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PDBsum entry 2ix4
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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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Structure of the mitochondrial beta-Ketoacyl-[Acyl carrier protein] synthase from arabidopsis and its role in fatty acid synthesis.
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Authors
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J.G.Olsen,
A.V.Rasmussen,
P.Von wettstein-Knowles,
A.Henriksen.
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Ref.
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FEBS Lett, 2004,
577,
170-174.
[DOI no: ]
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PubMed id
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Figure 1.
Fig. 1. Ribbon representation of A. thaliana mtKAS. Active
site Cys209, His350 and His389 are included. One subunit is
colored according to secondary structural elements, while in the
other subunit the core αβαβα structure is white and the cap
region is dark gray. The purple spheres represent cations
inferred to be K^+.
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Figure 2.
Fig. 2. Superposition of mtKAS (dark gray) and the high
resolution structure of KAS II from S. pneumoniae (light gray)
[21]. The parts of the mtKAS structure with the largest
deviations from KAS II structures are colored black: +, residues
67–83; ×, residues 98–105; ▸, residues 374–375.
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The above figures are
reproduced from the cited reference
with permission from the Federation of European Biochemical Societies
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