DB code: S00155

RLCP classification	8.131.160500.80 : Isomerization
	8.113.365000.100 : Isomerization
	8.113.365001.100 : Isomerization
CATH domain	2.60.120.10 : Jelly Rolls	Catalytic domain
E.C.	5.1.3.13
CSA	1dzr
M-CSA	1dzr
MACiE

CATH domain	Related DB codes (homologues)
2.60.120.10 : Jelly Rolls	S00145 D00842 D00843 T00255 M00216 T00101

Uniprot Enzyme Name
UniprotKB	Protein name	Synonyms	RefSeq	Pfam
O27818	dTDP-4-dehydrorhamnose 3,5-epimerase	EC 5.1.3.13 Thymidine diphospho-4-keto-rhamnose 3,5-epimerase dTDP-4-keto-6-deoxyglucose 3,5-epimerase dTDP-6-deoxy-D-xylo-4-hexulose 3,5-epimerase dTDP-L-rhamnose synthase	NP_276896.1 (Protein) NC_000916.1 (DNA/RNA sequence)	PF00908 (dTDP_sugar_isom) [Graphical View]
P26394	dTDP-4-dehydrorhamnose 3,5-epimerase	EC 5.1.3.13 Thymidine diphospho-4-keto-rhamnose 3,5-epimerase dTDP-4-keto-6-deoxyglucose 3,5-epimerase dTDP-6-deoxy-D-xylo-4-hexulose 3,5-epimerase dTDP-L-rhamnose synthase	NP_461039.1 (Protein) NC_003197.1 (DNA/RNA sequence)	PF00908 (dTDP_sugar_isom) [Graphical View]
O06330	dTDP-4-dehydrorhamnose 3,5-epimerase	EC 5.1.3.13 Thymidine diphospho-4-keto-rhamnose 3,5-epimerase dTDP-4-keto-6-deoxyglucose 3,5-epimerase dTDP-6-deoxy-D-xylo-4-hexulose 3,5-epimerase dTDP-L-rhamnose synthase	NP_217982.1 (Protein) NC_000962.3 (DNA/RNA sequence) NP_338097.1 (Protein) NC_002755.2 (DNA/RNA sequence) YP_006516954.1 (Protein) NC_018143.1 (DNA/RNA sequence)	PF00908 (dTDP_sugar_isom) [Graphical View]
Q8GIQ0		DTDP-4-dehydrorhamnose 3,5-epimerase EC 5.1.3.13		PF00908 (dTDP_sugar_isom) [Graphical View]
Q9HU21	dTDP-4-dehydrorhamnose 3,5-epimerase	EC 5.1.3.13 Thymidine diphospho-4-keto-rhamnose 3,5-epimerase dTDP-4-keto-6-deoxyglucose 3,5-epimerase dTDP-6-deoxy-D-xylo-4-hexulose 3,5-epimerase dTDP-L-rhamnose synthase	NP_253851.1 (Protein) NC_002516.2 (DNA/RNA sequence)	PF00908 (dTDP_sugar_isom) [Graphical View]

KEGG enzyme name
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

UniprotKB: Accession Number	Entry name	Activity	Subunit
O27818	O27818_METTH
P26394	RFBC_SALTY	dTDP-4-dehydro-6-deoxy-D-glucose = dTDP-4- dehydro-6-deoxy-L-mannose.	Homodimer.
O06330	O06330_MYCTU
Q8GIQ0	Q8GIQ0_STRSU
Q9HU21	Q9HU21_PSEAE

KEGG Pathways
Map code	Pathways	E.C.
MAP00520	Nucleotide sugars metabolism
MAP00521	Streptomycin biosynthesis
MAP00523	Polyketide sugar unit biosynthesis

Compound table
	Substrates	Products	Intermediates
KEGG-id	C11907	C00688
E.C.
Compound	4,6-Dideoxy-4-oxo-dTDP-D-glucose	dTDP-4-dehydro-6-deoxy-L-mannose
Type	amide group,carbohydrate,nucleotide	amide group,carbohydrate,nucleotide
ChEBI	16128 16128	45868 45868
PubChem	439292 439292	443211 443211

1ep0A	Unbound	Unbound
1epzA	Analogue:TYD	Unbound
1dzrA	Unbound	Unbound
1dzrB	Unbound	Unbound
1dztA	Analogue:TPE	Unbound
1dztB	Analogue:ATY	Unbound
1pm7A	Unbound	Unbound
1pm7B	Unbound	Unbound
1upiA	Unbound	Unbound
1nxmA	Unbound	Unbound
1nxmB	Unbound	Unbound
1nywA	Analogue:DAU	Unbound
1nywB	Analogue:DAU	Unbound
1nzcA	Analogue:TDX	Unbound
1nzcB	Analogue:TDX	Unbound
1nzcC	Analogue:TDX	Unbound
1nzcD	Analogue:TDX	Unbound
1rtvA	Analogue:SRT	Unbound

Reference for Active-site residues
resource	references	E.C.
literature [2], [3], [7], [8]

Active-site residues
PDB	Catalytic residues	Cofactor-binding residues	Modified residues	Main-chain involved in catalysis	Comment

