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PDBsum entry 4xaa
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Oxidoreductase
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PDB id
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4xaa
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References listed in PDB file
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Key reference
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Title
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Oxidative cyclizations in orthosomycin biosynthesis expand the known chemistry of an oxygenase superfamily.
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Authors
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K.M.Mcculloch,
E.K.Mccranie,
J.A.Smith,
M.Sarwar,
J.L.Mathieu,
B.L.Gitschlag,
Y.Du,
B.O.Bachmann,
T.M.Iverson.
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Ref.
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Proc Natl Acad Sci U S A, 2015,
112,
11547-11552.
[DOI no: ]
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PubMed id
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Abstract
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Orthosomycins are oligosaccharide antibiotics that include avilamycin,
everninomicin, and hygromycin B and are hallmarked by a rigidifying
interglycosidic spirocyclic ortho-δ-lactone (orthoester) linkage between at
least one pair of carbohydrates. A subset of orthosomycins additionally contain
a carbohydrate capped by a methylenedioxy bridge. The orthoester linkage is
necessary for antibiotic activity but rarely observed in natural products.
Orthoester linkage and methylenedioxy bridge biosynthesis require similar
oxidative cyclizations adjacent to a sugar ring. We have identified a conserved
group of nonheme iron, α-ketoglutarate-dependent oxygenases likely responsible
for this chemistry. High-resolution crystal structures of the EvdO1 and EvdO2
oxygenases of everninomicin biosynthesis, the AviO1 oxygenase of avilamycin
biosynthesis, and HygX of hygromycin B biosynthesis show how these enzymes
accommodate large substrates, a challenge that requires a variation in metal
coordination in HygX. Excitingly, the ternary complex of HygX with cosubstrate
α-ketoglutarate and putative product hygromycin B identified an orientation of
one glycosidic linkage of hygromycin B consistent with metal-catalyzed hydrogen
atom abstraction from substrate. These structural results are complemented by
gene disruption of the oxygenases evdO1 and evdMO1 from the everninomicin
biosynthetic cluster, which demonstrate that functional oxygenase activity is
critical for antibiotic production. Our data therefore support a role for these
enzymes in the production of key features of the orthosomycin antibiotics.
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