EzCatDB: D00406

DB codeD00406
RLCP classification4.12.642300.465
5.201.1660000.464
CATH domainDomain 13.40.140.10Catalytic domain
Domain 23.40.140.10
E.C.3.5.4.5
CSA1ctt
MACiEM0097

CATH domainRelated DB codes (homologues)
3.40.140.10S00808,S00810

Enzyme Name
Swiss-protKEGG

P0ABF6
Protein nameCytidine deaminasecytidine deaminase
cytosine nucleoside deaminase
SynonymsEC 3.5.4.5
Cytidine aminohydrolase
CDA

KEGG pathways
MAP codePathways
MAP00240Pyrimidine metabolism
MAP00983Drug metabolism - other enzymes

Swiss-prot:Accession NumberP0ABF6
Entry nameCDD_ECOLI
ActivityCytidine + H(2)O = uridine + NH(3).
SubunitHomodimer.
Subcellular location
CofactorBinds 1 zinc ion.


CofactorsSubstratesProductsintermediates
KEGG-idC00038C00475C00001C00299C00014I00148
CompoundZincCytidineH2OUridineNH34-hydroxy-cytidine
Typeheavy metalamine group,nucleosideH2Oamide group,nucleosideamine group,organic ion
1af2A01Bound:_ZNUnbound
Bound:__UUnboundUnbound
1alnA01Bound:_ZNAnalogue:CTD
UnboundUnboundUnbound
1cttA01Bound:_ZNUnbound
Analogue:DHZUnboundUnbound
1ctuA01Bound:_ZNUnbound
Analogue:ZEBUnboundUnbound
1af2A02UnboundUnbound
UnboundUnboundUnbound
1alnA02UnboundUnbound
UnboundUnboundUnbound
1cttA02UnboundUnbound
UnboundUnboundUnbound
1ctuA02UnboundUnbound
UnboundUnboundUnbound

Active-site residues
resource
Swiss-prot;P0ABF6
pdbCatalytic residuesCofactor-binding residuesMain-chain involved in catalysis
1af2A01GLU 104
HIS 102;CYS 129;CYS 132(Zn2+ binding)
THR 127
1alnA01GLU 104
HIS 102;CYS 129;CYS 132(Zn2+ binding)
THR 127
1cttA01GLU 104
HIS 102;CYS 129;CYS 132(Zn2+ binding)
THR 127
1ctuA01GLU 104
HIS 102;CYS 129;CYS 132(Zn2+ binding)
THR 127
1af2A02


1alnA02


1cttA02


1ctuA02



References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[1]p.651-653, Fig.123
[2]p.6471-6472
[3]Fig.7, p.973
[4]p.4223-4224
[5]p.4522
[6]p.954
[7]p.1338-1341, Fig.4
[9]p.4772-4774
[15]p.662-663
[17]p.3928-3930

