Polyketide

Polyketide
In organic chemistry, polyketides are a

class of natural products derived from a
precursor molecule consisting of a chain
of alternating ketone (>C=O, or its reduced
forms) and methylene (>CH2) groups:
[−C(=O)−CH2−]n.[1] First studied in the early
20th century, discovery, biosynthesis, and
application of polyketides has evolved. It is
a large and diverse group of secondary
metabolites caused by its complex
biosynthesis which resembles that of fatty
acid synthesis. Because of this diversity,
polyketides can have various medicinal,
agricultural, and industrial applications.
Many polyketides are medicinal or exhibit
acute toxicity. Biotechnology has enabled
discovery of more naturally-occurring
polyketides and evolution of new
polyketides with novel or improved
bioactivity.
History
Naturally produced polyketides by various
plants and organisms have been used by
humans since before studies on them
began in the 19th and 20th century. In
1893, J. Norman Collie synthesized
detectable amounts of orcinol by heating
dehydracetic acid with barium hydroxide
causing the pyrone ring to open into a
triketide.[2] Further studies in 1903 by Collie
on the triketone polyketide intermediate
noted the condensation occurring amongst
compounds with multiple keten groups
coining the term polyketides.[3]
Biosynthesis of orsellinic acid from polyketide intermediate.
It wasn't until 1955 that the biosynthesis of

polyketides were understood.[4] Arthur
Birch used radioisotope labeling of carbon
in acetate to trace the biosynthesis of 2-
hydroxy-6-methylbenzoic acid in
Penicillium patulum and demonstrate the
head-to-tail linkage of acetic acids to form
the polyketide.[5] In the 1980s and 1990s,
advancements in genetics allowed for
isolation of the genes associated to
polyketides to understand the
biosynthesis.[4]
Discovery
Polyketides can be produced in bacteria,
fungi, plants, and certain marine
organisms.[6] Earlier discovery of naturally
occurring polyketides involved the isolation
of the compounds being produced by the
specific organism using organic chemistry
purification methods based on bioactivity
screens.[7] Later technology allowed for
the isolation of the genes and
heterologous expression of the genes to
understand the biosynthesis.[8] In addition,
further advancements in biotechnology
have allowed for the use of metagenomics
and genome mining to find new
polyketides using similar enzymes to
known polyketides.[9]
Biosynthesis
Polyketides are synthesized by
multienzyme polypeptides that resemble
eukaryotic fatty acid synthase but are
often much larger.[4] They include acyl-
carrier domains plus an assortment of
enzymatic units that can function in an
iterative fashion, repeating the same
elongation/modification steps (as in fatty
acid synthesis), or in a sequential fashion
so as to generate more heterogeneous
types of polyketides.[10]
Biosynthesis of carminic acid
Polyketide synthase
Polyketides are produced by polyketide

synthases (PKSs). The core biosynthesis
involves stepwise condensation of a
starter unit (typically acetyl-CoA or
propionyl-CoA) with an extender unit (either
malonyl-CoA or methylmalonyl-CoA). The
condensation reaction is accompanied by
the decarboxylation of the extender unit,
yielding a beta-keto functional group and
releasing a carbon dioxide.[10] The first
condensation yields an acetoacetyl group,
a diketide. Subsequent condensations
yield triketides, tetraketide, etc.[11] Other
starter units attached to a coezyme A
include isobutyrate,
cyclohexanecarboxylate, malonate, and
benzoate.[12]
PKSs are multi-domain enzymes or

enzyme complex consisting of various
domains. The polyketide chains produced
by a minimal polyketide synthase
(consisting of a acyltransferase and
ketosynthase for the stepwise
condensation of the starter unit and
extender units) are almost invariably
modified.[13] Each polyketide synthases is
unique to each polyketide chain because
they contain different combinations of
domains that reduce the carbonyl group to
a hydroxyl (via a ketoreductase), an olefin
(via a dehydratase), or a methylene (via an
enoylreductase).[14]
Termination of the polyketide scaffold

biosynthesis can also vary. It is sometimes
accompanied by a thioesterase that
releases the polyketide via hydrating the
thioester linkage (as in fatty acid
synthesis) creating a linear polyketide
scaffold. However, if water is not able to
reach the active site, the hydrating reaction
will not occur and an intramolecular
reaction is more probable creating a
macrocyclic polyketide. Another possibility
is spontaneous hydrolysis without the aid
of a thioesterase.[15]
Post-tailoring enzymes
Further possible modifications to the

