Communications Chemistry,
Год журнала:
2024,
Номер
7(1)
Опубликована: Авг. 24, 2024
Abstract
Modular
polyketide
synthases
(PKSs)
play
a
vital
role
in
the
biosynthesis
of
complex
natural
products
with
pharmaceutically
relevant
properties.
Their
modular
architecture
makes
them
an
attractive
target
for
engineering
to
produce
platform
chemicals
and
drugs.
In
this
study,
we
demonstrate
that
promiscuous
malonyl/acetyl-transferase
domain
(MAT)
from
murine
fatty
acid
synthase
serves
as
highly
versatile
tool
production
analogs.
We
evaluate
relevance
MAT
using
three
PKSs;
short
trimodular
venemycin
(VEMS),
well
modules
PKSs
deoxyerythronolide
B
(DEBS)
pikromycin
(PIKS)
responsible
antibiotic
precursors
erythromycin
pikromycin.
To
assess
performance
MAT-swapped
PKSs,
analyze
protein
quality
run
engineered
syntheses
vitro.
Our
experiments
include
chemoenzymatic
synthesis
fluorinated
macrolactones.
study
showcases
MAT-based
reprogramming
facile
option
regioselective
editing
substituents
decorating
scaffold.
Organic Letters,
Год журнала:
2025,
Номер
27(4), С. 1036 - 1041
Опубликована: Янв. 22, 2025
Bioactivity-guided
isolation
identified
the
main
antifungal
compounds
produced
by
Acrophialophora
levis
as
new
polyhydroxy-polyketides
acrophialocinol
(1)
and
acrophialocin
(2).
Their
biosynthesis
was
elucidated
heterologous
reconstitution
in
Aspergillus
oryzae
involves
an
α-ketoglutarate-dependent
dioxygenase-catalyzed
α-hydroxylation,
resulting
formation
of
a
tertiary
alcohol
that
is
indispensable
for
activity.
Furthermore,
self-resistance
toward
mediated
conserved
RTA1-like
protein
encoded
acr
biosynthetic
gene
cluster.
Natural Product Reports,
Год журнала:
2022,
Номер
40(1), С. 89 - 127
Опубликована: Сен. 20, 2022
Covering:
2010
to
2022Heterologous
expression
of
natural
product
biosynthetic
gene
clusters
(BGCs)
has
become
a
widely
used
tool
for
genome
mining
cryptic
pathways,
bottom-up
investigation
enzymes,
and
engineered
biosynthesis
new
variants.
In
the
field
fungal
products,
heterologous
complete
pathway
was
first
demonstrated
in
tenellin
Natural Product Reports,
Год журнала:
2023,
Номер
40(9), С. 1498 - 1520
Опубликована: Янв. 1, 2023
Time
span
of
literature
covered:
up
to
mid-2023Iterative
type
I
polyketide
synthases
(iPKSs)
are
outstanding
natural
chemists:
megaenzymes
that
repeatedly
utilize
their
catalytic
domains
synthesize
complex
products
with
diverse
bioactivities.
Perhaps
the
most
fascinating
but
least
understood
question
about
iPKSs
is
how
they
perform
iterative
yet
programmed
reactions
in
which
usage
domain
combinations
varies
during
synthetic
cycle.
The
patterns
fulfilled
by
multiple
factors,
and
strongly
influence
complexity
resulting
products.
This
article
reviews
selected
reports
on
structural
enzymology
iPKSs,
focusing
individual
structures
followed
highlighting
representative
programming
activities
each
may
contribute.
Angewandte Chemie International Edition,
Год журнала:
2023,
Номер
63(4)
Опубликована: Окт. 19, 2023
Abstract
Megasynthases,
such
as
type
I
fatty
acid
and
polyketide
synthases
(FASs
PKSs),
are
multienzyme
complexes
responsible
for
producing
primary
metabolites
complex
natural
products.
Fatty
acids
(FAs)
polyketides
(PKs)
built
by
assembling
modifying
small
acyl
moieties
in
a
stepwise
manner.
A
central
aspect
of
FA
PK
biosynthesis
involves
the
shuttling
substrates
between
domains
complex.
This
essential
process
is
mediated
carrier
proteins
(ACPs).
The
ACPs
must
navigate
to
different
catalytic
within
particular
order
guarantee
fidelity
pathway.
However,
precise
mechanisms
underlying
ACP‐mediated
substrate
shuttling,
particularly
factors
contributing
programming
ACP
movement,
still
need
be
fully
understood.
Review
illustrates
current
understanding
including
concepts
conformational
specificity
control,
proposes
confined
movement
megasynthases.
Communications Chemistry,
Год журнала:
2024,
Номер
7(1)
Опубликована: Апрель 18, 2024
Abstract
Natural
products
are
small
molecules
synthesized
by
fungi,
bacteria
and
plants,
which
historically
have
had
a
profound
effect
on
human
health
quality
of
life.
These
natural
evolved
over
millions
years
resulting
in
specific
biological
functions
that
may
be
interest
for
pharmaceutical,
agricultural,
or
nutraceutical
use.
Often
need
to
structurally
modified
make
them
suitable
applications.
Combinatorial
biosynthesis
is
method
alter
the
composition
enzymes
needed
synthesize
product
diversified
molecules.
In
this
review
we
discuss
different
approaches
combinatorial
via
engineering
fungal
biosynthetic
pathways.
We
highlight
knowledge
gained
from
these
studies
provide
examples
new-to-nature
bioactive
molecules,
including
using
combinations
non-fungal
enzymes.
Journal of the American Chemical Society,
Год журнала:
2024,
Номер
146(9), С. 6189 - 6198
Опубликована: Фев. 22, 2024
Polyketides
with
the
isochroman-3-one
pharmacophore
are
rare
among
fungal
natural
products
as
their
biosynthesis
requires
an
unorthodox
S-type
aromatic
ring
cyclization.
Genome
mining
uncovered
a
conserved
gene
cluster
in
select
leotiomycetous
fungi
that
encodes
of
cytosporones,
including
congeners.
Combinatorial
total
biosynthetic
and
biocatalytic
formats
Saccharomyces
cerevisiae
vitro
reconstitution
key
reactions
purified
enzymes
revealed
how
cytosporone
structural
bioactivity
diversity
is
generated.
The
acyl
dihydroxyphenylacetic
acid
(ADA)
core
cytosporones
assembled
by
collaborating
polyketide
synthase
pair.
Thioesterase
domain-catalyzed
transesterification
releases
ADA
esters,
some
which
known
Nur77
modulators.
Alternatively,
hydrolytic
release
allows
C6
hydroxylation
flavin-dependent
monooxygenase,
yielding
trihydroxybenzene
moiety.
Reduction
C9
carbonyl
short
chain
dehydrogenase/reductase
initiates
formation,
affording
cytotoxic
antimicrobial
activity.
Enoyl
di-
or
trihydroxyphenylacetic
acids
generated
shunt
products,
while
isocroman-3,4-diones
formed
autoxidation.
pathway
offers
novel
for
combinatorial
synthetic
biology
to
advance
production
"unnatural"
drug
discovery.
