polyketide
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Polyketides are a class of
natural product A natural product is a natural Chemical compound, compound or chemical substance, substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural product ...
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 bon ...
(or reduced forms of a ketone) and
methylene group In organic chemistry, a methylene group is any part of a molecule that consists of two hydrogen atoms chemical bond, bound to a carbon atom, which is connected to the remainder of the molecule by two single bond, single bonds. The group may be re ...
s: (-CO-CH2-). 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 Secondary metabolites, also called specialised metabolites, toxins, secondary products, or natural products, are organic compounds produced by any lifeform, e.g. bacteria, fungi, animals, or plants, which are not directly involved in the norma ...
caused by its complex biosynthesis which resembles that of
fatty acid synthesis In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes called fatty acid synthases. This process takes place in the cytoplasm of the Cell (biology), cell. Most of the acetyl-Co ...
. 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. 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'' 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 of the genes to understand the biosynthesis. In addition, further advancements in biotechnology have allowed for the use of
metagenomics Metagenomics is the study of genetics, genetic material recovered directly from Natural environment, environmental or clinical samples by a method called sequencing. The broad field may also be referred to as environmental genomics, ecogenomics ...
and genome mining 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 synthase Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or Carbonyl reduction, reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, ...
s. 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 Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining che ...
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. 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 Cyclohexanecarboxylic acid is the organic compound with the formula C6H11CO2H. It is the carboxylic acid of cyclohexane. It is a colorless oil that crystallizes near room temperature.. Preparation and reactions It is prepared by hydrogenation of ...
,
malonate The conjugate acids are in :Carboxylic acids. {{Commons category, Carboxylate ions, Carboxylate anions Carbon compounds Oxyanions ...
, and
benzoate Benzoic acid is a white (or colorless) solid organic compound with the formula , whose Chemical structure, structure consists of a benzene ring () with a carboxyl () substituent. It is the simplest aromaticity, aromatic carboxylic acid. The nam ...
. PKSs are multi-domain enzymes or enzyme complex consisting of various domains. The polyketide chains produced by a minimal
polyketide synthase Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or Carbonyl reduction, reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, ...
(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 See also * Acetyltransferase ...
and
ketosynthase Ketoacyl synthases (KSs) catalyze the condensation reaction of acyl-CoA or acyl-acyl ACP with malonyl-CoA to form 3-ketoacyl-CoA or with malonyl-ACP to form 3-ketoacyl-ACP. This reaction is a key step in the fatty acid synthesis cycle, as the result ...
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 Dehydratases are a group of lyase enzymes that form double and triple bonds in a substrate through the removal of water. They can be found in many places including the mitochondria, peroxisome and cytosol. There are more than 150 different dehydrat ...
), 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 cluster A gene family is a set of Homology (biology), homologous genes within one organism. A gene cluster is a group of two or more genes found within an organism's DNA that encode similar peptide, polypeptides, or proteins, which collectively share a gen ...
s in the genome close to the polyketide synthase genes.


Classification

Polyketides are structurally diverse family. There are various subclasses of polyketides including: aromatics, macrolactones/
macrolide The Macrolides are a class of natural products that consist of a large macrocycle, macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-memb ...
s, decalin ring containing, polyether, and
polyene In organic chemistry, polyenes are poly-Saturated and unsaturated compounds, unsaturated, organic compounds that contain at least three alternating Double bond, double () and Single bond, single () carbon–carbon bonds. These carbon–carbon dou ...
s. 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 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.


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 pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy, ...
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 Cryptoc ...
, cytostatics, anticholesteremic,
antiparasitics Antiparasitics are a class of medications which are indicated for the treatment of parasitic diseases, such as those caused by helminths, amoeba, parasitic nutrition#Ectoparasitism, ectoparasites, Microsporum, parasitic fungi, and protozoa, among o ...
, coccidiostats, animal growth promoters and natural
insecticide Insecticides are substances used to kill insect Insects (from Latin ') are pancrustacean Hexapoda, hexapod invertebrates of the class (biology), class Insecta. They are the largest group within the arthropod phylum. Insects have a chit ...
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

