EzCatDB: S00155

DB codeS00155
RLCP classification8.131.160500.80
8.113.365000.100
8.113.365001.100
CATH domainDomain 12.60.120.10Catalytic domain
E.C.5.1.3.13
CSA1dzr

CATH domainRelated DB codes (homologues)
2.60.120.10S00145,D00842,D00843,T00255,M00216,T00101

Enzyme Name
Swiss-protKEGG

O27818P26394O06330Q8GIQ0Q9HU21
Protein name
dTDP-4-dehydrorhamnose 3,5-epimerase(dTDP-4-DEHYDRORHAMNOSE 3,5-EPIMERASE RMLC

dTDP-4-dehydrorhamnose 3,5-epimerase
dTDP-L-rhamnose synthetase
dTDP-L-rhamnose synthetase
thymidine diphospho-4-ketorhamnose 3,5-epimerase
TDP-4-ketorhamnose 3,5-epimerase
dTDP-4-dehydro-6-deoxy-D-glucose 3,5-epimerase
TDP-4-keto-L-rhamnose-3,5-epimerase
SynonymsDTDP-4-dehydrorhamnose 3,5-epimerase
EC 5.1.3.13
dTDP-4-keto-6-deoxyglucose 3,5-epimerase
dTDP-L-rhamnose synthetase
DTDP-4-KETO-6-DEOXYGLUCOSE 3,5-EPIMERASE
DTDP-L-RHAMNOSE SYNTHETASE) (THYMIDINE DIPHOSPHO-4-KETO-RHAMNOSE 3,5-EPIMERASE)
EC 5.1.3.13
DTDP-4-dehydrorhamnose 3,5-epimerase
EC 5.1.3.13
DTDP-4-dehydrorhamnose 3,5-epimerase
EC 5.1.3.13
dTDP-4-dehydrorhamnose 3,5-epimerase
DTDP-4-keto-6-deoxy-D-glucose 3,5 epimerase

KEGG pathways
MAP codePathways
MAP00520Nucleotide sugars metabolism
MAP00521Streptomycin biosynthesis
MAP00523Polyketide sugar unit biosynthesis

Swiss-prot:Accession NumberO27818P26394O06330Q8GIQ0Q9HU21
Entry nameO27818_METTHRFBC_SALTYO06330_MYCTUQ8GIQ0_STRSUQ9HU21_PSEAE
Activity
dTDP-4-dehydro-6-deoxy-D-glucose = dTDP-4- dehydro-6-deoxy-L-mannose.


Subunit
Homodimer.


Subcellular location




Cofactor






SubstratesProducts
KEGG-idC11907C00688
Compound4,6-Dideoxy-4-oxo-dTDP-D-glucosedTDP-4-dehydro-6-deoxy-L-mannose
Typeamide group,carbohydrate,nucleotideamide group,carbohydrate,nucleotide
1ep0AUnboundUnbound
1epzAAnalogue:TYDUnbound
1dzrAUnboundUnbound
1dzrBUnboundUnbound
1dztAAnalogue:TPEUnbound
1dztBAnalogue:ATYUnbound
1pm7AUnboundUnbound
1pm7BUnboundUnbound
1upiAUnboundUnbound
1nxmAUnboundUnbound
1nxmBUnboundUnbound
1nywAAnalogue:DAUUnbound
1nywBAnalogue:DAUUnbound
1nzcAAnalogue:TDXUnbound
1nzcBAnalogue:TDXUnbound
1nzcCAnalogue:TDXUnbound
1nzcDAnalogue:TDXUnbound
1rtvAAnalogue:SRTUnbound

Active-site residues
resource
literature [2], [3], [7], [8]
pdbCatalytic residuesModified residues
1ep0AASN 51;HIS 64;LYS 73;TYR 133;ASP 172

1epzAASN 51;HIS 64;LYS 73;TYR 133;ASP 172

1dzrAASN 50;HIS 63;LYS 73;TYR 133;ASP 170

1dzrBASN 50;HIS 63;LYS 73;TYR 133;ASP 170

1dztAASN 50;HIS 63;LYS 73;TYR 133;ASP 170

1dztBASN 50;HIS 63;LYS 73;TYR 133;ASP 170

1pm7AASN 49;HIS 62;LYS 72;TYR 132;ASP 171

1pm7BASN 49;HIS 62;LYS 72;TYR 132;ASP 171

1upiAASN 49;HIS 62;LYS 72;TYR 132;ASP 171
CME 134;CME 147(S,S-(2-hydroxyethyl)-thiocystein)
1nxmAASN 63;HIS 76;LYS 82;TYR 140;ASP 180

1nxmBASN 63;HIS 76;LYS 82;TYR 140;ASP 180

1nywAASN 63;HIS 76;LYS 82;TYR 140;ASP 180

1nywBASN 63;HIS 76;LYS 82;TYR 140;ASP 180

1nzcAASN 63;HIS 76;LYS 82;TYR 140;ASP 180

1nzcBASN 63;HIS 76;LYS 82;TYR 140;ASP 180

1nzcCASN 63;HIS 76;LYS 82;TYR 140;ASP 180

1nzcDASN 63;HIS 76;LYS 82;TYR 140;ASP 180

1rtvAASN 49;HIS 62;LYS 71;TYR 131;ASP 168


References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[2]Fig.5, p.691-6935
[3]p.24612
[4]p.401
[7]Fig.4, p.718-721
[9]p.32689

