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Combinatorial Biosynthesis of Natural Products - …

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Combinatorial biosynthesis of lipopeptide antibiotics …

Our faculty leads a wide variety of research ranging across multiple disciplines within and even beyond the field of chemistry. Brian Bachmann is leading the search for new avenues for "green" drug discovery by combinatorial biosynthesis. Recently, a team led by Jeff Johnston announced a novel method for chemically synthesizing peptides that promises to lower the cost and increase the availability of drugs based on natural compounds. David Wright, who specializes in bioinorganic and biomaterials chemistry, was recently awarded a Gates Foundation grant to develop a field test for malaria for the developing world that required no refrigeration, special equipment or expertise to administer.

Combinatorial biosynthesis of polyketides — a …

Two disparate polyketide families, the benzenediol lactones and the azaphilones, are produced by fungi using iterative polyketide synthase (iPKS) enzymes consisting of collaborating partner subunits. Exploitation of this common biosynthetic logic using iPKS subunit shuffling allowed the diversity-oriented combinatorial biosynthesis of unprecedented polyketide scaffolds new to nature, bearing structural motifs from both of these orthogonal natural product families. Starter unit acyltransferase domain replacements proved necessary but not sufficient to guarantee communication between iPKS subunits.

Combinatorial Biosynthesis - an overview | …

Combinatorial biosynthesis of sapogenins and saponins in Saccharomyces cerevisiae using a C-16α hydroxylase from Bupleurum falcatum.

Combinatorial Biosynthesis of Tetrahydrocannabinol - The LEGO-Principle to Construct an Artifical Biosynthetic Pathway for THCA will be available on

Natural products continue to play a pivotal role in drug-discovery efforts and in the understanding if human health. The ability to extend nature's chemistry through combinatorial biosynthesis-altering functional groups, regiochemistry and scaffold backbones through the manipulation of biosynthetic enzymes-offers unique opportunities to create natural product analogs. Incorporating emerging synthetic biology techniques has the potential to further accelerate the refinement of combinatorial biosynthesis as a robust platform for the diversification of natural chemical drug leads. Two decades after the field originated, we discuss the current limitations, the realities and the state of the art of combinatorial biosynthesis, including the engineering of substrate specificity of biosynthetic enzymes and the development of heterologous expression systems for biosynthetic pathways. We also propose a new perspective for the combinatorial biosynthesis of natural products that could reinvigorate drug discovery by using synthetic biology in combination with synthetic chemistry.

Combinatorial Biosynthesis of Reduced Polyketides …

Combinatorial biosynthesis of novel antibiotics related …

ABSTRACT

Intellectual Merit:

The overall goal of this project is to initiate metabolic engineering efforts in Catharanthus roseus madagascar periwinkle) to produce non-natural alkaloids. Combinatorial biosynthesis, which entails the swapping of wild type enzymes with enzymes having altered substrate specificity, has been successfully applied to a variety of prokaryotic biosynthetic pathways to yield nonnatural versions of natural products. This research describes how combinatorial biosynthesis can be accomplished in C. roseus to yield complex terpene indole alkaloid analogues. The substrate flexibility of the terpene indole alkaloid biosynthetic machinery in C. roseus has been shown to be tolerant to non-natural substrates. Additionally, the first committed enzyme of the pathway (strictosidine synthase) has been reengineered to display altered substrate specificity. These reengineered enzymes will be transformed into C. roseus cell culture and the production levels of terpene indole alkaloid analogues will be monitored in the transgenic C. roseus strains.

Broader Impact:

Graduate, undergraduate and post-doctoral researchers are exposed to chemical synthesis, protein expression and mutagenesis and molecular biology protocols. Since this research uses a multidisciplinary approach to solve problems in the area of natural product biosynthesis, students have numerous opportunities to interact with other labs with complementary areas of expertise. Furthermore, a graduate level course in natural product biosynthesis has been developed and is being refined. This course material is made available to the general public through MIT's open courseware site URL. Strategies to enhance the teaching of an introductory chemistry course are also described.

