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PDBsum entry 1f6d
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* Residue conservation analysis
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DOI no:
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Biochemistry
39:14993-15001
(2000)
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PubMed id:
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The structure of UDP-N-acetylglucosamine 2-epimerase reveals homology to phosphoglycosyl transferases.
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R.E.Campbell,
S.C.Mosimann,
M.E.Tanner,
N.C.Strynadka.
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ABSTRACT
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Bacterial UDP-N-acetylglucosamine 2-epimerase catalyzes the reversible
epimerization at C-2 of UDP-N-acetylglucosamine (UDP-GlcNAc) and thereby
provides bacteria with UDP-N-acetylmannosamine (UDP-ManNAc), the activated donor
of ManNAc residues. ManNAc is critical for several processes in bacteria,
including formation of the antiphagocytic capsular polysaccharide of pathogens
such as Streptococcus pneumoniae types 19F and 19A. We have determined the X-ray
structure (2.5 A) of UDP-GlcNAc 2-epimerase with bound UDP and identified a
previously unsuspected structural homology with the enzymes glycogen
phosphorylase and T4 phage beta-glucosyltransferase. The relationship to these
phosphoglycosyl transferases is very intriguing in terms of possible
similarities in the catalytic mechanisms. Specifically, this observation is
consistent with the proposal that the UDP-GlcNAc 2-epimerase-catalyzed
elimination and re-addition of UDP to the glycal intermediate may proceed
through a transition state with significant oxocarbenium ion-like character. The
homodimeric epimerase is composed of two similar alpha/beta/alpha sandwich
domains with the active site located in the deep cleft at the domain interface.
Comparison of the multiple copies in the asymmetric unit has revealed that the
epimerase can undergo a 10 degrees interdomain rotation that is implicated in
the regulatory mechanism. A structure-based sequence alignment has identified
several basic residues in the active site that may be involved in the proton
transfer at C-2 or stabilization of the proposed oxocarbenium ion-like
transition state. This insight into the structure of the bacterial epimerase is
applicable to the homologous N-terminal domain of the bifunctional mammalian
UDP-GlcNAc "hydrolyzing" 2-epimerase/ManNAc kinase that catalyzes the
rate-determining step in the sialic acid biosynthetic pathway.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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A.L.Lovering,
L.Y.Lin,
E.W.Sewell,
T.Spreter,
E.D.Brown,
and
N.C.Strynadka
(2010).
Structure of the bacterial teichoic acid polymerase TagF provides insights into membrane association and catalysis.
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Nat Struct Mol Biol,
17,
582-589.
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PDB codes:
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N.Kurochkina,
T.Yardeni,
and
M.Huizing
(2010).
Molecular modeling of the bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase and predictions of structural effects of mutations associated with HIBM and sialuria.
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Glycobiology,
20,
322-337.
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E.S.Rangarajan,
A.Proteau,
Q.Cui,
S.M.Logan,
Z.Potetinova,
D.Whitfield,
E.O.Purisima,
M.Cygler,
A.Matte,
T.Sulea,
and
I.C.Schoenhofen
(2009).
Structural and functional analysis of Campylobacter jejuni PseG: a udp-sugar hydrolase from the pseudaminic acid biosynthetic pathway.
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J Biol Chem,
284,
20989-21000.
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PDB codes:
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M.Rejzek,
V.Sri Kannathasan,
C.Wing,
A.Preston,
E.L.Westman,
J.S.Lam,
J.H.Naismith,
D.J.Maskell,
and
R.A.Field
(2009).
Chemical synthesis of UDP-Glc-2,3-diNAcA, a key intermediate in cell surface polysaccharide biosynthesis in the human respiratory pathogens B. pertussis and P. aeruginosa.
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Org Biomol Chem,
7,
1203-1210.
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A.Buschiazzo,
and
P.M.Alzari
(2008).
Structural insights into sialic acid enzymology.
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Curr Opin Chem Biol,
12,
565-572.
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B.Liu,
Y.A.Knirel,
L.Feng,
A.V.Perepelov,
S.N.Senchenkova,
Q.Wang,
P.R.Reeves,
and
L.Wang
(2008).
Structure and genetics of Shigella O antigens.
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FEMS Microbiol Rev,
32,
627-653.
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L.L.Lairson,
B.Henrissat,
G.J.Davies,
and
S.G.Withers
(2008).
Glycosyltransferases: structures, functions, and mechanisms.
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Annu Rev Biochem,
77,
521-555.
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L.M.Velloso,
S.S.Bhaskaran,
R.Schuch,
V.A.Fischetti,
and
C.E.Stebbins
(2008).
A structural basis for the allosteric regulation of non-hydrolysing UDP-GlcNAc 2-epimerases.
