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Abstract
<p class="first" id="P2">Nonheme diiron monooxygenases make up a rapidly growing family
of oxygenases that
are rarely identified in secondary metabolism. Herein, we report the
<i>in vivo</i>,
<i>in vitro</i>, and structural characterizations of a nonheme diiron monooxygenase,
PtmU3, that
installs a C-5 β-hydroxyl group in the unified biosynthesis of platensimycin and platencin,
two highly functionalized diterpenoids that act as potent and selective inhibitors
of bacterial and mammalian fatty acid synthases. This hydroxylation sets the stage
for the subsequent A-ring cleavage step key to the unique diterpene-derived scaffolds
of platensimycin and platencin. PtmU3 adopts an unprecedented triosephosphate isomerase
(TIM)-barrel structural fold for this class of enzymes and possesses a noncanonical
diiron active site architecture with a saturated six-coordinate iron center lacking
a μ-oxo bridge. This study reveals the first member of a previously unidentified superfamily
of TIM-barrel fold enzymes for metal-dependent dioxygen activation, with the majority
predicted to act on CoA-linked substrates, thus expanding our knowledge of nature’s
repertoire of nonheme diiron monooxygenases and TIM-barrel fold enzymes.
</p><p id="P3">
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[1
]Midwest Center for Structural Genomics and Structural Biology Center, Biosciences
Division, Argonne National Laboratory, Argonne, Illinois 60439, United States
[2
]Department of Biosciences, Rice University, Houston, Texas 77030, United States