Bioinspired iterative synthesis of polyketides (original) (raw)
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Steps towards the synthetic biology of polyketide biosynthesis
2014
Nature is providing a bountiful pool of valuable secondary metabolites, many of which possess therapeutic properties. However, the discovery of new bioactive secondary metabolites is slowing down, at a time when the rise of multidrug-resistant pathogens and the realization of acute and long-term side effects of widely used drugs lead to an urgent need for new therapeutic agents. Approaches such as synthetic biology are promising to deliver a much-needed boost to secondary metabolite drug development through plug-and-play optimized hosts and refactoring novel or cryptic bacterial gene clusters. Here, we discuss this prospect focusing on one comprehensively studied class of clinically relevant bioactive molecules, the polyketides. Extensive efforts towards optimization and derivatization of compounds via combinatorial biosynthesis and classical engineering have elucidated the modularity, flexibility and promiscuity of polyketide biosynthetic enzymes. Hence, a synthetic biology approach can build upon a solid basis of guidelines and principles, while providing a new perspective towards the discovery and generation of novel and new-to-nature compounds. We discuss the lessons learned from the classical engineering of polyketide synthases and indicate their importance when attempting to engineer biosynthetic pathways using synthetic biology approaches for the introduction of novelty and overexpression of products in a controllable manner.
The Stereocontrolled Total Synthesis of Polyketide Natural Products: A Thirty-Year Journey
Bulletin of the Chemical Society of Japan
received her BSc (Hons) and LLB (Hons) degrees (2016) from the University of Queensland, working in the labs of Prof James de Voss and Prof Joanne Blanchfield on the bioavailability of steroidal saponin natural products, isolation of bioactive products from traditional medicinal plants and synthesis of mechanistic probe molecules for cytochrome P 450 enzymes. She is currently pursuing her PhD at the University of Cambridge under the supervision of Prof Ian Paterson as a Herchel Smith Scholar, embarking on the total synthesis of the stereochemically-ambiguous natural product hemicalide. Nelson Y. S. Lam Nelson Lam received his BSc (Hons) degree (2015) from the University of Auckland, working in the lab of Prof Christian Hartinger. He obtained his PhD at the University of Cambridge (2019) under the supervision of Prof Ian Paterson as a Woolf Fisher Scholar, where he worked on the total synthesis of polyketide natural products. He is currently a postdoctoral associate and Lindemann Fellow with Prof Jin-Quan Yu at the Scripps Research Institute, developing novel Pd-catalysed C(sp 3)-H functionalisation transformations. Matthew J. Anketell Matthew Anketell received his BA and MA from the University of Cambridge, reading the Natural Sciences Tripos. In 2015, he joined the Paterson group where he embarked on the synthesis of the stereochemicallyambiguous patellazole marine natural products. He then continued research in the same group as a Herchel Smith Scholar, where he completed the total synthesis of the actinoallolide class of anti-trypanosomal macrolides, to obtain his PhD (2020). He is currently a postdoctoral associate with Prof Robert Britton at
An artificial pathway for polyketide biosynthesis
Nature Catalysis, 2020
Polyketide synthases are multi-domain enzymes that catalyse the construction of many bioactive natural products. Now, some of the inefficiencies and limitations of these systems have been solved by designing an artificial pathway for carbon-carbon bond formation via iterative rounds of non-decarboxylative thio-Claisen reactions. Anuran k. Gayen, lindsay nichols and Gavin J. Williams P olyketides are a class of natural products with diverse and potent biological activities, owing to their structural complexity and chemical diversity. Notable examples of polyketides include lovastatin (anticholesterol), doxorubicin (anticancer), ivermectin (antiparasitic), and erythromycin A (macrolide antibiotic). All polyketides are assembled via the repeated decarboxylative thio-Claisen condensation between malonyl-coenzyme A (malonyl-CoA) derivatives catalysed by enzyme machinery called polyketide synthases (PKSs). Type I PKSs are multi-modular mega-enzyme complexes, type II PKSs are a collection of cooperative enzymes, and type III PKSs iteratively catalyse chain elongation via ketosynthase domains. Though they differ in complexity and molecular organization, the three PKS types share similar substrate scopes, which largely consist of malonyl-and methylmalonyl-CoA extender units and simple acyl-CoA starter units, such as acetyl-, propionyl-, and isobutyryl-CoA. Site-selective modular control of oxidation levels by PKSs facilitates structural diversity in the polyketide scaffold that contributes to their biological activity 1. In spite of the proven ability to leverage PKSs for the production of blockbuster polyketide drugs, polyketide biosynthesis suffers from slow reaction kinetics, low energy efficiency, and poor carbon economy-only two out of three extender unit carbons incorporate into the polyketide backbone with loss of CO 2. In addition, the formation of the commonly utilized malonyl-CoA extender unit from acetyl-CoA, ATP and bicarbonate by acetyl-CoA carboxylase (ACC) is highly regulated and a likely rate-limiting step 2. While type II and III PKSs can be less complicated than their type I counterparts, they often do not express well in tractable heterologous hosts such as Escherichia coli (E. coli) and access to substrates is susceptible to competition with primary metabolism. Now, writing in Nature Catalysis, Gonzalez and colleagues report the
