Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-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 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.
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 bacteria inside these organisms. While there exist a wide range of peptides that are not synthesized by ribosomes, the term nonribosomal peptide typically refers to a very specific set of these as discussed in this article.
Geldanamycin is a 1,4-benzoquinone ansamycin antitumor antibiotic that inhibits the function of Hsp90 by binding to the unusual ADP/ATP-binding pocket of the protein. HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis.
Epothilones are a class of potential cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials, epothilones have better efficacy and milder adverse effects than taxanes.
Flavones are a class of flavonoids based on the backbone of 2-phenylchromen-4-one (2-phenyl-1-benzopyran-4-one).
Tropolone is an organic compound with the chemical formula C7H5(OH)O. It is a pale yellow solid that is soluble in organic solvents. The compound has been of interest to research chemists because of its unusual electronic structure and its role as a ligand precursor. Although not usually prepared from tropone, it can be viewed as its derivative with a hydroxyl group in the 2-position.
Polyketide synthases (PKSs) are a family of multi-domain enzymes or enzyme complexes that produce polyketides, a large class of secondary metabolites, in bacteria, fungi, plants, and a few animal lineages. The biosyntheses of polyketides share striking similarities with fatty acid biosynthesis.
Doxorubicin (DXR) is a 14-hydroxylated version of daunorubicin, the immediate precursor of DXR in its biosynthetic pathway. Daunorubicin is more abundantly found as a natural product because it is produced by a number of different wild type strains of streptomyces. In contrast, only one known non-wild type species, streptomyces peucetius subspecies caesius ATCC 27952, was initially found to be capable of producing the more widely used doxorubicin. This strain was created by Arcamone et al. in 1969 by mutating a strain producing daunorubicin, but not DXR, at least in detectable quantities. Subsequently, Hutchinson's group showed that under special environmental conditions, or by the introduction of genetic modifications, other strains of streptomyces can produce doxorubicin. His group has also cloned many of the genes required for DXR production, although not all of them have been fully characterized. In 1996, Strohl's group discovered, isolated and characterized dox A, the gene encoding the enzyme that converts daunorubicin into DXR. By 1999, they produced recombinant Dox A, a Cytochrome P450 oxidase, and found that it catalyzes multiple steps in DXR biosynthesis, including steps leading to daunorubicin. This was significant because it became clear that all daunorubicin producing strains have the necessary genes to produce DXR, the much more therapeutically important of the two. Hutchinson's group went on to develop methods to improve the yield of DXR, from the fermentation process used in its commercial production, not only by introducing Dox A encoding plasmids, but also by introducing mutations to deactivate enzymes that shunt DXR precursors to less useful products, for example baumycin-like glycosides. Some triple mutants, that also over-expressed Dox A, were able to double the yield of DXR. This is of more than academic interest because at that time DXR cost about $1.37 million per kg and current production in 1999 was 225 kg per annum. More efficient production techniques have brought the price down to $1.1 million per kg for the non-liposomal formulation. Although DXR can be produced semi-synthetically from daunorubicin, the process involves electrophilic bromination and multiple steps and the yield is poor. Since daunorubicin is produced by fermentation, it would be ideal if the bacteria could complete DXR synthesis more effectively.
Zaragozic acids are a family of natural products produced by fungi. The first characterized zaragozic acids, A, B, and C were isolated from an unidentified sterile fungal culture, Sporormiella intermedia, and L. elatius, respectively. just outside the European city Zaragoza, Spain on the Jalón river. This family of natural products possesses a unique 4,8-dioxabicyclo[3.2.1]octane core, and vary in their 1-alkyl and their 6-acyl side chains.
Macrophomic acid is a fungal metabolite isolated from the fungus Macrophoma commelinae. The enzyme macrophomate synthase converts 5-acetyl-4-methoxy-6-methyl-2-pyrone to 4-acetyl-3-methoxy-5-methyl-benzoic acid through an unusual intermolecular Diels-Alder reaction. The pathway to formation of macrophomic acid suggests that the enzyme is a natural Diels-Alderase. Formation of this type of aromatic ring compound normally proceeds via the shikimate and polyketide pathways; however, the production of macrophomic acid by macrophomate synthase proceeds totally differently. Learning about the production of macrophomic acid by a possible natural Diels-Alderase enzyme is important in understanding enzyme catalytic mechanisms. This knowledge can then be applied to organic synthesis.
