Concerted
Action of P450 Plus Helper Protein To Form
the Amino-hydroxy-piperidone Moiety of the Potent Protease Inhibitor
Crocapeptin
Posted on 2013-11-13 - 00:00
The crocapeptins are described here
as cyclic depsipeptides, isolated
from cultures of the myxobacterium Chondromyces crocatus. Structure elucidation of the compounds revealed a cyanopeptolin-like
skeleton, containing the characteristic amino-hydroxy-piperidone (Ahp)-heterocycle.
Like the cyanopeptolins, the myxobacterial crocapeptins proved to
be serine protease inhibitors. The nonribosomal origin of the peptide
was confirmed by mutagenesis experiments, and the biosynthesis gene
cluster was sequenced. It could be shown that the Ahp-heterocycle
originates from a proline residue in the precursor molecule precrocapeptin,
which is converted to crocapeptin by the tailoring enzymes CpnE and
CpnF. Conversion of precrocapeptin isolated from a cpnF mutant into crocapeptin was achieved using recombinant CpnF, a cytochrome
P450 enzyme responsible for hydroxylation of the proline residue in
precrocapeptin. Addition of protein CpnE resulted in strongly increased
conversion rates toward Ahp containing product. A mutant with 10-fold
increased production of crocapeptin A was created through insertion
of the Pnpt-promotor in front of the NRPS gene.
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Viehrig, Konrad; Surup, Frank; Harmrolfs, Kirsten; Jansen, Rolf; Kunze, Brigitte; Müller, Rolf (2016). Concerted
Action of P450 Plus Helper Protein To Form
the Amino-hydroxy-piperidone Moiety of the Potent Protease Inhibitor
Crocapeptin. ACS Publications. Collection. https://doi.org/10.1021/ja4047153
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AUTHORS (6)
KV
Konrad Viehrig
FS
Frank Surup
KH
Kirsten Harmrolfs
RJ
Rolf Jansen
BK
Brigitte Kunze
RM
Rolf Müller