)

2wyiB02
type: Pdb
references: 2wyi
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2wyi
cofactor binding residue: HIS 351(Zinc binding)

1o7dC01
type: Pdb
references: 1o7d
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1o7d
cofactor binding residue: HIS 446(Zinc binding)

Human lysosomal and jack bean alpha-mannosidases are retaining glycosidases.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/9325188
journal: Biochem Biophys Res Commun
volume: 238
pages: 896-8
published year: 1997
authors:
  item: Howard S
  item: Braun C
  item: McCarter J
  item: Moremen KW
  item: Liao YF
  item: Withers SG

Identification of Asp197 as the catalytic nucleophile in the family 38 alpha-mannosidase from bovine kidney lysosomes.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/11078873
journal: FEBS Lett
volume: 484
pages: 175-8
published year: 2000
authors:
  item: Numao S
  item: He S
  item: Evjen G
  item: Howard S
  item: Tollersrud OK
  item: Withers SG

The structure of bovine lysosomal alpha-mannosidase suggests a novel mechanism for low-pH activation.
type: BibliographicResource
comment: X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 52-999.
references: http://www.ncbi.nlm.nih.gov/pubmed/12634058
journal: J Mol Biol
volume: 327
pages: 631-44
published year: 2003
authors:
  item: Heikinheimo P
  item: Helland R
  item: Leiros HK
  item: Leiros I
  item: Karlsen S
  item: Evjen G
  item: Ravelli R
  item: Schoehn G
  item: Ruigrok R
  item: Tollersrud OK
  item: McSweeney S
  item: Hough E
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: Q29451

Structure and kinetic investigation of Streptococcus pyogenes family GH38 alpha-mannosidase.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/20140249
journal: PLoS One
volume: 5
pages: e9006
published year: 2010
authors:
  item: Suits MD
  item: Zhu Y
  item: Taylor EJ
  item: Walton J
  item: Zechel DL
  item: Gilbert HJ
  item: Davies GJ

Analogue
compound: alpha-D-Mannose
pdb: 2wyiA01
ligand het code: SWA

Analogue
compound: alpha-D-Mannose
pdb: 2wyiB01
ligand het code: SWA

ReferenceForCatalyticMechanism
reference index: 3
reference section: p.635, p.637

ReferenceForCatalyticMechanism
reference index: 4
reference section: Fig.5