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Polyketides and nonribosomal peptides

In contrast to the above PKSs, the biosynthetic gene cluster for the closely related R1128 anthraquinones (2) revealed not one but two KS and ACP genes in addition to the expected genes for downstream tailoring enzymes. This led to the speculation that R1128 biosynthesis required the action of two successive PKS modules, the first of which was dedicated to the construction of the alkyl appendage on the anthraquinone, and the second was the minimal PKS. An entirely analogous set of genes was also identified in the frenolicin (4) biosynthetic gene cluster,, presumably to enable formation of the propyl moiety of this natural product. However, sequence analysis of the R1128 and frenolicin biosynthetic gene clusters raised several confounding questions. For example, a MAT-like protein was also encoded within both gene clusters, although its function was not clear. Also unclear was the source of ketoreductase (KR), dehydratase (DH) and enoylreductase (ER) activity required for the biosynthesis of the fully reduced alkyl moieties of these natural products. Last but not least, the need for a second ACP was unclear, given the prevailing consensus at the time that ACPs were functionally interchangeable. These and other mysteries were solved through the investigations summarized below.

Polyketides and nonribosomal peptides

Thus far, the ability to probe the tolerance and specificity of downstream enzymes that act upon nascent polyketide chains has been severely constrained by the scope of accessible substrates. Although the tailoring enzymes in a polyketide pathway (e.g. the C-3 ketoreductase involved in actinorhodin biosynthesis) recognize freely diffusible substrates, available crystal structures and biosynthetic data suggests that upstream enzymes such as the C-9 specific act KR or the act ARO/CYC catalyze reactions on ACP-bound substrates, and should therefore be considered as auxiliary components of the PKS. Analogs of these ACP-bound poly-β-ketone substrates are highly unstable in water and therefore difficult to study. Nonetheless, limited data suggests that, some of these enzymes (e.g. act KR and the urdGT2 glycosyltransferase from the urdamycin pathway) have broad specificity whereas others (e.g. act ARO/CYC) have narrower specificity. If the goal is to prepare a diverse library of compounds for screening applications, there is immense potential for identifying more members of the former category and exploiting their tolerance. However, if the goal is to prepare specific analogs of existing natural products of medicinal relevance, then the most specific tailoring enzyme(s) are the bottleneck(s), and one has little choice but to turn towards protein engineering as a way to expand their substrate scope in desired directions.

Polyketide synthases - Rasmus Frandsen

Polyketides areusually categorised on the basis of their chemical structures.

Genetic manipulation techniques have resulted inthe identification, cloning, sequencing and functional analyses of severalpolyketide biosynthetic pathways.

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History of p olyketid e research

The following cartoon depicts the hypothetical"dynamic" model of an aromatic polyketide synthase:

Each of these proteins consists ofmultiple active domains organised into modules. Each module is responsiblefor the construction of a carbon-carbon bond, via the decarboxylative condensationof a ketide extender unit with the growing polyketide chain, followed bya programmed reductive cycle.

A number of polycyclic aromatic natural products—including several noteworthy anticancer, antibacterial, antifungal, antiviral, antiparasitic, and other medicinally significant substances—are synthesized by polyketide synthases (PKSs) in soil-borne bacteria called actinomycetes. Concerted biosynthetic, enzymological, and structural biological investigations into these modular enzyme systems have yielded interesting mechanistic insights. A core module called the minimal PKS is responsible for synthesizing a highly reactive, protein-bound poly-β-ketothioester chain. In the absence of other enzymes, the minimal PKS also catalyzes chain initiation and release, yielding an assortment of polycyclic aromatic compounds. In the presence of an initiation PKS module, polyketide backbones bearing additional alkyl, alkenyl, or aryl primer units are synthesized, whereas a range of auxiliary PKS enzymes and tailoring enzymes convert the product of the minimal PKS into the final natural product. In this Account, we summarize the knowledge that has been gained regarding this family of PKSs through recent investigations into the biosynthetic pathways of two natural products, actinorhodin and R1128 (A–D).

Figure 10 is anexample of a successful inter-polypeptide chain transfer between fusedmodules of
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Steps towards the synthetic biology of polyketide biosynthesis

This is supported by our long-standing relationships with a worldwide fabric of producers ensuring the greatest prospects for uninterrupted supply in markets that are often volatile and unpredictable.

5-11-2015 · In the studies on fungal polyketides ..

In contrast, the structures of glycans, lipids, polyketides, nonribosomal peptides, and various secondary metabolites are determined by biosynthetic pathways.

oryzae in the biosynthesis of fungal polyketides ..

Indeed the September 1997 issue of Chemical Reviews is devoted completelyto discussion of a few representative polyketides and polypeptides.

Polyketides are usually biosynthesized through the decarboxylative ..

Metabolism1.0 Global and overview maps1.1 Carbohydrate metabolism1.2 Energy metabolism1.3 Lipid metabolism1.4 Nucleotide metabolism1.5 Amino acid metabolism1.6 Metabolism of other amino acids1.7 Glycan biosynthesis and metabolism1.8 Metabolism of cofactors and vitamins1.9 Metabolism of terpenoids and polyketides1.10 Biosynthesis of other secondary metabolites1.11 Xenobiotics biodegradation and metabolism1.12 Chemical structure transformation maps

The biosynthesis of polyketides is modular at many levels

Many polyketide products are well-known compoundssuch as Erythromycin A, a broad spectrum macrolide antibiotic, the antihelminticagent avermectin or the immunosuppresants FK506 and rapamycin.

Biosynthesis of polyketides by trans-AT polyketide synthases

Additionaldegrees of complexity arise from the use of different starter units andchain elongation units as well as the generation of new stereo-isomers.

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