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EMBO Rep,
9,
199-205.
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PDB code:
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S.C.Namboori,
and
D.E.Graham
(2008).
Acetamido sugar biosynthesis in the Euryarchaea.
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J Bacteriol,
190,
2987-2996.
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D.N.Bolam,
S.Roberts,
M.R.Proctor,
J.P.Turkenburg,
E.J.Dodson,
C.Martinez-Fleites,
M.Yang,
B.G.Davis,
G.J.Davies,
and
H.J.Gilbert
(2007).
The crystal structure of two macrolide glycosyltransferases provides a blueprint for host cell antibiotic immunity.
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Proc Natl Acad Sci U S A,
104,
5336-5341.
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PDB codes:
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F.Liu,
and
M.E.Tanner
(2006).
PseG of pseudaminic acid biosynthesis: a UDP-sugar hydrolase as a masked glycosyltransferase.
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J Biol Chem,
281,
20902-20909.
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S.Ikeno,
D.Aoki,
M.Hamada,
M.Hori,
and
K.S.Tsuchiya
(2006).
DNA sequencing and transcriptional analysis of the kasugamycin biosynthetic gene cluster from Streptomyces kasugaensis M338-M1.
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J Antibiot (Tokyo),
59,
18-28.
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W.B.Jeon,
S.T.Allard,
C.A.Bingman,
E.Bitto,
B.W.Han,
G.E.Wesenberg,
and
G.N.Phillips
(2006).
X-ray crystal structures of the conserved hypothetical proteins from Arabidopsis thaliana gene loci At5g11950 and AT2g37210.
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Proteins,
65,
1051-1054.
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PDB codes:
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B.D.Lazarus,
M.D.Roos,
and
J.A.Hanover
(2005).
Mutational analysis of the catalytic domain of O-linked N-acetylglucosaminyl transferase.
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J Biol Chem,
280,
35537-35544.
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E.F.Mulrooney,
K.K.Poon,
D.J.McNally,
J.R.Brisson,
and
J.S.Lam
(2005).
Biosynthesis of UDP-N-acetyl-L-fucosamine, a precursor to the biosynthesis of lipopolysaccharide in Pseudomonas aeruginosa serotype O11.
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J Biol Chem,
280,
19535-19542.
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A.Blume,
A.J.Benie,
F.Stolz,
R.R.Schmidt,
W.Reutter,
S.Hinderlich,
and
T.Peters
(2004).
Characterization of ligand binding to the bifunctional key enzyme in the sialic acid biosynthesis by NMR: I. Investigation of the UDP-GlcNAc 2-epimerase functionality.
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J Biol Chem,
279,
55715-55721.
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B.Eisenhaber,
S.Maurer-Stroh,
M.Novatchkova,
G.Schneider,
and
F.Eisenhaber
(2003).
Enzymes and auxiliary factors for GPI lipid anchor biosynthesis and post-translational transfer to proteins.
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Bioessays,
25,
367-385.
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M.A.Ringenberg,
S.M.Steenbergen,
and
E.R.Vimr
(2003).
The first committed step in the biosynthesis of sialic acid by Escherichia coli K1 does not involve a phosphorylated N-acetylmannosamine intermediate.
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Mol Microbiol,
50,
961-975.
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M.Edman,
S.Berg,
P.Storm,
M.Wikström,
S.Vikström,
A.Ohman,
and
A.Wieslander
(2003).
Structural features of glycosyltransferases synthesizing major bilayer and nonbilayer-prone membrane lipids in Acholeplasma laidlawii and Streptococcus pneumoniae.
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J Biol Chem,
278,
8420-8428.
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N.Handa,
T.Terada,
Y.Kamewari,
H.Hamana,
J.R.Tame,
S.Y.Park,
K.Kinoshita,
M.Ota,
H.Nakamura,
S.Kuramitsu,
M.Shirouzu,
and
S.Yokoyama
(2003).
Crystal structure of the conserved protein TT1542 from Thermus thermophilus HB8.
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Protein Sci,
12,
1621-1632.
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PDB code:
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L.Larivière,
J.Kurzeck,
U.Aschke-Sonnenborn,
W.Rüger,
and
S.Moréra
(2002).
Crystallization and preliminary crystallographic study of a ternary complex between the T4 phage beta-glucosyltransferase, uridine diphosphoglucose and a DNA fragment containing an abasic site.
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Acta Crystallogr D Biol Crystallogr,
58,
1484-1486.
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Y.Bourne,
and
B.Henrissat
(2001).
Glycoside hydrolases and glycosyltransferases: families and functional modules.
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Curr Opin Struct Biol,
11,
593-600.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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