Hutchinson's legacy: keeping on polyketide biosynthesis
J Antibiot, 2011
Professor Charles Richard Hutchinson (Hutch) dedicated his research to the study of polyketide compounds, in particular, those produced by actinomycetes. Hutch principally centered his efforts to study the biosynthesis of bioactive compounds, antibiotic and antitumor drugs, and to develop new derivatives with improved therapeutic properties. After dedicating 40 years to the study of polyketides, Hutch leaves us, as legacy, the knowledge that he and his collaborators have accumulated and shared with the scientific community. The best tribute we can offer to him is keeping on the study of polyketides and other bioactive compounds, in an effort to generate more safer and useful drugs. In this review, the work on the polyketides, borrelidin, steffimycin and streptolydigin, performed at the laboratory of Professors Salas and Mé ndez at University of Oviedo (Spain) during the last 10 years, is summarized.
New Start and Finish for Complex Polyketide Biosynthesis
Chemistry & Biology, 2004
as well as a loading module for transferring the starter acyl group onto the first KS domain. This modular orga-Biosynthesis nization allows programmed assembly of a defined sequence of starter and extender units, together with controlled processing of each -ketone group. The final The polyketide vicenistatin has significant anticancer product may be cyclized by a thioesterase (TE) to give activity. In the January issue of Chemistry & Biology, a macrolactone.
Recombinatorial biosynthesis of polyketides
Journal of Industrial Microbiology & Biotechnology, 2011
Modular polyketide synthases (PKSs) from Streptomyces and related genera of bacteria produce many important pharmaceuticals. A program called CompGen was developed to carry out in silico homologous recombination between gene clusters encoding PKSs and determine whether recombinants have cluster architectures compatible with the production of polyketides. The chemical structure of recombinant polyketides was also predicted. In silico recombination was carried out for 47 well-characterised clusters. The predicted recombinants would produce 11,796 different polyketide structures. The molecular weights and average degree of reduction of the chemical structures are dispersed around the parental structures indicating that they are likely to include pharmaceutically interesting compounds. The details of the recombinants and the chemical structures were entered in a database called r-CSDB. The virtual compound library is a useful resource for computer-aided drug design and chemoinformatics ...
Synthetic biology enabling access to designer polyketides
Current Opinion in Chemical Biology, 2020
The full potential of polyketide discovery has yet to be reached due to a lack of suitable technologies and knowledge required to advance engineering of polyketide biosynthesis. Recent investigations on the discovery, enhancement, and non-natural utilization of these biosynthetic gene clusters via computational biology, metabolic engineering, structural biology, and enzymology-guided approaches have facilitated improved access to designer polyketides. Here, we discuss recent successes in gene cluster discovery, host strain engineering, precursor-directed biosynthesis, combinatorial biosynthesis, polyketide tailoring, and high-throughput synthetic biology, as well as challenges and outlooks for rapidly generating useful target polyketides.
Proceedings of the National Academy of Sciences, 2008
The enediynes, unified by their unique molecular architecture and mode of action, represent some of the most potent anticancer drugs ever discovered. The biosynthesis of the enediyne core has been predicted to be initiated by a polyketide synthase (PKS) that is distinct from all known PKSs. Characterization of the enediyne PKS involved in C-1027 (SgcE) and neocarzinostatin (NcsE) biosynthesis has now revealed that (i) the PKSs contain a central acyl carrier protein domain and C-terminal phosphopantetheinyl transferase domain; (ii) the PKSs are functional in heterologous hosts, and coexpression with an enediyne thioesterase gene produces the first isolable compound, 1,3,5,7,9,11,13-pentadecaheptaene, in enediyne core biosynthesis; and (iii) the findings for SgcE and NcsE are likely shared among all nine-membered enediynes, thereby supporting a common mechanism to initiate enediyne biosynthesis.