EzCatDB: T00408
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DB codeT00408
RLCP classification9.1050.439980.119 : Hydride transfer
4.501.3944060.57 : Addition
9.1050.584160.119 : Hydride transfer
1.14.800.129 : Hydrolysis
CATH domainDomain 13.40.50.720 : Rossmann foldCatalytic domain
Domain 21.-.-.-Catalytic domain
Domain 33.40.50.720 : Rossmann foldCatalytic domain
E.C.1.1.1.132

CATH domainRelated DB codes (homologues)
3.40.50.720 : Rossmann foldS00543,S00551,S00552,S00553,S00602,S00604,S00605,S00608,S00610,S00625,S00319,S00328,S00329,S00330,S00331,S00332,D00456,D00457,D00458,S00324,S00320,S00325,S00326,S00327,D00459,S00335,S00336,S00334,T00219,S00339,D00513,D00001,D00002,D00003,D00005,D00007,D00008,D00010,D00012,D00017,D00018,D00023,D00027,D00028,D00031,D00032,D00033,D00034,D00035,D00037,D00048,D00071,D00476,D00481,D00482,D00490,D00492,D00494,D00545,D00601,D00603,D00604,D00605,D00615,D00845,D00857,D00858,M00161,M00171,M00210,T00002,T00010,T00011,T00015,T00227,T00247,T00414,D00827,D00262,D00274,D00275,M00035,T00109

Enzyme Name
UniProtKBKEGG

P11759
Protein nameGDP-mannose 6-dehydrogenaseGDP-mannose 6-dehydrogenase
Guanosine diphosphomannose dehydrogenase
GDP-mannose dehydrogenase
Guanosine diphosphomannose dehydrogenase
Guanosine diphospho-D-mannose dehydrogenase
SynonymsGMD
EC 1.1.1.132
RefSeqNP_252230.1 (Protein)
NC_002516.2 (DNA/RNA sequence)
PfamPF00984 (UDPG_MGDP_dh)
PF03720 (UDPG_MGDP_dh_C)
PF03721 (UDPG_MGDP_dh_N)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00051Fructose and mannose metabolism
MAP00520Amino sugar and nucleotide sugar metabolism

UniProtKB:Accession NumberP11759
Entry nameALGD_PSEAE
ActivityGDP-D-mannose + 2 NAD(+) + H(2)O = GDP-D-mannuronate + 2 NADH.
SubunitHomotetramer (Potential). According to Ref.6, this enzyme exists as a homotetramer, but results obtained in Ref.3 and Ref.5 indicate that it is a homohexamer.
Subcellular location
Cofactor

Compound table: links to PDB-related databases & PoSSuM

SubstratesProductsintermediates
KEGG-idC00096C00003C00001C00976C00004C00080I00103I00104I00105
CompoundGDP-D-mannoseNAD+H2OGDP-D-mannuronateNADHH+GDP-6-dehydro-D-mannoseProtein [GDP-6-S-D-mannose]-L-cysteineProtein [GDP-6-S-6-dehydro-D-mannose]-L-cysteine
Typeamide group,amine group,carbohydrate,nucleotideamide group,amine group,nucleotideH2Oamide group,amine group,carbohydrate,carboxyl group,nucleotideamide group,amine group,nucleotideothers


