Naturally occurring hydrazones are
rare despite the ubiquitous
usage of synthetic hydrazones in the preparation of organic compounds
and functional materials. In this study, we discovered a family of
novel microbial metabolites (tasikamides) that share a unique cyclic
pentapeptide scaffold. Surprisingly, tasikamides A–C (1–3) contain a hydrazone group (CNN)
that joins the cyclic peptide scaffold to an alkyl 5-hydroxylanthranilate
(AHA) moiety. We discovered that the biosynthesis of 1–3 requires two discrete gene clusters, with
one encoding a nonribosomal peptide synthetase (NRPS) pathway for
assembling the cyclic peptide scaffold and another encoding the AHA-synthesizing
pathway. The AHA gene cluster encodes three ancillary enzymes that
catalyze the diazotization of AHA to yield an aryl diazonium species
(diazo-AHA). The electrophilic diazo-AHA undergoes nonenzymatic Japp–Klingemann
coupling with a β-keto aldehyde-containing cyclic peptide precursor
to furnish the hydrazone group and yield 1–3. The studies together unraveled a novel mechanism whereby
specialized metabolites are formed by the coupling of two biosynthetic
pathways via an unprecedented in vivo Japp–Klingemann reaction. The findings raise the prospect
of exploiting the arylamine-diazotizing enzymes (AAD) for the in vivo synthesis of aryl compounds and modification of
biological macromolecules.
Anthraquinone-fused enediynes (AQEs)
are renowned for their distinctive
molecular architecture, reactive enediyne warhead, and potent anticancer
activity. Although the first members of AQEs, i.e., dynemicins, were
discovered three decades ago, how their nitrogen-containing carbon
skeleton is synthesized by microbial producers remains largely a mystery.
In this study, we showed that the recently discovered sungeidine pathway
is a “degenerative” AQE pathway that contains upstream
enzymes for AQE biosynthesis. Retrofitting the sungeidine pathway
with genes from the dynemicin pathway not only restored the biosynthesis
of the AQE skeleton but also produced a series of novel compounds
likely as the cycloaromatized derivatives of chemically unstable biosynthetic
intermediates. The results suggest a cascade of highly surprising
biosynthetic steps leading to the formation of the anthraquinone moiety,
the hallmark C8–C9 linkage via alkyl–aryl cross-coupling,
and the characteristic epoxide functionality. The findings provide
unprecedented insights into the biosynthesis of AQEs and pave the
way for examining these intriguing biosynthetic enzymes.
A new cyclic decapeptide, trikoramide A (1), has been
isolated from samples of the marine cyanobacterium Symploca
hydnoides, collected from Bintan Island, Indonesia. Trikoramide
A (1) is a C-prenylated cyclotryptophan-containing cyanobactin.
Its planar structure was deduced by 1D and 2D NMR spectroscopy as
well as HR–MS/MS data. In addition, its absolute configuration
was determined by Marfey’s method and 2D NOESY NMR spectroscopic
analysis. Compound 1 possessed cytotoxicity against the
MOLT-4 and AML2 cancer cell lines with IC50 values of 4.8
and 8.2 μM, respectively.
A family of novel cyclic lipopeptides named tasikamides A−H (Tsk A−H) were discovered recently in Streptomyces tasikensis P46. Aside from the unique cyclic pentapeptide scaffold shared by the tasikamides, Tsk A−C contain a hydrazone bridge that connects the cyclic pentapeptide to the lipophilic alkyl 5‐hydroxylanthranilate (AHA) moiety. Here we report the production of tasikamides I−K (Tsk I−K) by a mutant strain of S. tasikensis P46 that overexpresses two pathway‐specific transcription regulators. Unlike Tsk A−C, Tsk I−K feature a rare enaminone‐bridge that links the cyclic peptide scaffold to the AHA moiety. Our experimental data suggest that Tsk I−K are generated by the coupling of two biosynthetic pathways via a nonenzymatic condensation reaction between an arylamine and a β‐keto aldehyde‐containing precursor. The results underscore the nucleophilic and electrophilic reactivity of the β‐keto aldehyde moiety and its ability to promote fragment coupling reactions in live microbial cells.
Angucyclines are structurally diverse aromatic polyketides that have attracted considerable attention due to their potent bioactivity and intriguing biosynthetic origin. Balmoralmycin is a representative of a small family of angucyclines with unique structural features and an unknown biosynthetic origin.
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