polyketide scaffolds can be made. This
can include glycosylation via a
glucosyltransferase or oxidation via a
monooxygenase.[16] Similarly, cyclization
and aromatization can be introduced via a
cyclase, sometimes proceeded by the enol
tautomers of the polyketide.[17] These
enzymes are not part of the domains of
the polyketide synthase. Instead, they are
found in gene clusters in the genome close
to the polyketide synthase genes.[18]
Classification
Polyketides are a structurally diverse
family.[19] There are various subclasses of
polyketides including: aromatics,
macrolactones/macrolides, decalin ring
containing, polyether, and polyenes.[15]
Polyketide synthases are also broadly
divided into three classes: Type I PKSs
(multimodular megasynthases that are
non-iterative, often producing macrocodes,
polyethers, and polyenes), Type II PKSs
(dissociated enzymes with iterative action,
often producing aromatics), and Type III
PKSs (chalcone synthase-like, producing
small aromatic molecules).[20]
In addition to these subclasses, there also

exist polyketides that are hybridized with
nonribosomal peptides (Hybrid NRP-PK
and PK-NRP). Since nonribosomal peptide
assembly lines use carrier proteins similar
to those use in polyketide synthases,
convergence of the two systems evolved
to form hybrids, resulting in polypeptides
with nitrogen in the skeletal structure and
complex function groups similar to those
found in amino acids.[21]
Applications
Polyketide antibiotics,[22] antifungals,[23]
cytostatics,[24] anticholesteremic,[25]
antiparasitics,[23] coccidiostats, animal
growth promoters and natural
insecticides[26] are in commercial use.
Medicinal
There are more than 10,000 known

polyketides, 1% of which are known to
have potential for drug activity.[27]
Polyketides comprise 20% of the top-
selling pharmaceuticals with combined
worldwide revenues of over USD 18 billion
per year.[28]
Polyketides
Aflatoxin B1
Doxycycline,
Geldanamycin, Erythromycin, known
an
an antibiotic. an antibiotic. carcinogenic
antibiotic.
compound.
Examples
Macrolides
Pikromycin, the first isolated
macrolide (1951[29])
The antibiotics erythromycin A,
clarithromycin, and azithromycin
The antihelminthics ivermectin
Ansamycins
The antitumor agents geldanamycin
and macbecin,
The antibiotic rifamycin
Polyenes
The antifungals amphotericin,
nystatin and pimaricin
Polyethers
The antibiotic monensin
Tetracyclines
The antibiotic agent doxycycline
Acetogenins
bullatacin
squamocin
molvizarin
uvaricin
annonacin
Others
The immunosuppressants
tacrolimus (FK506) (a calcineurin
inhibitor) and sirolimus (rapamycin)
(a mTOR inhibitor)
Radicicol and the pochonin family
(HSP90 inhibitors)
The cholesterol lowering agent
lovastatin
Discodermolide
Aflatoxin
Usnic acid
Anthracimycin
Anthramycin
Olivetolic acid (intermediate in
cannabinoid pathways)[30]
Agricultural
Polyketides can be used for crop

protection as pesticides.[31]
Examples
Pesticides
spinosad or spinosyn (an
insecticide)
avermectin
polynactins
tetramycin
Industrial
Polyketides can be used for industrial

purposes, such as pigmentation[32] and
dietary flavonoids.[33]
Examples
Pigments
azaphilones
hydroxyanthraquinones
naphthoquinones
Flavonoids
curcumin
silymarin
daidzein
Biotechnology
Protein engineering has opened avenues
for creating polyketides not found in
nature. For example, the modular nature of
PKSs allows for domains to be replaced,
added or deleted. Introducing diversity in
assembly lines enables the discovery of
new polyketides with increased bioactivity
or new bioactivity.[21]
Furthermore, the use of genome mining
allows for discovery of new natural
polyketides and their assembly lines.[9]
See also
Esterase Wikimedia
Commons
Nonribosomal peptide has media
related to
ThYme (database)
Polyketides.
(2010)
References
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Polyketide

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Polyketide

In organic chemistry, polyketides are a

Biosynthesis of orsellinic acid from polyketide intermediate.

It wasn't until 1955 that the biosynthesis of

Polyketides are produced by polyketide

PKSs are multi-domain enzymes or

Termination of the polyketide scaffold

Further possible modifications to the

In addition to these subclasses, there also

There are more than 10,000 known

Polyketides can be used for crop

Polyketides can be used for industrial

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