1ep0A	ASN 51;HIS 64;LYS 73;TYR 133;ASP 172
1epzA	ASN 51;HIS 64;LYS 73;TYR 133;ASP 172
1dzrA	ASN 50;HIS 63;LYS 73;TYR 133;ASP 170
1dzrB	ASN 50;HIS 63;LYS 73;TYR 133;ASP 170
1dztA	ASN 50;HIS 63;LYS 73;TYR 133;ASP 170
1dztB	ASN 50;HIS 63;LYS 73;TYR 133;ASP 170
1pm7A	ASN 49;HIS 62;LYS 72;TYR 132;ASP 171
1pm7B	ASN 49;HIS 62;LYS 72;TYR 132;ASP 171
1upiA	ASN 49;HIS 62;LYS 72;TYR 132;ASP 171		CME 134;CME 147(S,S-(2-hydroxyethyl)-thiocystein)
1nxmA	ASN 63;HIS 76;LYS 82;TYR 140;ASP 180
1nxmB	ASN 63;HIS 76;LYS 82;TYR 140;ASP 180
1nywA	ASN 63;HIS 76;LYS 82;TYR 140;ASP 180
1nywB	ASN 63;HIS 76;LYS 82;TYR 140;ASP 180
1nzcA	ASN 63;HIS 76;LYS 82;TYR 140;ASP 180
1nzcB	ASN 63;HIS 76;LYS 82;TYR 140;ASP 180
1nzcC	ASN 63;HIS 76;LYS 82;TYR 140;ASP 180
1nzcD	ASN 63;HIS 76;LYS 82;TYR 140;ASP 180
1rtvA	ASN 49;HIS 62;LYS 71;TYR 131;ASP 168

References for Catalytic Mechanism
References	Sections	No. of steps in catalysis
[2]	Fig.5, p.691-693	5
[3]	p.24612
[4]	p.401
[7]	Fig.4, p.718-721
[9]	p.32689

References
[1]
Resource
Comments
Medline ID
PubMed ID	9020123
Journal	J Biol Chem
Year	1997
Volume	272
Pages	4121-8
Authors	Koplin R, Brisson JR, Whitfield C
Title	UDP-galactofuranose precursor required for formation of the lipopolysaccharide O antigen of Klebsiella pneumoniae serotype O1 is synthesized by the product of the rfbDKPO1 gene.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID	11114506
Journal	Curr Opin Struct Biol
Year	2000
Volume	10
Pages	687-96
Authors	Giraud MF, Naismith JH
Title	The rhamnose pathway.
Related PDB
Related UniProtKB
[3]
Resource
Comments	X-ray crystallography
Medline ID
PubMed ID	10827167
Journal	J Biol Chem
Year	2000
Volume	275
Pages	24608-12
Authors	Christendat D, Saridakis V, Dharamsi A, Bochkarev A, Pai EF, Arrowsmith CH, Edwards AM
Title	Crystal structure of dTDP-4-keto-6-deoxy-D-hexulose 3,5-epimerase from Methanobacterium thermoautotrophicum complexed with dTDP.
Related PDB	1ep0 1epz
Related UniProtKB
[4]
Resource
Comments	X-RAY CRYSTALLOGRAPHY (2.17 ANGSTROMS).
Medline ID	20264521
PubMed ID	10802738
Journal	Nat Struct Biol
Year	2000
Volume	7
Pages	398-402
Authors	Giraud MF, Leonard GA, Field RA, Berlind C, Naismith JH
Title	RmlC, the third enzyme of dTDP-L-rhamnose pathway, is a new class of epimerase.
Related PDB	1dzr 1dzt
Related UniProtKB	P26394
[5]
Resource
Comments	X-ray crystallography
Medline ID
PubMed ID	12951098
Journal	Bioorg Med Chem Lett
Year	2003
Volume	13
Pages	3227-30
Authors	Babaoglu K, Page MA, Jones VC, McNeil MR, Dong C, Naismith JH, Lee RE
Title	Novel inhibitors of an emerging target in Mycobacterium tuberculosis; substituted thiazolidinones as inhibitors of dTDP-rhamnose synthesis.
Related PDB	1pm7
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID	12785757
Journal	J Am Chem Soc
Year	2003
Volume	125
Pages	6348-9
Authors	Leriche C, He X, Chang CW, Liu HW
Title	Reversal of the apparent regiospecificity of NAD(P)H-dependent hydride transfer: the properties of the difluoromethylene group, a carbonyl mimic.
Related PDB
Related UniProtKB
[7]
Resource
Comments	X-ray crystallography
Medline ID
PubMed ID	12791259
Journal	Structure (Camb)
Year	2003
Volume	11
Pages	715-23
Authors	Dong C, Major LL, Allen A, Blankenfeldt W, Maskell D, Naismith JH
Title	High-resolution structures of RmlC from Streptococcus suis in complex with substrate analogs locate the active site of this class of enzyme.
Related PDB	1nxm 1nyw 1nzc
Related UniProtKB
[8]
Resource
Comments	X-ray crystallography
Medline ID
PubMed ID	15103135
Journal	Acta Crystallogr D Biol Crystallogr
Year	2004
Volume	60
Pages	895-902
Authors	Kantardjieff KA, Kim CY, Naranjo C, Waldo GS, Lekin T, Segelke BW, Zemla A, Park MS, Terwilliger TC, Rupp B
Title	Mycobacterium tuberculosis RmlC epimerase (Rv3465): a promising drug-target structure in the rhamnose pathway.
Related PDB	1upi
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID	15159413
Journal	J Biol Chem
Year	2004
Volume	279
Pages	32684-91
Authors	Merkel AB, Major LL, Errey JC, Burkart MD, Field RA, Walsh CT, Naismith JH
Title	The 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.
Related PDB
Related UniProtKB

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.

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.

Created	Updated
2004-04-06	2009-03-17