EzCatDB: D00873
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DB codeD00873
RLCP classification4.12.642320.458 : Addition
5.201.2781500.453 : Elimination
CATH domainDomain 12.30.40.10 : Urease, subunit C; domain 1
Domain 23.20.20.140 : TIM BarrelCatalytic domain
E.C.3.5.4.3

CATH domainRelated DB codes (homologues)
2.30.40.10 : Urease, subunit C; domain 1D00673,D00675,D00801,M00030,M00225,M00226
3.20.20.140 : TIM BarrelS00231,S00232,M00186,D00673,D00675,D00801,M00030,M00225,M00226

Enzyme Name
UniProtKBKEGG

Q9Y2T3
Protein nameGuanine deaminaseGuanine deaminase
Guanase
Guanine aminase
GAH
SynonymsGuanase
Guanine aminase
EC 3.5.4.3
Guanine aminohydrolase
GAH
p51-nedasin
RefSeqNP_001229434.1 (Protein)
NM_001242505.2 (DNA/RNA sequence)
NP_001229435.1 (Protein)
NM_001242506.2 (DNA/RNA sequence)
NP_001229436.1 (Protein)
NM_001242507.2 (DNA/RNA sequence)
NP_004284.1 (Protein)
NM_004293.4 (DNA/RNA sequence)
MEROPSM38.981 (Metallo)
PfamPF01979 (Amidohydro_1)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00230Purine metabolism

UniProtKB:Accession NumberQ9Y2T3
Entry nameGUAD_HUMAN
ActivityGuanine + H(2)O = xanthine + NH(3).
SubunitHomodimer.
Subcellular location
CofactorBinds 1 zinc ion per subunit.

Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProductsintermediates
KEGG-idC00038C00242C00001C00385C00014I00149
CompoundZincguanineH2OxanthineNH32-hydroxy-guanine
Typeheavy metalamide group,amine group,aromatic ring (with nitrogen atoms)H2Oamide group,aromatic ring (with nitrogen atoms)amine group,organic ion
ChEBI29105
16235
15377
17712
48517
16134

PubChem32051
764
962
22247451
1188
222

              
2uz9A01UnboundUnbound UnboundUnboundUnbound
3e0lA01UnboundUnbound UnboundUnboundUnbound
3e0lB01UnboundUnbound UnboundUnboundUnbound
4aqlA01UnboundUnbound UnboundUnboundUnbound
2uz9A02Bound:_ZNUnbound Bound:XANUnboundUnbound
3e0lA02Bound:_ZNUnbound UnboundUnboundUnbound
3e0lB02Bound:_ZNUnbound UnboundUnboundUnbound
4aqlA02Bound:_ZNAnalogue:TXC UnboundUnboundUnbound

Active-site residues
resource
literature[2]
pdbCatalytic residuesCofactor-binding residues
          
2uz9A01 
 
3e0lA01 
 
3e0lB01 
 
4aqlA01 
 
2uz9A02GLU 243;HIS 279;ASP 330
HIS 82;HIS 84;HIS 240;ASP 330(Zinc binding)
3e0lA02GLU 241;HIS 277;ASP 328
HIS 82;HIS 84;HIS 238;ASP 328(Zinc binding)
3e0lB02GLU 241;HIS 277;ASP 328
HIS 82;HIS 84;HIS 238;ASP 328(Zinc binding)
4aqlA02GLU 243;HIS 279;ASP 330
HIS 82;HIS 84;HIS 240;ASP 330(Zinc binding)

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[2]


references
[1]
PubMed ID17803218
JournalProteins
Year2008
Volume70
Pages873-81
AuthorsFernandez JR, Welsh WJ, Firestein BL
TitleStructural characterization of the zinc binding domain in cytosolic PSD-95 interactor (cypin): Role of zinc binding in guanine deamination and dendrite branching.
Related PDB2i9u
[2]
PubMed ID19470646
JournalProc Natl Acad Sci U S A
Year2009
Volume106
Pages9215-20
AuthorsMurphy PM, Bolduc JM, Gallaher JL, Stoddard BL, Baker D
TitleAlteration of enzyme specificity by computational loop remodeling and design.
Related PDB3e0l
[3]
PubMed ID22662200
JournalPLoS One
Year2012
Volume7
Pagese37724
AuthorsEgeblad L, Welin M, Flodin S, Graslund S, Wang L, Balzarini J, Eriksson S, Nordlund P
TitlePan-pathway based interaction profiling of FDA-approved nucleoside and nucleobase analogs with enzymes of the human nucleotide metabolism.
Related PDB4aql

comments
This enzyme is homologous to adenosine deaminase (EC 3.5.4.4; S00232 in EzCatDB) and cytosine deaminase (EC 3.5.4.1; D00675 in EzCatDB), sharing a similar active site. This enzyme and adenosine deaminase use zinc ion as cofactor, whereas cytosine deaminase adopts Fe2+ (Ferrous ion) as cofactor.
On the other hand, this enzyme is not homologous to the bacterial guanase (EC 3.5.4.3; S00810 in EzCatDB).
As this enzyme seems to have the same catalytic site with those homologous enzymes, the reaction mechanism can be similar to those by homologues. Thus, this enzyme catalyzes two successive reactions (rather than hydrolysis) as follows:
(A) Addition of water to imine carbon to form a tetrahedral intermediate (I00149).
(A1) Asp330 acts as a general base to deprotonate the zinc-bound water. Here, the positive charge of His279 seems to stabilize the activated water. His279 may assist the catalytic function of Glu243 as well (see D00675 literature [12]).
(A2) The activated water makes a nucleophilic attack on the C2 atom of guanine, whilst Glu243 acts as a general acid to protonate the N3 atom (protonation site) of the guanine. This reaction leads to the formation of tetrahedral intermediate at the C2 atom, transforming N3-C2 bond from a double bond to a single bond (I00149).
(B) Elimination of amine group from the intermediate (I00149), forming a carbonyl group.
(B1) Asp330 acts as a general acid to protonate the eliminated amine group, releasing the ammonia.
(B2) Asp330 acts as a general base to deprotonate the hydroxyl group, bound to the zinc ion and His279. (Here, His279 may assist the catalytic function of Asp330 as well.) This reaction leads to the enol form of the product, xanthine.

createdupdated
2012-10-092012-10-17


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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)
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