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Polyketide AI simulator
(@Polyketide_simulator)
Hub AI
Polyketide AI simulator
(@Polyketide_simulator)
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. 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.
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.
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 and genome mining to find new polyketides using similar enzymes to known polyketides.
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.
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. 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 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.
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. 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.
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.
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 and genome mining to find new polyketides using similar enzymes to known polyketides.
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.
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. 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 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.