EzCatDB: D00543
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DB codeD00543
RLCP classification9.1050.440000.8011 : Hydride transfer
8.131.164850.131 : Isomerization
5.14.411700.1 : Elimination
9.5010.536210.8011 : Hydride transfer
CATH domainDomain 13.40.50.720 : Rossmann foldCatalytic domain
Domain 23.90.25.10 : UDP-galactose 4-epimerase; domain 1Catalytic domain
E.C.4.2.1.47
CSA1db3


Enzyme Name
UniProtKBKEGG

P0AC88Q51366O60547
Protein nameGDP-mannose 4,6-dehydrataseGDP-mannose 4,6-dehydrataseGDP-mannose 4,6 dehydrataseGDP-mannose 4,6-dehydratase
guanosine 5'-diphosphate-D-mannose oxidoreductase
guanosine diphosphomannose oxidoreductase
guanosine diphosphomannose 4,6-dehydratase
GDP-D-mannose dehydratase
GDP-D-mannose 4,6-dehydratase
Gmd
GDP-mannose 4,6-hydro-lyase
SynonymsEC 4.2.1.47
GDP-D-mannose dehydratase
EC 4.2.1.47
GDP-D-mannose dehydratase
EC 4.2.1.47
GDP-D-mannose dehydratase
GMD
RefSeqNP_416557.1 (Protein)
NC_000913.2 (DNA/RNA sequence)
YP_490295.1 (Protein)
NC_007779.1 (DNA/RNA sequence)
NP_254140.1 (Protein)
NC_002516.2 (DNA/RNA sequence)
NP_001240775.1 (Protein)
NM_001253846.1 (DNA/RNA sequence)
NP_001491.1 (Protein)
NM_001500.3 (DNA/RNA sequence)
PfamPF01370 (Epimerase)
[Graphical view]
PF01370 (Epimerase)
[Graphical view]
PF01370 (Epimerase)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00051Fructose and mannose metabolism

UniProtKB:Accession NumberP0AC88Q51366O60547
Entry nameGM4D_ECOLIGM4D_PSEAEGMDS_HUMAN
ActivityGDP-mannose = GDP-4-dehydro-6-deoxy-D-mannose + H(2)O.GDP-mannose = GDP-4-dehydro-6-deoxy-D-mannose + H(2)O.GDP-mannose = GDP-4-dehydro-6-deoxy-D-mannose + H(2)O.
SubunitHomodimer.

Subcellular location


CofactorNADP.NAD.NADP.

Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProductsintermediates
KEGG-idC00003C00006C00096C01222C00001I00088I00089I00090
CompoundNAD+NADP+GDP-mannoseGDP-4-dehydro-6-deoxy-D-mannoseH2OGDP-4-dehydro-mannoseGDP-4,5-ene-mannoseGDP-6-deoxy-4-dehydro-5,6-ene-mannose
Typeamide group,amine group,nucleotideamide group,amine group,nucleotideamide group,amine group,carbohydrate,nucleotideamide group,amine group,carbohydrate,nucleotideH2O


ChEBI15846
18009
15820
16955
15377



PubChem5893
5886
18396
439446
962
22247451



                
1db3A01UnboundUnboundUnboundUnbound UnboundUnboundUnbound
1rpnA01UnboundBound:NDPUnboundUnbound UnboundUnboundUnbound
1rpnB01UnboundBound:NDPUnboundUnbound UnboundUnboundUnbound
1rpnC01UnboundBound:NDPUnboundUnbound UnboundUnboundUnbound
1rpnD01UnboundBound:NDPUnboundUnbound UnboundUnboundUnbound
1t2aA01UnboundUnboundUnboundUnbound UnboundUnboundUnbound
1t2aB01UnboundUnboundUnboundUnbound UnboundUnboundUnbound
1t2aC01UnboundUnboundUnboundUnbound UnboundUnboundUnbound
1t2aD01UnboundUnboundUnboundUnbound UnboundUnboundUnbound
1db3A02UnboundUnboundUnboundUnbound UnboundUnboundUnbound
1rpnA02UnboundUnboundAnalogue:GDPUnbound UnboundUnboundUnbound
1rpnB02UnboundUnboundAnalogue:GDPUnbound UnboundUnboundUnbound
1rpnC02UnboundUnboundAnalogue:GDPUnbound UnboundUnboundUnbound
1rpnD02UnboundUnboundAnalogue:GDPUnbound UnboundUnboundUnbound
1t2aA02UnboundUnboundAnalogue:GDPUnbound UnboundUnboundUnbound
1t2aB02UnboundUnboundAnalogue:GDPUnbound UnboundUnboundUnbound
1t2aC02UnboundUnboundAnalogue:GDPUnbound UnboundUnboundUnbound
1t2aD02UnboundUnboundAnalogue:GDPUnbound UnboundUnboundUnbound

Active-site residues
resource
literature [1], [4], [5]
pdbCatalytic residues
         
1db3A01THR 132;GLU 134;TYR 156;LYS 160
1rpnA01THR 126;GLU 128;TYR 150;LYS 154
1rpnB01THR 126;GLU 128;TYR 150;LYS 154
1rpnC01THR 126;GLU 128;TYR 150;LYS 154
1rpnD01THR 126;GLU 128;TYR 150;LYS 154
1t2aA01THR 155;GLU 157;TYR 179;LYS 183
1t2aB01THR 155;GLU 157;TYR 179;LYS 183
1t2aC01THR 155;GLU 157;TYR 179;LYS 183
1t2aD01THR 155;GLU 157;TYR 179;LYS 183
1db3A02ARG 224
1rpnA02ARG 218
1rpnB02ARG 218
1rpnC02ARG 218
1rpnD02ARG 218
1t2aA02ARG 247
1t2aB02ARG 247
1t2aC02ARG 247
1t2aD02ARG 247

