User:Abnerndabad/Polyketide

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-). It is a large and diverse group of secondary metabolites. Many polyketides are medicinal or exhibit acute toxicity.

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 detectible 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.

Biosynthesis of orsellinic acid from polyketide intermediate.

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 1980's and 1990's, advancements in genetics allowed for isolation of the genes associated to polyketides to understand of 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. Later technology allowed for the isolation of the genes and heterolygous expression of the genes to understand the biosynthesis. 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.

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.

Biosynthesis of carbonic acid

Polyketide Synthase (PKS)

Polyketides are produced by polyketide synthases. 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. 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.

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 od 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 ketodeductase), 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 glycolysation via glucosyltransferase or oxidation via monooxygenase. Similarly, cyclization and aromatization can be introduced, 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 sythases 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 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.

Polyketide-Terpene hybrids?

Applications

Polyketide antibiotics, antifungals, cytostatics, anticholesteremic, antiparasitics, coccidiostats, animal growth promoters and natural insecticides 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
• 
  Geldanamycin, an antibiotic.
• 
  Doxycycline, an antibiotic.
• 
  Erythromycin, an antibiotic.
• 
  Aflatoxin B1 known carcinogenic compounds

Examples:

• Macrolides
  • Pikromycin, the first isolated macrolide (1951)
  • 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 mTORinhibitor)
  • Radicicol and the pochonin family (HSP90 inhibitors)
  • The cholesterol lowering agent lovastatin
  • Discodermolide
  • Aflatoxin
  • Usnic acid
  • Anthracimycin
  • Anthramycin
  • Olivetolic acid (intermediate in cannabinoid pathways)

Agricultural

Polyketides can be used for crop protection as pesticides.

Examples

• Pesticides
  • spinosad or spinosyn (an insecticide)
  • avermectin
  • polynactins
  • tetramycin

Industrial

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

Examples

• Pigments
  • azaphilones
  • hydroxyanthraquinones
  • naphthoquinones
• Flavonoids
  • curcumin
  • silymarin
  • daidzein