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PDBsum entry 1zz8
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Oxidoreductase
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PDB id
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1zz8
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References listed in PDB file
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Key reference
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Title
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Structural insight into antibiotic fosfomycin biosynthesis by a mononuclear iron enzyme.
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Authors
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L.J.Higgins,
F.Yan,
P.Liu,
H.W.Liu,
C.L.Drennan.
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Ref.
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Nature, 2005,
437,
838-844.
[DOI no: ]
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PubMed id
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Abstract
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The biosynthetic pathway of the clinically important antibiotic fosfomycin uses
enzymes that catalyse reactions without precedent in biology. Among these is
hydroxypropylphosphonic acid epoxidase, which represents a new subfamily of
non-haem mononuclear iron enzymes. Here we present six X-ray structures of this
enzyme: the apoenzyme at 2.0 A resolution; a native Fe(II)-bound form at 2.4 A
resolution; a tris(hydroxymethyl)aminomethane-Co(II)-enzyme complex structure at
1.8 A resolution; a substrate-Co(II)-enzyme complex structure at 2.5 A
resolution; and two substrate-Fe(II)-enzyme complexes at 2.1 and 2.3 A
resolution. These structural data lead us to suggest how this enzyme is able to
recognize and respond to its substrate with a conformational change that
protects the radical-based intermediates formed during catalysis. Comparisons
with other family members suggest why substrate binding is able to prime iron
for dioxygen binding in the absence of alpha-ketoglutarate (a co-substrate
required by many mononuclear iron enzymes), and how the unique epoxidation
reaction of hydroxypropylphosphonic acid epoxidase may occur.
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Figure 1.
Figure 1: Fosfomycin biosynthesis. The fosfomycin
biosynthetic pathway requires phosphoenolpyruvate mutase (Fom1),
phosphonopyruvate decarboxylase (Fom2), phosphonoacetaldehyde
methyltransferase (Fom3) and HppE (Fom4). 1, phosphoenolpyruvate
(PEP); 2, phosphonopyruvate (PnPy); 3, phosphonoacetaldehyde
(PnAA); 4, (S)-2-hydroxypropylphosphonic acid (S-HPP); 5,
fosfomycin. C1 and C2 positions are shown in blue.
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Figure 2.
Figure 2: Overall structure of Fe(ii)-HppE. a, An HppE
monomer consists of an  -domain
(blue), an interdomain linker (green) to a single  -strand
1 (cyan) and a -domain
(blue). This stereoview highlights the cantilever hairpin ( -strands
2 and 3) in cyan, facial triad ligands (Glu 142, His 138 and His
180) in ball-and-stick, and iron as a brown sphere. Helices and
strands are numbered separately and sequentially with respect to
the primary structure. b, HppE tetramer, coloured by molecule,
is shown down one of the three two-fold axes of symmetry. The
cantilever hairpin is coloured cyan in the blue molecule,
magenta in the red molecule, dark yellow in the yellow molecule,
and dark green in the green molecule. c, HppE tetramer oriented
along a second two-fold axis of symmetry, orthogonal to that in
b. The cantilever hairpins are coloured as in b. Figs 2-4 were
made in PyMol31.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2005,
437,
838-844)
copyright 2005.
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