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[1]Fig.8, p.131-1323
[4]Fig.1, p.155863
[5]Fig.4, p.533-535

references
[1]
CommentsX-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
Medline ID20139699
PubMed ID10673432
JournalStructure Fold Des
Year2000
Volume8
Pages123-35
AuthorsSomoza JR, Menon S, Schmidt H, Joseph-McCarthy D, Dessen A, Stahl ML, Somers WS, Sullivan FX
TitleStructural and kinetic analysis of Escherichia coli GDP-mannose 4,6 dehydratase provides insights into the enzyme's catalytic mechanism and regulation by GDP-fucose.
Related PDB1db3
Related UniProtKBP0AC88
[2]
PubMed ID11444851
JournalBiochem Biophys Res Commun
Year2001
Volume285
Pages364-71
AuthorsWu B, Zhang Y, Wang PG
TitleIdentification and characterization of GDP-d-mannose 4,6-dehydratase and GDP-l-fucose snthetase in a GDP-l-fucose biosynthetic gene cluster from Helicobacter pylori.
[3]
PubMed ID11096116
JournalJ Biol Chem
Year2001
Volume276
Pages5577-83
AuthorsKneidinger B, Graninger M, Adam G, Puchberger M, Kosma P, Zayni S, Messner P
TitleIdentification of two GDP-6-deoxy-D-lyxo-4-hexulose reductases synthesizing GDP-D-rhamnose in Aneurinibacillus thermoaerophilus L420-91T.
[4]
PubMed ID12501186
JournalBiochemistry
Year2002
Volume41
Pages15578-89
AuthorsMulichak AM, Bonin CP, Reiter WD, Garavito RM
TitleStructure of the MUR1 GDP-mannose 4,6-dehydratase from Arabidopsis thaliana: implications for ligand binding and specificity.
Related PDB1n7g,1n7h
[5]
PubMed ID14739333
JournalProtein Sci
Year2004
Volume13
Pages529-39
AuthorsWebb NA, Mulichak AM, Lam JS, Rocchetta HL, Garavito RM
TitleCrystal structure of a tetrameric GDP-D-mannose 4,6-dehydratase from a bacterial GDP-D-rhamnose biosynthetic pathway.
Related PDB1rpn
[6]
PubMed ID15493979
JournalBiochem Soc Trans
Year2004
Volume32
Pages647-54
AuthorsNaismith JH
TitleChemical insights from structural studies of enzymes.

comments
This enzyme belongs to the Short-chain dehydrogenases/reductases (SDR).
Although a catalytic residue is different, this enzyme is homologous to the counterpart enzyme from Arabidopsis (D00513 in EzCatDB).
This enzyme catalyzes reactions similar to those by its homologous enzyme, dTDP-D-glucose-4,6-dehydratase (EC 4.2.1.46, D00262 in EzCatDB) (see [5] and [6]). The difference from the homologous enzyme is that this enzyme has only one acidic residue as a general acid/base, whearas the homologue uses two acidic residues.
According to the literature [4], [5] and [6], this enzyme catalyzes at least three reactions: oxidation of GDP-mannose (hydride transfer from GDP-mannose to nicotinamide), dehydration (elimination of a hydroxyl group from C6), and rereduction of C5-C6 double bond to methyl group (hydride transfer from nicotinamide to the intermediate).
Taken together, this enzyme catalyzes the following reactions:
(A) Hydride transfer from C4 atom of substrate to NAD(P), forming a 4-keto intermediate (I00088):
(A0) Lys154 (of 1rpn) modulates the activity (or pKa) of Tyr150 via 2'-hydroxyl group of NAD(P), along with the N1 atom of the nicotinamide group in NAD(P), whereas Thr126 modulates the pKa of 4-hydroxyl oxygen of the substrate.
(A1) Tyr150 acts as a general base to deprotonate the 4-hydroxyl oxygen of the substrate. Meanwhile, the hydride transfer occurs from the C4-carbon of the substrate to the C4 atom of the nicotinamide, forming 4-keto intermediate.
(B) Isomerization from the 4-keto intermediato to form an enol/enolate intermediate (I00089):
(B0) Arg218 might modulate the pKa of Glu128 as a general base. Moreover, the 4-keto carbonyl group may increase the acidity of the C5 atom.
(B1) Glu128 acts as a general base to deprotonate the C5 atom, leading to formation of enol/enolate intermediate.
(C) Elimination of hydroxyl group from C6 of the enol/enolate intermediate, forming 4-keto-5,6-mannosen intermediate (I00090):
(C0) GDP-phosphoryl groups in the intermediate might modulate the pKa of Glu128 as a general acid.
(C1) Glu128 acts as a general acid to protonate O6 hydroxyl group, to release a water molecule, and to form the 4-keto-5,6-ene intermediate from the enol/enolate intermediate.
(D) Hydride transfer from NAD(P)H to C6 atom of the intermediate:
(D0) A slight rotation of the hexose ring of intermediate might be necessary for the reaction. Lys154 modulates the activity (or pKa) of Tyr150 via 2'-hydroxyl group of NAD(P), along with the N1 atom of the nicotinamide group in NAD(P).
(D1) Hydride transfer from NAD(P)H to C6 atom of the hexose ring in the intermediate. Meanwhile, a general acid must protonate the C5 atom of the hexose. According to the literature [5], Thr126 seems to be positioned to play a role as a general acid. Since this residue is close enough to Tyr150, Tyr150 might act as a general acid via Thr126 to protonate the C5 atom.

createdupdated
2004-06-282011-12-26


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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