Natural organic compounds derived from a [C(O)–CH2] chain
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.[1] 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 synthesized detectable amounts of
orcinol by heating
dehydracetic acid with barium hydroxide causing the pyrone ring to open into a triketide.[2] 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.[3]
It wasn't until 1955 that the biosynthesis of polyketides were understood.[4] 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.[5] In the 1980s and 1990s, advancements in genetics allowed for isolation of the genes associated to polyketides to understand the biosynthesis.[4]
Discovery
Polyketides can be produced in bacteria, fungi, plants, and certain marine organisms.[6] 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.[7] Later technology allowed for the isolation of the genes and
heterologous expression of the genes to understand the biosynthesis.[8] 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.[9]
Biosynthesis
Polyketides are synthesized by multienzyme polypeptides that resemble eukaryotic fatty acid synthase but are often much larger.[4] 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.[10]
Polyketide synthase
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.[10] The first condensation yields an acetoacetyl group, a diketide. Subsequent condensations yield triketides, tetraketide, etc.[11] Other starter units attached to a
coezyme A include
isobutyrate,
cyclohexanecarboxylate,
malonate, and
benzoate.[12]
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.[13] 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).[14]
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.[15]
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.[16] Similarly, cyclization and aromatization can be introduced via a
cyclase, sometimes proceeded by the enol tautomers of the polyketide.[17] 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.[18]
Polyketide synthases are also broadly divided into three classes: Type I PKSs (multimodular megasynthases that are non-iterative, often producing macrocodes, polyethers, and polyenes), Type II PKSs (dissociated
enzymes with iterative action, often producing aromatics), and Type III PKSs (
chalcone synthase-like, producing small aromatic molecules).[20]
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.[21]
There are more than 10,000 known polyketides, 1% of which are known to have potential for drug activity.[27] Polyketides comprise 20% of the top-selling pharmaceuticals with combined worldwide revenues of over USD 18 billion per year.[28]
Protein engineering 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.[21]
Furthermore, the use of
genome mining allows for discovery of new natural polyketides and their assembly lines.[9]
See also
Wikimedia Commons has media related to Polyketides.
^Johnston C, Ibrahim A, Magarvey N (2012-08-01). "Informatic strategies for the discovery of polyketides and nonribosomal peptides". MedChemComm. 3 (8): 932–937.
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^Robinson JA (May 1991). "Polyketide synthase complexes: their structure and function in antibiotic biosynthesis". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 332 (1263): 107–114.
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^Katz L (November 1997). "Manipulation of Modular Polyketide Synthases". Chemical Reviews. 97 (7): 2557–2576.
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^Shen B (April 2003). "Polyketide biosynthesis beyond the type I, II and III polyketide synthase paradigms". Current Opinion in Chemical Biology. 7 (2): 285–295.
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^Brockmann H, Henkel W (1951). "Pikromycin, ein bitter schmeckendes Antibioticum aus Actinomyceten" [Pikromycin, a bitter tasting antibiotic from an actinomycete]. Chem. Ber. (in German). 84 (3): 284–288.
doi:
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^Li S, Yang B, Tan GY, et al. (June 2021). "Polyketide pesticides from actinomycetes". Current Opinion in Biotechnology. Chemical Biotechnology ● Pharmaceutical Biotechnology. 69: 299–307.
doi:
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PMID34102376.
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^Caro Y, Venkatachalam M, Lebeau J, et al. (2016). "Pigments and Colorants from Filamentous Fungi". In Merillon JM, Ramawat KG (eds.). Fungal Metabolites. Reference Series in Phytochemistry. Cham: Springer International Publishing. pp. 1–70.
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