Polyketides are a class of
natural product
A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical syn ...
s derived from a precursor molecule consisting of a chain of alternating
ketone
In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...
(or
reduced forms of a ketone) and
methylene groups: (-CO-CH
2-). 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
Professor John Norman Collie FRSE FRS (10 September 1859 – 1 November 1942), commonly referred to as J. Norman Collie, was an English scientist, mountaineer and explorer.
Life and work
He was born in Alderley Edge, Cheshire, the second of ...
synthesized detectable amounts of
orcinol by heating
dehydracetic acid with barium hydroxide causing the pyrone ring to open into a triketide. 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.
It wasn't until 1955 that the biosynthesis of polyketides were understood.
Arthur Birch used radioisotope labeling of carbon in acetate to trace the biosynthesis of
2-hydroxy-6-methylbenzoic acid in ''
Penicillium patulum
''Penicillium griseofulvum'' is a species of the genus of ''Penicillium'' which produces patulin, penifulvin A, cyclopiazonic acid, roquefortine C, shikimic acid, griseofulvin, and 6-Methylsalicylic acid (via a polyketide synthase
Polyketides a ...
'' and demonstrate the head-to-tail linkage of acetic acids to form the polyketide. In the 1980s and 1990s, advancements in genetics allowed for isolation of the genes associated to polyketides to understand the biosynthesis.
Discovery
Polyketides can be produced in bacteria, fungi, plants, and certain marine organisms. 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. Later technology allowed for the isolation of the genes and
heterologous expression Heterologous expression refers to the expression of a gene or part of a gene in a host organism that does not naturally have the gene or gene fragment in question. Insertion of the gene in the heterologous host is performed by recombinant DNA techno ...
of the genes to understand the biosynthesis. In addition, further advancements in biotechnology have allowed for the use of
metagenomics and
genome mining
Genome mining describes the exploitation of genomic information for the discovery of biosynthetic pathways of natural products and their possible interactions. It depends on computational technology and bioinformatics tools. The mining process reli ...
to find new polyketides using similar enzymes to known polyketides.
Biosynthesis
Polyketides are synthesized by multienzyme polypeptides that resemble eukaryotic fatty acid synthase but are often much larger.
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.
Polyketide Synthase (PKS)
Polyketides are produced by
polyketide synthases. The core biosynthesis involves stepwise condensation of a starter unit (typically
acetyl-CoA
Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...
or
propionyl-CoA) with an extender unit (either
malonyl-CoA
Malonyl-CoA is a coenzyme A derivative of malonic acid.
Functions
It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis.
Fatty acid biosynthesis
Malonyl-CoA provides 2-carbon units to fatty acids and commi ...
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.
The first condensation yields an acetoacetyl group, a diketide. Subsequent condensations yield triketides, tetraketide, etc. Other starter units attached to a
coezyme A include
isobutyrate,
cyclohexanecarboxylate,
malonate, and
benzoate
Benzoic acid is a white (or colorless) solid organic compound with the formula , whose structure consists of a benzene ring () with a carboxyl () substituent. It is the simplest aromatic carboxylic acid. The name is derived from gum benzoin, wh ...
.
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
Acyltransferase is a type of transferase enzyme that acts upon acyl groups.
Examples include:
* Glyceronephosphate O-acyltransferase
* Lecithin-cholesterol acyltransferase
*Long-chain-alcohol O-fatty-acyltransferase
In enzymology, a long-chain- ...
and
ketosynthase for the stepwise condensation of the starter unit and extender units) are almost invariably modified. 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).
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.
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. Similarly, cyclization and aromatization can be introduced via a
cyclase, sometimes proceeded by the enol tautomers of the polyketide.
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.
Classification
Polyketides are structurally diverse family. There are various subclasses of polyketides including:
aromatics, macrolactones/
macrolides,
decalin ring containing,
polyether, and
polyenes.
