Biosynthesis of Polyketides and Related Compounds | …
Biosynthesis of Polyketides and Related Compounds | Science
Biosynthesis of Polyketides and Related Compounds
The recognition between an ACP and a KS is essential for polyketide biosynthesis. Although the KSCLF and ACP subunits from many (but not all) type II PKSs are qualitatively interchangeable, the variable affinity can be kinetically distinguished and likely contributes to polyketide titers in at least some cases.– An extreme example is actinorhodin and spore pigment biosynthesis in S. coelicolor. Even though both products are synthesized by closely related type II PKSs in the same host, their KSCLF and ACP subunits have orthogonal specificity. The solution structures of the act ACP, fren ACP and otc (oxytetracycline) ACP have been determined by NMR spectroscopy.– Together with the X-ray structure of the act KS-CLF, this has provided insight into their relative docking orientation. However, re-engineering of this protein interface has not yet been successful, a testament to the difficulty associated with the general problem of engineering weak but specific protein-protein interactions. NMR spectroscopy has also shown that the ACP backbone adopts multiple conformations in dynamic equilibrium with each other. Presumably this is necessary in order to allow the ACP to dock with multiple enzyme partners during polyketide chain initiation, elongation, modification and release. Yet again, a solid understanding of the mechanistic principles for this extraordinary tolerance and specificity remains a major challenge towards a deeper understanding of assembly line biosynthesis of antibiotics.
What is the origin of the pederin-type biosynthetic pathways in these diverse animals? The close similarity and complexity of the ped and onn systems suggest that they are derived from a common ancestral gene cluster. As a direct symbiont or gene transfer between sponges and beetles is very unlikely, this cluster should have once belonged to a free-living bacterium. This idea raises the intriguing question of why metabolites of the pederin group, which are highly conspicuous in biological assays because of their potent activity, have never been found in a nonsymbiotic strain. One possible explanation is that if these compounds confer an advantage to animal hosts rather than to the producers themselves, the biosynthetic genes would be preferentially maintained in symbionts. Ecological studies on the effect of the polyketides on sponge epibionts or predators would help to clarify this issue.
Biosynthesis of Polyketides and Related ..
Synthetic biology often employs enzymes in the biosynthesis of compounds for purposeful function. Here, we define synthetic enzymology as the application of enzymological principles in synthetic biology and describe its use as an enabling platform in synthetic biology for the purposeful production of compounds of biomedical and commercial importance. In particular, we demonstrated the use of synthetic polyketide enzymology as a means to develop lead polyketide based compounds for antimicrobial therapeutics, as exemplified by the modular coupling of acid:CoA ligases to type III polyketide synthases in the biosynthesis and development of polyketide-based biochemicals. Using wild-type and rationally designed mutants of a type III polyketide synthase isolated from (OsPKS), we produced a chemically diverse library of novel polyketides and identified two bioactive antimicrobials, 4-hydroxy-6-[(1)-2-(4-hydroxyphenyl)ethenyl]-2-pyran-2-one (bisnoryangonin) and 3,6,7-trihydroxy-2-(4-methoxybenzyl)-4-1-benzopyran-4,5,8-trione (26OH), respectively, from a screen against a collection of Gram-positive and Gram-negative bacteria. The purification, crystallization, and structural resolution of recombinant OsPKS at 1.93 Å resolution are also reported. Using the described route of synthetic polyketide enzymology, a library of OsPKS mutants was generated as an additional means to increase the diversity of the polyketide product library. We expect the utility of synthetic enzymology to be extended to other classes of biomolecules and translated to various purposeful functions as the field of synthetic biology progresses.
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).
Antitumor polyketide biosynthesis by an uncultivated bacterial ..
A number of polycyclic aromatic natural products are synthesized by polyketide synthases (PKSs) in soil-borne bacteria called actinomycetes. They exhibit anticancer (e.g. doxorubicin), antibacterial (e.g. oxytetracycline), antifungal (e.g. pradimicin), antiviral (e.g. A-74528), antiparasitic (e.g. frenolicin) and other related activities. These PKSs, also called type II PKSs because of their relationship to type II fatty acid synthases from bacteria and plants, are comprised of a set of highly conserved 5–50 kDa protein subunits. The chemistry, biology and biosynthesis of this family of polyketides have been the subjects of several comprehensive reviews in the past decade.– This article provides a narrative of what has been learned within the past eight years regarding the biosynthetic logic of type II PKSs through structural, mechanistic and biosynthetic investigations into two prototypical synthases – the actinorhodin PKS and the R1128 PKS. The structures of actinorhodin (1) and R1128 (2), as well as those of related aromatic polyketides discussed in this article, are shown in .
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).
the biosynthesis of closely related compounds
Biosynthesis of Aromatic Polyketides in ..
Science. ISSN 0036-8075 (print), 1095-9203 (online) News | Science Journals
yielding an assortment of polycyclic aromatic compounds.
compounds 1 also ..
Polyketide | Alkene | Biosynthesis
Biosynthesis of polyketides
Polyketide - Free download as ..
However, the number of ways for biosynthetically designing and producing a desired compound is still limited, and developing methods that allow free rein to design molecules remains a major challenge.A research group led by graduate student Lihan Zhang and Professor Ikuro Abe at the University of Tokyo Graduate School of Pharmaceutical Sciences focused on the enzyme that produces the medicinally important substance polyketide, and analyzed its functions.
Synthetic Polyketide Enzymology: Platform for Biosynthesis ..
Polyketides are a structurally diverse but biosynthetically related family of natural products that includes a number of medicinally important substances such as lovastatin (a cholesterol-lowering agent), erythromycin (an antibiotic), and FK506 (an immunosuppressant) . Their structural and stereochemical complexity makes systematic chemical manipulation a formidable undertaking. Consequently, there has been considerable interest in the potential of harnessing combinatorial biosynthesis to introduce novel functionality into these bioactive compounds and to produce altogether new chemotypes.
Platform for Biosynthesis of Antimicrobial Polyketides
Bacterial symbionts have long been suspected to be the true producers of many drug candidates isolated from marine invertebrates. Sponges, the most important marine source of biologically active natural products, have been frequently hypothesized to contain compounds of bacterial origin. This symbiont hypothesis, however, remained unproven because of a general inability to cultivate the suspected producers. However, we have recently identified an uncultured Pseudomonas sp. symbiont as the most likely producer of the defensive antitumor polyketide pederin in Paederus fuscipes beetles by cloning the putative biosynthesis genes. Here we report closely related genes isolated from the highly complex metagenome of the marine sponge Theonella swinhoei, which is the source of the onnamides and theopederins, a group of polyketides that structurally resemble pederin. Sequence features of the isolated genes clearly indicate that it belongs to a prokaryotic genome and should be responsible for the biosynthesis of almost the entire portion of the polyketide structure that is correlated with antitumor activity. Besides providing further proof for the role of the related beetle symbiont-derived genes, these findings raise intriguing ecological and evolutionary questions and have important general implications for the sustainable production of otherwise inaccessible marine drugs by using biotechnological strategies.
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