*
Macrolide The Macrolides are a class of natural products that consist of a large macrocycle, macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-memb ...
s ** 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 pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy, ...
s
erythromycin A Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used during ...
,
clarithromycin Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, ''Helicobacter pylori, H. pylori'' infection, and Lyme disease, a ...
, and
azithromycin Azithromycin, sold under the brand names Zithromax (in oral form) and Azasite (as an eye drop), is an antibiotic medication used for the treatment of a number of bacterial infections. This includes otitis media, middle ear infections, strep th ...
** The
antihelminthic Anthelmintics or antihelminthics are a group of antiparasitic, antiparasitic drugs that expel parasitic worms (helminths) and other internal parasites from the body by either stunning or killing them and without causing significant damage to the h ...
s
ivermectin Ivermectin (, ''Help:Pronunciation respelling key, EYE-vər-MEK-tin'') is an antiparasitic drug. After its discovery in 1975, its first uses were in veterinary medicine to prevent and treat heartworm and acariasis. Approved for human use in 1 ...
** *
Ansamycin Ansamycins is a family of bacterial secondary metabolites that show antimicrobial activity against many Gram-positive and some Gram-negative bacteria, and includes various compounds, including streptovaricins and rifamycins. In addition, these c ...
s ** The
antitumor Cancer can be treated by surgery, chemotherapy, radiation therapy, hormonal therapy (oncology), hormonal therapy, targeted therapy (including immunotherapy such as monoclonal antibody therapy) and synthetic lethality, most commonly as a series ...
agents
geldanamycin Geldanamycin is a 1,4-benzoquinone ansamycin antitumor antibiotic that inhibits the function of Hsp90 (Heat Shock Protein 90) by binding to the unusual ADP/ATP-binding pocket of the protein. HSP90 client proteins play important roles in the regulat ...
and macbecin, ** The
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy, ...
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 ...
*
Polyene In organic chemistry, polyenes are poly-Saturated and unsaturated compounds, unsaturated, organic compounds that contain at least three alternating Double bond, double () and Single bond, single () carbon–carbon bonds. These carbon–carbon dou ...
s ** 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 Cryptoc ...
amphotericin,
nystatin Nystatin, sold under the brandname Mycostatin among others, is an antifungal medication. It is used to treat ''Candida (fungus), Candida'' infections of the skin including diaper rash, Candidiasis, thrush, esophageal candidiasis, and vaginal yeast ...
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 pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy, ...
monensin *
Tetracycline Tetracycline, sold under various brand names, is an oral antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacteri ...
s **The antibiotic agent
doxycycline Doxycycline is a Broad-spectrum antibiotic, broad-spectrum tetracycline antibiotic, tetracycline class antibiotic used in the treatment of infections caused by bacteria and certain parasites. It is used to treat pneumonia, bacterial pneumonia, a ...
* Acetogenins ** bullatacin ** squamocin ** molvizarin ** uvaricin **
annonacin Annonacin is a chemical compound with toxic effects, especially in the nervous system In Biology, biology, the nervous system is the Complex system, highly complex part of an animal that coordinates its Behavior, actions and Sense, sensory ...
* Others ** The
immunosuppressant Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are medication, drugs that inhibit or prevent activity of the immune system. Classification Immunosuppressive drugs can be cla ...
s tacrolimus (FK506) (a
calcineurin Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine protein phosphatase (also known as protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemis ...
inhibitor) and sirolimus (rapamycin) (a
mTOR The mammalian target of sirolimus, rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MT ...
inhibitor) **
Radicicol Radicicol, also known as monorden, is a natural product that binds to Hsp90 (Heat Shock Protein 90) and alters its function. HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, ang ...
and the pochonin family (
HSP90 Hsp90 (heat shock protein 90) is a chaperone (protein), chaperone protein that assists other proteins to protein folding, fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of ...
inhibitors) **The
cholesterol Cholesterol is any of a class of certain organic compound, organic molecules called lipids. It is a sterol (or chemical modification, modified steroid), a type of lipid. Cholesterol is biosynthesis, biosynthesized by all animal Cell (biology)# ...
lowering agent lovastatin ** Discodermolide **
Aflatoxin Aflatoxins are various poisonous carcinogens and mutagens that are produced by certain molds, particularly '' Aspergillus'' species. The fungi grow in soil, decaying vegetation and various staple foodstuffs and commodities such as hay, swe ...
** Usnic acid ** Anthracimycin ** Anthramycin ** Olivetolic acid (intermediate in
cannabinoid Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid te ...
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, ...
s.


Examples

* Pesticides ** spinosad or spinosyn (an
insecticide Insecticides are substances used to kill insect Insects (from Latin ') are pancrustacean Hexapoda, hexapod invertebrates of the class (biology), class Insecta. They are the largest group within the arthropod phylum. Insects have a chit ...
) ** avermectin ** polynactins ** tetramycin


Industrial

Polyketides can be used for industrial purposes, such as pigmentation and dietary flavonoids.


Examples

* Pigments ** azaphilones ** hydroxyanthraquinones ** naphthoquinones * Flavonoids **
curcumin Curcumin is a bright yellow chemical produced by plants of the ''Curcuma longa'' species. It is the principal curcuminoid of turmeric (''Curcuma longa''), a member of the ginger family, Zingiberaceae. It is sold as a herbal supplement, cosmetic ...
** silymarin **
daidzein Daidzein (7-hydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one) is a naturally occurring compound found exclusively in soybeans and other legumes and structurally belongs to a class of compounds known as isoflavones. Daidzein and other isoflavones ar ...


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 allows for discovery of new natural polyketides and their assembly lines.


See also

* Esterase * Nonribosomal peptide * ThYme (database) (2010)


References

{{reflist NADH dehydrogenase inhibitors Plant toxin insecticides