Polyketide synthases are also broadly divided into three classes: Type I PKS (multimodular megasynthases that are non-iterative, often producing macrocodes, polyethers, and polyenes), Type II PKS (dissociated
enzymes
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
with iterative action, often producing aromatics), and Type III PKS (
chalcone synthase-like PKSs, producing small aromatic molecules).
In addition to these subclasses, there also exist polyketides that are hybridized with
nonribosomal peptide Nonribosomal peptides (NRP) are a class of peptide secondary metabolites, usually produced by microorganisms like bacteria and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be made by bacter ...
s (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.
Applications
Polyketide
antibiotic
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
s,
antifungals
An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as crypto ...
,
cytostatics,
anticholesteremic Lipid-lowering agents, also sometimes referred to as hypolipidemic agents, cholesterol-lowering drugs, or antihyperlipidemic agents are a diverse group of pharmaceuticals that are used to lower the level of lipids and lipoproteins such as cholestero ...
,
antiparasitics,
coccidiostats,
animal growth promoters and natural
insecticide
Insecticides are substances used to kill insects. They include ovicides and larvicides used against insect eggs and larvae, respectively. Insecticides are used in agriculture, medicine, industry and by consumers. Insecticides are claimed to b ...
s are in commercial use.
Medicinal
There are more than 10,000 known polyketides, 1% of which are known to have potential for drug activity. Polyketides comprise 20% of the top-selling pharmaceuticals with combined worldwide revenues of over USD 18 billion per year.
Examples
*
Macrolides
**
Pikromycin, the first isolated macrolide (1951)
** The
antibiotic
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
s
erythromycin A,
clarithromycin, and
azithromycin
** The
antihelminthics
ivermectin
**
*
Ansamycins
** The
antitumor
Cancer can be treated by surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy (including immunotherapy such as monoclonal antibody therapy) and synthetic lethality, most commonly as a series of separate treatments (e.g. ...
agents
geldanamycin and
macbecin
Macbecin belongs to the ansamycin family of antibiotics and was first isolated from actinomycete bacteria. Macbecin possesses potent antitumor properties. In-vitro studies have shown that Macbecin is effective in the eradication of Gram-positive ...
,
** The
antibiotic
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
rifamycin
The rifamycins are a group of antibiotics that are synthesized either naturally by the bacterium ''Amycolatopsis rifamycinica'' or artificially. They are a subclass of the larger family of ansamycins. Rifamycins are particularly effective again ...
*
Polyenes
** The
antifungals
An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as crypto ...
amphotericin,
nystatin and
pimaricin
*
Polyethers
** The
antibiotic
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
monensin
Monensin is a polyether antibiotic isolated from ''Streptomyces cinnamonensis''. It is widely used in ruminant animal feeds.
The structure of monensin was first described by Agtarap et al. in 1967, and was the first polyether antibiotic to have i ...
*
Tetracyclines
**The antibiotic agent
doxycycline
Doxycycline is a broad-spectrum tetracycline class antibiotic used in the treatment of infections caused by bacteria and certain parasites. It is used to treat bacterial pneumonia, acne, chlamydia infections, Lyme disease, cholera, typhus, an ...
*
Acetogenins
**
bullatacin
Bullatacin is a bis(tetrahydrofuranoid) fatty acid lactone found in some fruits from Annonaceae family. It is a member of the class of compounds known as acetogenin
Acetogenins are a class of polyketide natural products found in plants of the f ...
**
squamocin
**
molvizarin
Molvizarin is a cytotoxic acetogenin derivate with the molecular formula C35H62O7 which has been isolated from the bark of the plant '' Annona cherimolia''. Molvizarin has ''in vitro
''In vitro'' (meaning in glass, or ''in the glass'') stud ...
**
uvaricin
Uvaricin is a bis(tetrahydrofuranoid) fatty acid lactone that was first isolated in 1982 from the roots of the Annonaceae ''Uvaria acuminata''. Uvaricin was the first known example in a class of compounds known as acetogenins. Acetogenins, which ar ...
