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PDBsum entry 2iwz
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References listed in PDB file
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Key reference
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Title
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Structure of the human beta-Ketoacyl [acp] synthase from the mitochondrial type ii fatty acid synthase.
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Authors
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C.E.Christensen,
B.B.Kragelund,
P.Von wettstein-Knowles,
A.Henriksen.
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Ref.
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Protein Sci, 2007,
16,
261-272.
[DOI no: ]
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PubMed id
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Abstract
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Two distinct ways of organizing fatty acid biosynthesis exist: the
multifunctional type I fatty acid synthase (FAS) of mammals, fungi, and lower
eukaryotes with activities residing on one or two polypeptides; and the
dissociated type II FAS of prokaryotes, plastids, and mitochondria with
individual activities encoded by discrete genes. The beta-ketoacyl [ACP]
synthase (KAS) moiety of the mitochondrial FAS (mtKAS) is targeted by the
antibiotic cerulenin and possibly by the other antibiotics inhibiting
prokaryotic KASes: thiolactomycin, platensimycin, and the alpha-methylene
butyrolactone, C75. The high degree of structural similarity between
mitochondrial and prokaryotic KASes complicates development of novel antibiotics
targeting prokaryotic KAS without affecting KAS domains of cytoplasmic FAS.
KASes catalyze the C(2) fatty acid elongation reaction using either a
Cys-His-His or Cys-His-Asn catalytic triad. Three KASes with different substrate
specificities participate in synthesis of the C(16) and C(18) products of
prokaryotic FAS. By comparison, mtKAS carries out all elongation reactions in
the mitochondria. We present the X-ray crystal structures of the
Cys-His-His-containing human mtKAS and its hexanoyl complex plus the hexanoyl
complex of the plant mtKAS from Arabidopsis thaliana. The structures explain (1)
the bimodal (C(6) and C(10)-C(12)) substrate preferences leading to the C(8)
lipoic acid precursor and long chains for the membranes, respectively, and (2)
the low cerulenin sensitivity of the human enzyme; and (3) reveal two different
potential acyl-binding-pocket extensions. Rearrangements taking place in the
active site, including subtle changes in the water network, indicate a change in
cooperativity of the active-site histidines upon primer binding.
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Figure 2.
Figure 2. Ca RMSDs between (A) HsmtKAS and HsmtKAS:C6 and (B) AtmtKAS and AtmtKAS:C6. The tube diameter is
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Figure 4.
Figure 4. Stereoviews of the HsmtKAS active site. (A) C6 in the acyl-binding pocket. Balls and sticks are colored according to atom
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The above figures are
reprinted
from an Open Access publication published by the Protein Society:
Protein Sci
(2007,
16,
261-272)
copyright 2007.
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Secondary reference #1
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Title
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Cloning, Expression, And characterization of the human mitochondrial beta-Ketoacyl synthase. Complementation of the yeast cem1 knock-Out strain.
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Authors
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L.Zhang,
A.K.Joshi,
J.Hofmann,
E.Schweizer,
S.Smith.
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Ref.
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J Biol Chem, 2005,
280,
12422-12429.
[DOI no: ]
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PubMed id
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Figure 3.
FIG. 3. Complementation of the yeast cem1 mutation by the
human mitochondrial  -ketoacyl synthase.
pKS[mit]-GFP transformed (A) and untransformed (B) BY4743 cells
were sporulated, and spore tetrads were dissected by
micromanipulation. Individual spores from two representative
tetrads were grown on the indicated media for 2–4 days at 30
°C.
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Figure 7.
FIG. 7. Inhibition of -ketoacyl synthase by
cerulenin.
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The above figures are
reproduced from the cited reference
with permission from the ASBMB
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