ChEBI15820
15846
15377
85507
16908
15378



PubChem18396
5893
962
22247451
447152
439153
1038



                 
1mfzA01UnboundUnbound UnboundUnbound    
1mfzB01UnboundUnbound UnboundUnbound    
1mfzC01UnboundUnbound UnboundUnbound    
1mfzD01UnboundUnbound UnboundUnbound    
1muuA01UnboundAnalogue:NAD UnboundUnbound    
1muuB01UnboundAnalogue:NAD UnboundUnbound    
1muuC01UnboundAnalogue:NAD UnboundUnbound    
1muuD01UnboundAnalogue:NAD UnboundUnbound    
1mv8A01UnboundAnalogue:NAD UnboundUnbound    
1mv8B01UnboundAnalogue:NAD UnboundUnbound    
1mv8C01UnboundAnalogue:NAD UnboundUnbound    
1mv8D01UnboundAnalogue:NAD UnboundUnbound    
1mfzA02UnboundUnbound UnboundUnbound    
1mfzB02UnboundUnbound UnboundUnbound    
1mfzC02UnboundUnbound UnboundUnbound    
1mfzD02UnboundUnbound UnboundUnbound    
1muuA02UnboundUnbound UnboundUnbound    
1muuB02UnboundUnbound UnboundUnbound    
1muuC02UnboundUnbound UnboundUnbound    
1muuD02UnboundUnbound UnboundUnbound    
1mv8A02UnboundUnbound UnboundUnbound    
1mv8B02UnboundUnbound UnboundUnbound    
1mv8C02UnboundUnbound UnboundUnbound    
1mv8D02UnboundUnbound UnboundUnbound    
1mfzA03UnboundUnbound Bound:GDXUnbound    
1mfzB03UnboundUnbound Bound:GDXUnbound    
1mfzC03UnboundUnbound Bound:GDXUnbound    
1mfzD03UnboundUnbound Bound:GDXUnbound    
1muuA03UnboundUnbound Bound:GDXUnbound    
1muuB03UnboundUnbound Bound:GDXUnbound    
1muuC03UnboundUnbound Bound:GDXUnbound    
1muuD03UnboundUnbound Bound:GDXUnbound    
1mv8A03UnboundUnbound Bound:GDXUnbound    
1mv8B03UnboundUnbound Bound:GDXUnbound    
1mv8C03UnboundUnbound Bound:GDXUnbound    
1mv8D03UnboundUnbound Bound:GDXUnbound    

Active-site residues
resource
literature [1], [4], [5]
pdbCatalytic residues
         
1mfzA01THR 124;GLU 157
1mfzB01THR 124;GLU 157
1mfzC01THR 124;GLU 157
1mfzD01THR 124;GLU 157
1muuA01THR 124;GLU 157
1muuB01THR 124;GLU 157
1muuC01THR 124;GLU 157
1muuD01THR 124;GLU 157
1mv8A01THR 124;GLU 157
1mv8B01THR 124;GLU 157
1mv8C01THR 124;GLU 157
1mv8D01THR 124;GLU 157
1mfzA02LYS 210;ASN 214
1mfzB02LYS 210;ASN 214
1mfzC02LYS 210;ASN 214
1mfzD02LYS 210;ASN 214
1muuA02LYS 210;ASN 214
1muuB02LYS 210;ASN 214
1muuC02LYS 210;ASN 214
1muuD02LYS 210;ASN 214
1mv8A02LYS 210;ASN 214
1mv8B02LYS 210;ASN 214
1mv8C02LYS 210;ASN 214
1mv8D02LYS 210;ASN 214
1mfzA03CYS 268;LYS 271;ASP 272
1mfzB03CYS 268;LYS 271;ASP 272
1mfzC03CYS 268;LYS 271;ASP 272
1mfzD03CYS 268;LYS 271;ASP 272
1muuA03CYS 268;LYS 271;ASP 272
1muuB03CYS 268;LYS 271;ASP 272
1muuC03CYS 268;LYS 271;ASP 272
1muuD03CYS 268;LYS 271;ASP 272
1mv8A03CYS 268;LYS 271;ASP 272
1mv8B03CYS 268;LYS 271;ASP 272
1mv8C03CYS 268;LYS 271;ASP 272
1mv8D03CYS 268;LYS 271;ASP 272