references
[1]
CommentsX-ray crystallography (2.3 Angstroms)
Medline ID94118314
PubMed ID8289286
JournalJ Mol Biol
Year1994
Volume235
Pages635-56
AuthorsBetts L, Xiang S, Short SA, Wolfenden R, Carter CW Jr
TitleCytidine deaminase. The 2.3 A crystal structure of an enzyme: transition-state analog complex.
Related Swiss-protP0ABF6
[2]
PubMed ID8204580
JournalBiochemistry
Year1994
Volume33
Pages6468-74
AuthorsSmith AA, Carlow DC, Wolfenden R, Short SA
TitleMutations affecting transition-state stabilization by residues coordinating zinc at the active site of cytidine deaminase.
[3]
PubMed ID7599282
JournalBiochimie
Year1995
Volume77
Pages92-8
AuthorsCarter CW Jr
TitleThe nucleoside deaminases for cytidine and adenosine: structure, transition state stabilization, mechanism, and evolution.
[4]
PubMed ID7703234
JournalBiochemistry
Year1995
Volume34
Pages4220-4
AuthorsCarlow DC, Smith AA, Yang CC, Short SA, Wolfenden R
TitleMajor contribution of a carboxymethyl group to transition-state stabilization by cytidine deaminase: mutation and rescue.
[5]
PubMed ID7718553
JournalBiochemistry
Year1995
Volume34
Pages4516-23
AuthorsXiang S, Short SA, Wolfenden R, Carter CW Jr
TitleTransition-state selectivity for a single hydroxyl group during catalysis by cytidine deaminase.
Related PDB1ctt,1ctu
[6]
PubMed ID8547277
JournalBiochemistry
Year1996
Volume35
Pages948-54
AuthorsCarlow DC, Short SA, Wolfenden R
TitleRole of glutamate-104 in generating a transition state analogue inhibitor at the active site of cytidine deaminase.
[7]
CommentsX-ray crystallography
PubMed ID8634261
JournalBiochemistry
Year1996
Volume35
Pages1335-41
AuthorsXiang S, Short SA, Wolfenden R, Carter CW Jr
TitleCytidine deaminase complexed to 3-deazacytidine: a "valence buffer" in zinc enzyme catalysis.
Related PDB1aln
[8]
PubMed ID8664259
JournalBiochemistry
Year1996
Volume35
Pages4697-703
AuthorsShih P, Wolfenden R
TitleEnzyme-substrate complexes of adenosine and cytidine deaminases: absence of accumulation of water adducts.
[9]
CommentsX-ray crystallography
PubMed ID9125497
JournalBiochemistry
Year1997
Volume36
Pages4768-74
AuthorsXiang S, Short SA, Wolfenden R, Carter CW Jr
TitleThe structure of the cytidine deaminase-product complex provides evidence for efficient proton transfer and ground-state destabilization.
Related PDB1af2
[10]
CommentsX-ray crystallography
PubMed ID9477944
JournalBiochemistry
Year1998
Volume37
Pages1199-203
AuthorsCarlow DC, Short SA, Wolfenden R
TitleComplementary truncations of a hydrogen bond to ribose involved in transition-state stabilization by cytidine deaminase.
[11]
PubMed ID9579661
JournalProtein Eng
Year1998
Volume11
Pages59-63
AuthorsCambi A, Vincenzetti S, Neuhard J, Costanzi S, Natalini P, Vita A
TitleIdentification of four amino acid residues essential for catalysis in human cytidine deaminase by site-directed mutagenesis and chemical modifications.
[12]
PubMed ID10933791
JournalBiochemistry
Year2000
Volume39
Pages9746-53
AuthorsSnider MJ, Gaunitz S, Ridgway C, Short SA, Wolfenden R
TitleTemperature effects on the catalytic efficiency, rate enhancement, and transition state affinity of cytidine deaminase, and the thermodynamic consequences for catalysis of removing a substrate "anchor".
[13]
PubMed ID11292850
JournalNucleic Acids Res
Year2001
Volume29
Pages1772-80
AuthorsDance GS, Beemiller P, Yang Y, Mater DV, Mian IS, Smith HC
TitleIdentification of the yeast cytidine deaminase CDD1 as an orphan C-->U RNA editase.
[14]
PubMed ID11420434
JournalProtein Sci
Year2001
Volume10
Pages1319-30
AuthorsAlper KO, Singla M, Stone JL, Bagdassarian CK
TitleCorrelated conformational fluctuations during enzymatic catalysis: Implications for catalytic rate enhancement.
[15]
PubMed ID11751045
JournalCurr Opin Struct Biol
Year2001
Volume11
Pages657-65
AuthorsSchramm VL, Shi W
TitleAtomic motion in enzymatic reaction coordinates.
[16]
PubMed ID11851403
JournalBiochemistry
Year2002
Volume41
Pages2563-70
AuthorsJohansson E, Mejlhede N, Neuhard J, Larsen S
TitleCrystal structure of the tetrameric cytidine deaminase from Bacillus subtilis at 2.0 A resolution.
[17]
PubMed ID11900535
JournalBiochemistry
Year2002
Volume41
Pages3925-30
AuthorsSnider MJ, Lazarevic D, Wolfenden R
TitleCatalysis by entropic effects: the action of cytidine deaminase on 5,6-dihydrocytidine.
[18]
PubMed ID12906827
JournalStructure (Camb)
Year2003
Volume11
Pages961-72
AuthorsIreton GC, Black ME, Stoddard BL
TitleThe 1.14 A crystal structure of yeast cytosine deaminase: evolution of nucleotide salvage enzymes and implications for genetic chemotherapy.
[19]
PubMed ID14565461
JournalNucleosides Nucleotides Nucleic Acids
Year2003
Volume22
Pages1539-43
AuthorsCostanzi S, Vincenzetti S, Vita A, Lambertucci C, Taffi S, Volpini R, Vittori S, Cristalli G
TitleHuman cytidine deaminase: understanding the catalytic mechanism.

comments
This enzyme belongs to the cytidine and deoxyxytidylate deaminase family.
According to the literature [1] & [3], this enzyme catalyzes two successive reactions (rather than hydrolysis) as follows:
(A) Addition of water to imine carbon to form a tetrahedral intermediate (I00148).
(B) Elimination of amine group from the intermediate, forming a carbonyl group.
####
(A) Addition of water to imine carbon to form a tetrahedral intermediate (I00148).
(A1) Glu104 play unusual multiple roles in this reaction, by abstracting a proton from the zinc-bound hydroxide, and subsequently by protonating to N-3 atom of the substrate.
(A2) Nucleophilic attack by the zinc bound hydroxide on C-4 atom of the substrate leads to a succession of two tetrahedral intermediate at the carbon atom.
(A3) Formation of the first tetrahedral intermediate with 4-amino group (-NH2) and hydroxy group (-OH) at C-4 atom (I00148); The leaving 4-amino group is stabilized by the carbonyl oxygen atom of Thr127.
(B) Elimination of amine group from the intermediate, forming a carbonyl group.
(B1) Glu104 acts as a general base to deprotonate the hydroxyl group of the first tetrahedral intermediate, forming the second intermediate.
(B2) Glu104 now acts as a general acid to protonate the amine group of the second tetrahedral intermediate, releasing ammonia. (Glu104 plays the shuttling role in the proton transfer.)
According to the paper [15], this nucleophilic displacement involves SN2-like reaction.
More interestingly, this unusual enzyme with zinc ligated by two cysteine residues and a histidine residue adopts an essential strategy, according to the literature [7] & [9]. The Zn-S gamma (Cys132) bond, which lengthens in transition state, shortens as the O-4 atom returns to a state of lower negative charge in the planar product, was proposed to function as a "valence buffer" which can accommodate changing negative charge on the hydroxy group.

createdupdated
2002-09-272012-10-16
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 2010)
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)

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