Betaenone B, like other betaenones, is a secondary metabolite isolated from the fungus Pleospora betae, a plant pathogen. Its phytotoxic properties have been shown to cause sugar beet leaf spots, which is characterized by black, pycnidia containing, concentric circles eventually leading to necrosis of the leaf tissue. Of the seven phytotoxins isolated in fungal leaf spots from sugar beet, betaenone B showed the least amount of phytotoxicity showing only 8% inhibition of growth while betaenone A and C showed 73% and 89% growth inhibition, respectively. Betaenone B is therefore not considered toxic to the plant, but will produce leaf spots when present in high concentrations (0.33 μg/μL). While the mechanism of action of betaenone B has yet to be elucidated, betaenone C has been shown to inhibit RNA and protein synthesis. Most of the major work on betaenone B, including the initial structure elucidation of betaenone A, B and C as well as the partial elucidation mechanism of biosynthesis, was presented in three short papers published between 1983–88. The compounds were found to inhibit a variety of protein kinases signifying a possible role in cancer treatment.
Pikromycin was studied by Brokmann and Hekel in 1951 and was the first antibiotic macrolide to be isolated. Pikromycin is synthesized through a type I polyketide synthase system in Streptomyces venezuelae, a species of Gram-positive bacterium in the genus Streptomyces. Pikromycin is derived from narbonolide, a 14-membered ring macrolide. Along with the narbonolide backbone, pikromycin includes a desosamine sugar and a hydroxyl group. Although Pikromycin is not a clinically useful antibiotic, it can be used as a raw material to synthesize antibiotic ketolide compounds such as ertythromycins and new epothilones.
Monocerin is a dihydroisocoumarin and a polyketide metabolite that originates from various fungal species. It has been shown to display antifungal, plant pathogenic, and insecticidal characteristics. Monocerin has been isolated from Dreschlera monoceras, D. ravenelii, Exserohilum turcicum, and Fusarium larvarum.
Apratoxin A - is a cyanobacterial secondary metabolite, known as a potent cytotoxic marine natural product. It is a derivative of the Apratoxin family of cytotoxins. The mixed peptide-polyketide natural product comes from a polyketide synthase/non-ribosomal peptide synthase pathway (PKS/NRPS). This cytotoxin is known for inducing G1-phase cell cycle arrest and apoptosis. This natural product's activity has made it a popular target for developing anticancer derivatives.
In molecular biology, the polyketide synthesis cyclase family of proteins includes a number of cyclases involved in polyketide synthesis in a number of actinobacterial species.
Atrop-abyssomicin C is a polycyclic polyketide-type natural product that is the atropisomer of abyssomicin C. It is a spirotetronate that belongs to the class of tetronate antibiotics, which includes compounds such as tetronomycin, agglomerin, and chlorothricin. In 2006, the Nicolaou group discovered atrop-abyssomicin C while working on the total synthesis of abyssomicin C. Then in 2007, Süssmuth and co-workers isolated atrop-abyssomicin C from Verrucosispora maris AB-18-032, a marine actinomycete found in sediment of the Japanese sea. They found that atrop-abyssomicin C was the major metabolite produced by this strain, while abyssomicin C was a minor product. The molecule displays antibacterial activity by inhibiting the enzyme PabB, thereby depleting the biosynthesis of p-aminobenzoate.
Aureothin is a natural product of a cytotoxic shikimate-polyketide antibiotic with the molecular formula C22H23NO6. Aureothin is produced by the bacterium Streptomyces thioluteus that illustrates antitumor, antifungal, and insecticidal activities and the new aureothin derivatives can be antifungal and antiproliferative. In addition, aureothin, a nitro compound from Streptomyces thioluteus, was indicated to have pesticidal activity against the bean weevil by interfering with mitochondrial respiratory complex II.
Pretenellin A is a secondary metabolite in Aspergillus oryzae. Pretenellin A is a substrate for tenellin because it undergoes an oxidative ring expansion to form Pretenellin B followed by N-hydroxylation to form Tenellin, an iron chelator in entomopathegnic fungus.
Cercosporin is a red toxin created by the fungal genus Cercospora.Cercospora act as pathogens on a variety of plants including corn, tobacco, soybean, and coffee. Cercosporin is a perylenequinone natural product that is photoactivated and uses reactive oxygen species (ROS) to damage cell components.
Pladienolide B is a natural product produced by bacterial strain, Streptomyces platensis MER-11107,which is a gram-positive bacteria isolated from soil in Japan. Pladienolide B is a molecule of interest due to its potential anti-cancer properties. Its anti-cancer mode of action includes binding to the SF3B complex in the U2 snRNP in the human spliceosome.