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[1]p.9384-9385
[4]Fig.1, p.4666-4667
[5]p.138-139

references
[1]
PubMed ID2470755
JournalJ Biol Chem
Year1989
Volume264
Pages9380-5
AuthorsRoychoudhury S, May TB, Gill JF, Singh SK, Feingold DS, Chakrabarty AM
TitlePurification and characterization of guanosine diphospho-D-mannose dehydrogenase. A key enzyme in the biosynthesis of alginate by Pseudomonas aeruginosa.
[2]
PubMed ID8638483
JournalAdv Enzymol Relat Areas Mol Biol
Year1995
Volume70
Pages221-55
AuthorsShankar S, Ye RW, Schlictman D, Chakrabarty AM
TitleExopolysaccharide alginate synthesis in Pseudomonas aeruginosa: enzymology and regulation of gene expression.
[3]
CommentsX-RAY CRYSTALLOGRAPHY (2.31 ANGSTROMS) IN COMPLEX WITH SUBSTRATE AND NAD, MUTAGENESIS OF CYS-260.
PubMed ID10841783
JournalBiochemistry
Year2000
Volume39
Pages7012-23
AuthorsCampbell RE, Mosimann SC, van De Rijn I, Tanner ME, Strynadka NC
TitleThe first structure of UDP-glucose dehydrogenase reveals the catalytic residues necessary for the two-fold oxidation.
Related PDB1dli,1dlj
Related UniProtKBP0C0F4
[4]
CommentsX-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) IN COMPLEX WITH NAD AND PRODUCT.
PubMed ID12705829
JournalBiochemistry
Year2003
Volume42
Pages4658-68
AuthorsSnook CF, Tipton PA, Beamer LJ
TitleCrystal structure of GDP-mannose dehydrogenase: a key enzyme of alginate biosynthesis in P. aeruginosa.
Related PDB1mfz,1muu,1mv8
Related UniProtKBP11759
[5]
PubMed ID16111644
JournalArch Biochem Biophys
Year2005
Volume441
Pages132-40
AuthorsKimmel JL, Tipton PA
TitleInactivation of GDP-mannose dehydrogenase from Pseudomonas aeruginosa by penicillic acid identifies a critical active site loop.

comments
This enzyme belongs to the small group of NAD+-dependent four-electron-transfer dehydrogenases (literature [5]).
This enzyme is homologous to UDP-glucose 6-dehydrogenase (EC=1.1.1.22, T00227 in EzCatDB), although their second domains are classified into different categories in the structural classification (CATH).
According to the literature [3] and [4], this enzyme catalyzes the following reactions:
(A) Hydride transfer from C6' atom of GDP-mannose to nicotinamide of NAD, forming an aldehyde intermediate, GDP-6-dehydro-D-mannose (I00103):
(A1) Lys210 acts as a general base to deprotonate the hydroxyl oxygen, whereas hydride transfer occurs from C6' atom to nicotinamide of NAD. (Here, instead of Lys210, Asp272' (from the adjacent chain) may act as a general base to deprotonate the C6' atom through a water, with Thr124 interacting with C6' through the same water molecule. Thr124 may modulate the pKa of C6' atom through the water, and Asn214 may modulate the pKa of Asp272'.)
(B) Addition of Cys268 to carbonyl C6' atom of the aldehyde intermediate, forming the second thiohemiacetal intermediate (I00104):
(B0) Lys271' (from adjacent chain) and (a positive charged dipole of) a nearby alpha-helix modulates and lowers the pKa of Cys268' to activate the nucleophilic residue.
(B1) The activated Cys268' makes a nucleophilic attack on the aldehyde intermediate.
(B2) Lys210 and Asp272'/Thr124 may stabilize the oxyanion produced by the addition reaction.
(C) Hydride transfer from C6' atom of the thiohemiacetal intermediate to nicotinamide of NAD, forming the third thioester intermediate (I00105):
(C0) Lys210 and Asp272'/Thr124 may stabilize the oxyanion of the intermediate. (Asp272' and Thr124 interact with the oxyanion through a water.)
(C1) Collapse of the oxyanion leads to the hydride transfer from C6' atom to nicotinamide of NAD, forming the thioester intermediate.
(D) Hydrolysis of the thioester intermediate:
(D1) Glu157 acts as a general base to deprotonate and activate a water molecule.
(D2) The activated water makes a nucleophilic attack on the thioester group, leading to an oxyanion transition-state. The oxyanion is stabilized by Lys210 and Asp272'/Thr124. (Asp272' and Thr124 interact with the oxyanion through a water.)
(D3) The oxyanion collapses and Cys268 is released.

createdupdated
2010-09-022011-09-13


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