**
annonacin
Annonacin is a chemical compound with toxic effects, especially in the nervous system, found in some fruits such as the paw paw, custard apples, soursop, and others from the family ''Annonaceae''. It is a member of the class of compounds known ...
* 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
Usnic acid is a naturally occurring dibenzofuran derivative found in several lichen species with the formula C18H16O7. It was first isolated by German scientist W. Knop in 1844 and first synthesized between 1933-1937 by Curd and Robertson. Usnic a ...
**
Anthracimycin
Anthracimycin is a polyketide antibiotic discovered in 2013. Anthracimycin is derived from marine actinobacteria. In preliminary laboratory research, it has shown activity against '' Bacillus anthracis'', the bacteria that causes anthrax, and ...
**
Anthramycin
Anthramycin is a pyrrolobenzodiazepine antibiotic with antitumor activity. First derived from the thermophilic actinomycete ''Streptomyces refuineus'' by M. D. Tendler and S Korman in the 1950s, it was first successfully synthesized in a lab ...
**
Olivetolic acid
Olivetolic acid is an organic compound that is an intermediate in the biosynthetic pathway of the cannabinoids in ''Cannabis sativa
''Cannabis sativa'' is an annual herbaceous flowering plant indigenous to Eastern Asia, but now of cosmopoli ...
(intermediate in
cannabinoid pathways)
Agricultural
Polyketides can be used for crop protection as
pesticide
Pesticides are substances that are meant to control pests. This includes herbicide, insecticide, nematicide, molluscicide, piscicide, avicide, rodenticide, bactericide, insect repellent, animal repellent, microbicide, fungicide, and lampri ...
s.
Examples
* Pesticides
**
spinosad
Spinosad is an insecticide based on chemical compounds found in the bacterial species ''Saccharopolyspora spinosa''. The genus ''Saccharopolyspora'' was discovered in 1985 in isolates from crushed sugarcane. The bacteria produce yellowish-pink ae ...
or spinosyn (an
insecticide
Insecticides are substances used to kill insects. They include ovicides and larvicides used against insect eggs and larvae, respectively. Insecticides are used in agriculture, medicine, industry and by consumers. Insecticides are claimed to b ...
)
**
avermectin
** polynactins
** tetramycin
Industrial
Polyketides can be used for industrial purposes, such as pigmentation and dietary flavonoids.
Examples
* Pigments
** azaphilones
**
hydroxyanthraquinone A hydroxyanthraquinone (formula: C14H9O2(OH)) is any of several organic compounds that can be viewed as derivatives of an anthraquinone through replacement of one hydrogen atom (H) by a hydroxyl group (-OH).
The IUPAC nomenclature recommends hydrox ...
s
**
naphthoquinones
* Flavonoids
**
curcumin
**
silymarin
**
daidzein
Biotechnology
Protein engineering
Protein engineering is the process of developing useful or valuable proteins. It is a young discipline, with much research taking place into the understanding of protein folding and recognition for protein design principles. It has been used to imp ...
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.
Furthermore, the use of
genome mining
Genome mining describes the exploitation of genomic information for the discovery of biosynthetic pathways of natural products and their possible interactions. It depends on computational technology and bioinformatics tools. The mining process reli ...
allows for discovery of new natural polyketides and their assembly lines.
See also
*
Esterase
*
Nonribosomal peptide Nonribosomal peptides (NRP) are a class of peptide secondary metabolites, usually produced by microorganisms like bacteria and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be made by bacter ...
*
ThYme (database)
ThYme (Thioester-active enzYme) is database of enzymes constituting the fatty acid synthesis and polyketide synthesis cycles.
See also
* Thioester
In organic chemistry, thioesters are organosulfur compounds with the functional group . They ar ...
(2010)
References
{{reflist
NADH dehydrogenase inhibitors
Plant toxin insecticides