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PDBsum entry 1x7h
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Oxidoreductase
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PDB id
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1x7h
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Contents |
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* Residue conservation analysis
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DOI no:
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Biochemistry
43:14529-14538
(2004)
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PubMed id:
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Structural analysis of actinorhodin polyketide ketoreductase: cofactor binding and substrate specificity.
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T.P.Korman,
J.A.Hill,
T.N.Vu,
S.C.Tsai.
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ABSTRACT
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Aromatic polyketides are a class of natural products that include many
pharmaceutically important aromatic compounds. Understanding the structure and
function of PKS will provide clues to the molecular basis of polyketide
biosynthesis specificity. Polyketide chain reduction by ketoreductase (KR)
provides regio- and stereochemical diversity. Two cocrystal structures of
actinorhodin polyketide ketoreductase (act KR) were solved to 2.3 A with either
the cofactor NADP(+) or NADPH bound. The monomer fold is a highly conserved
Rossmann fold. Subtle differences between structures of act KR and fatty acid
KRs fine-tune the tetramer interface and substrate binding pocket. Comparisons
of the NADP(+)- and NADPH-bound structures indicate that the alpha6-alpha7 loop
region is highly flexible. The intricate proton-relay network in the active site
leads to the proposed catalytic mechanism involving four waters, NADPH, and the
active site tetrad Asn114-Ser144-Tyr157-Lys161. Acyl carrier protein and
substrate docking models shed light on the molecular basis of KR regio- and
stereoselectivity, as well as the differences between aromatic polyketide and
fatty acid biosyntheses. Sequence comparison indicates that the above features
are highly conserved among aromatic polyketide KRs. The structures of act KR
provide an important step toward understanding aromatic PKS and will enhance our
ability to design novel aromatic polyketide natural products with different
reduction patterns.
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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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C.Olano,
C.Méndez,
and
J.A.Salas
(2010).
Post-PKS tailoring steps in natural product-producing actinomycetes from the perspective of combinatorial biosynthesis.
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Nat Prod Rep,
27,
571-616.
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H.Zhou,
Y.Li,
and
Y.Tang
(2010).
Cyclization of aromatic polyketides from bacteria and fungi.
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Nat Prod Rep,
27,
839-868.
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A.Das,
and
C.Khosla
(2009).
Biosynthesis of aromatic polyketides in bacteria.
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Acc Chem Res,
42,
631-639.
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A.Das,
and
C.Khosla
(2009).
In vivo and in vitro analysis of the hedamycin polyketide synthase.
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Chem Biol,
16,
1197-1207.
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A.Koglin,
and
C.T.Walsh
(2009).
Structural insights into nonribosomal peptide enzymatic assembly lines.
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Nat Prod Rep,
26,
987.
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S.C.Tsai,
and
B.D.Ames
(2009).
Structural enzymology of polyketide synthases.
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Methods Enzymol,
459,
17-47.
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S.K.Lim,
J.Ju,
E.Zazopoulos,
H.Jiang,
J.W.Seo,
Y.Chen,
Z.Feng,
S.R.Rajski,
C.M.Farnet,
and
B.Shen
(2009).
iso-Migrastatin, migrastatin, and dorrigocin production in Streptomyces platensis NRRL 18993 is governed by a single biosynthetic machinery featuring an acyltransferase-less type I polyketide synthase.
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J Biol Chem,
284,
29746-29756.
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B.D.Ames,
T.P.Korman,
W.Zhang,
P.Smith,
T.Vu,
Y.Tang,
and
S.C.Tsai
(2008).
Crystal structure and functional analysis of tetracenomycin ARO/CYC: implications for cyclization specificity of aromatic polyketides.
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Proc Natl Acad Sci U S A,
105,
5349-5354.
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PDB codes:
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G.Castaldo,
J.Zucko,
S.Heidelberger,
D.Vujaklija,
D.Hranueli,
J.Cullum,
P.Wattana-Amorn,
M.P.Crump,
J.Crosby,
and
P.F.Long
(2008).
Proposed arrangement of proteins forming a bacterial type II polyketide synthase.
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Chem Biol,
15,
1156-1165.
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S.M.Ma,
J.Zhan,
X.Xie,
K.Watanabe,
Y.Tang,
and
W.Zhang
(2008).
Redirecting the cyclization steps of fungal polyketide synthase.
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J Am Chem Soc,
130,
38-39.
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T.Oja,
K.Palmu,
H.Lehmussola,
O.Leppäranta,
K.Hännikäinen,
J.Niemi,
P.Mäntsälä,
and
M.Metsä-Ketelä
(2008).
Characterization of the alnumycin gene cluster reveals unusual gene products for pyran ring formation and dioxan biosynthesis.
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Chem Biol,
15,
1046-1057.
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T.P.Korman,
Y.H.Tan,
J.Wong,
R.Luo,
and
S.C.Tsai
(2008).
Inhibition kinetics and emodin cocrystal structure of a type II polyketide ketoreductase.
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Biochemistry,
47,
1837-1847.
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PDB codes:
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C.Hertweck,
A.Luzhetskyy,
Y.Rebets,
and
A.Bechthold
(2007).
Type II polyketide synthases: gaining a deeper insight into enzymatic teamwork.
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Nat Prod Rep,
24,
162-190.
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C.Khosla,
Y.Tang,
A.Y.Chen,
N.A.Schnarr,
and
D.E.Cane
(2007).
Structure and mechanism of the 6-deoxyerythronolide B synthase.
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Annu Rev Biochem,
76,
195-221.
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S.Smith,
and
S.C.Tsai
(2007).
The type I fatty acid and polyketide synthases: a tale of two megasynthases.
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Nat Prod Rep,
24,
1041-1072.
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W.Zhang,
K.Watanabe,
C.C.Wang,
and
Y.Tang
(2007).
Investigation of early tailoring reactions in the oxytetracycline biosynthetic pathway.
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J Biol Chem,
282,
25717-25725.
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J.J.Kohler
(2006).
A century at the chemistry-biology interface.
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Nat Chem Biol,
2,
288-292.
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W.Zhang,
B.D.Ames,
S.C.Tsai,
and
Y.Tang
(2006).
Engineered biosynthesis of a novel amidated polyketide, using the malonamyl-specific initiation module from the oxytetracycline polyketide synthase.
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Appl Environ Microbiol,
72,
2573-2580.
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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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Links