references
[1]
PubMed ID9020123
JournalJ Biol Chem
Year1997
Volume272
Pages4121-8
AuthorsKoplin R, Brisson JR, Whitfield C
TitleUDP-galactofuranose precursor required for formation of the lipopolysaccharide O antigen of Klebsiella pneumoniae serotype O1 is synthesized by the product of the rfbDKPO1 gene.
[2]
PubMed ID11114506
JournalCurr Opin Struct Biol
Year2000
Volume10
Pages687-96
AuthorsGiraud MF, Naismith JH
TitleThe rhamnose pathway.
[3]
CommentsX-ray crystallography
PubMed ID10827167
JournalJ Biol Chem
Year2000
Volume275
Pages24608-12
AuthorsChristendat D, Saridakis V, Dharamsi A, Bochkarev A, Pai EF, Arrowsmith CH, Edwards AM
TitleCrystal structure of dTDP-4-keto-6-deoxy-D-hexulose 3,5-epimerase from Methanobacterium thermoautotrophicum complexed with dTDP.
Related PDB1ep0,1epz
[4]
CommentsX-RAY CRYSTALLOGRAPHY (2.17 ANGSTROMS).
Medline ID20264521
PubMed ID10802738
JournalNat Struct Biol
Year2000
Volume7
Pages398-402
AuthorsGiraud MF, Leonard GA, Field RA, Berlind C, Naismith JH
TitleRmlC, the third enzyme of dTDP-L-rhamnose pathway, is a new class of epimerase.
Related PDB1dzr,1dzt
Related Swiss-protP26394
[5]
CommentsX-ray crystallography
PubMed ID12951098
JournalBioorg Med Chem Lett
Year2003
Volume13
Pages3227-30
AuthorsBabaoglu K, Page MA, Jones VC, McNeil MR, Dong C, Naismith JH, Lee RE
TitleNovel inhibitors of an emerging target in Mycobacterium tuberculosis; substituted thiazolidinones as inhibitors of dTDP-rhamnose synthesis.
Related PDB1pm7
[6]
PubMed ID12785757
JournalJ Am Chem Soc
Year2003
Volume125
Pages6348-9
AuthorsLeriche C, He X, Chang CW, Liu HW
TitleReversal of the apparent regiospecificity of NAD(P)H-dependent hydride transfer: the properties of the difluoromethylene group, a carbonyl mimic.
[7]
CommentsX-ray crystallography
PubMed ID12791259
JournalStructure (Camb)
Year2003
Volume11
Pages715-23
AuthorsDong C, Major LL, Allen A, Blankenfeldt W, Maskell D, Naismith JH
TitleHigh-resolution structures of RmlC from Streptococcus suis in complex with substrate analogs locate the active site of this class of enzyme.
Related PDB1nxm,1nyw,1nzc
[8]
CommentsX-ray crystallography
PubMed ID15103135
JournalActa Crystallogr D Biol Crystallogr
Year2004
Volume60
Pages895-902
AuthorsKantardjieff KA, Kim CY, Naranjo C, Waldo GS, Lekin T, Segelke BW, Zemla A, Park MS, Terwilliger TC, Rupp B
TitleMycobacterium tuberculosis RmlC epimerase (Rv3465): a promising drug-target structure in the rhamnose pathway.
Related PDB1upi
[9]
PubMed ID15159413
JournalJ Biol Chem
Year2004
Volume279
Pages32684-91
AuthorsMerkel AB, Major LL, Errey JC, Burkart MD, Field RA, Walsh CT, Naismith JH
TitleThe position of a key tyrosine in dTDP-4-Keto-6-deoxy-D-glucose-5-epimerase (EvaD) alters the substrate profile for this RmlC-like enzyme.

comments

According to the literature [2] & [7], this enzyme catalyzes two epimerization reactions, which are composed of four isomerization (shift of double-bond position) as follows:
Here, Asp170 (of 1dzr;PDB) modulates the activity of His63, whereas Asn50 modulates the activity of Tyr133.
(A) Shift of double-bond position from C4=O4 to C4=C5 (Isomerization):
(A1) His63 acts as a general base to deprotonate C5 atom, forming an enolate intermediate.
(A2) Lys73 stabilizes the negative charge on the O4 enolate intermediate.
(B) Shift of double-bond position from C4=C5 to C4=O4 (Isomerization):
(B1) Tyr133 acts as a general acid to protonate C5 atom from the opposite direction.
(B2) Here, there must be proton shuttle for His63 and Tyr133, since they will have to act as a general base and a general acid, respectively, in the next reaction. For Tyr133, a water bound to the residue might provide a new proton. Also for His63, a water molecule, which is hydrogen bonded to this residue, forms a wide network, suggesting a proton shuttle for it.
(C) Shift of double-bond position from C4=O4 to C4=C3 (Isomerization):
(C1) His63 acts as a general base to deprotonate C3 atom, forming an enolate intermediate.
(C2) Lys73 stabilizes the negative charge on the O4 enolate intermediate.
(D) Shift of double-bond position from C4=C3 to C4=O4 (Isomerization):
(D1) Tyr133 acts as a general acid to protonate C5 atom through a water from the opposite direction.
(D2) Here, there must be proton shuttle for His63 and Tyr133, since they will have to act as a general base and a general acid, respectively, for a next substrate. For Tyr133, a water bound to the residue might provide a new proton. Also for His63, a water molecule, which is hydrogen bonded to this residue, forms a wide network, suggesting a proton shuttle for it.

createdupdated
2004-04-062009-03-17
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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