N2 - Two disparate polyketide families, the benzenediol lactones and the azaphilones, are produced by fungi using iterative polyketide synthase (iPKS) enzymes consisting of collaborating partner subunits. Exploitation of this common biosynthetic logic using iPKS subunit shuffling allowed the diversity-oriented combinatorial biosynthesis of unprecedented polyketide scaffolds new to nature, bearing structural motifs from both of these orthogonal natural product families. Starter unit acyltransferase domain replacements proved necessary but not sufficient to guarantee communication between iPKS subunits.

Combinatorial Biosynthesis of Legume Natural and …
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    Combinatorial biosynthesis

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Diversity-Oriented Combinatorial Biosynthesis of …

AB - Two disparate polyketide families, the benzenediol lactones and the azaphilones, are produced by fungi using iterative polyketide synthase (iPKS) enzymes consisting of collaborating partner subunits. Exploitation of this common biosynthetic logic using iPKS subunit shuffling allowed the diversity-oriented combinatorial biosynthesis of unprecedented polyketide scaffolds new to nature, bearing structural motifs from both of these orthogonal natural product families. Starter unit acyltransferase domain replacements proved necessary but not sufficient to guarantee communication between iPKS subunits.

combinatorial biosynthesis | Chemistry

Why Natural Products?

Natural products remain the best sources of drugs and drug leads

Natural products remain the best sources of drugs and drug leads, and this remains true today despite the fact that many pharmaceutical companies have deemphasized natural products research in favor of HTP screening of combinatorial libraries during the past 2 decades. From 1940s to date, 131 (74.8%) out of 175 small molecule anticancer drugs are natural product-based/inspired, with 85 (48.6%) being either natural products or derived therefrom. From 1981 to date, 79 (80%) out of 99 small molecule anticancer drugs are natural product-based/inspired, with 53 (53%) being either natural products or derived therefrom. Among the 20 approved small molecule New Chemical Entities (NCEs) in 2010, a half of them are natural products.

Natural products possess enormous structural and chemical diversity that is unsurpassed by any synthetic libraries. About 40% of the chemical scaffolds found in natural products are absent in today’s medicinal chemistry repertoire. Based on various chemical properties, combinatorial compounds occupy a much smaller area in molecular space than natural products. Although combinatorial compounds occupy a well-defined area, natural products and drugs occupy all of this space as well as additional volumes. Most importantly, natural products are evolutionarily optimized as drug-like molecules. This is evident upon realization that natural products and drugs occupy approximately the same molecular space.

Natural products represent the richest source of novel molecular scaffolds and chemistry. No one can predict, in advance, the details of how a small molecule will interact with the myriad of targets that we now know drive fundamental biological processes. The history of natural product discovery is full of remarkable stories of how the discovery of a natural product profoundly impacted advances in biology and therapy. For instance, Taxol's impact on tubulin polymerization, and correlation to antitumor action or rapamycin's binding to mTOR and the ramifications of mTOR inhibitors could never be predicted . The discovery of new natural products promises significant advances not only in chemistry, but also, biochemistry and medicine.


Natural products are significantly underrepresented in current small molecule libraries

In spite of the great success of natural products in the history of drug discovery, natural products are significantly underrepresented in current small molecule libraries. Challenges of natural products in drug discovery and development include (i) extremely low yields, (ii) limited supply, (iii) complex structures posing enormous difficulty for structural modifications, and (iv) complex structures precluding practical synthesis. These difficulties lead to the pharmaceutical industry to embrace new technologies in the past two decades, particularly combinatorial chemistry, at the detriment to interest in natural product discovery.


Microbial natural products as preferred sources of new drugs and drug leads

Microbial natural products have several intrinsic properties favoring their consideration in drug discovery and development. Microbial natural products can be produced by large-scale fermentation. Microorganisms can be engineered to overproduce the desired natural products hence to solving the supply bottleneck. Microbial natural product analogues can be produced by metabolic pathway engineering, thereby providing a focused library for structure-activity-relationship studies. The vast, untapped, ecological biodiversity of microbes holds great promise for the discovery of novel natural products, thereby improving the odds of finding novel drug leads.

The exponential growth in cloning and characterization of natural product biosynthetic machinery from microbes in the last two decades has unveiled unprecedented molecular insights into natural product biosynthesis, including the observation that genes for natural product biosynthesis are clustered in the microbial genome and that variations of a few common biosynthetic machineries can account for vast structural diversity observed for natural products. These findings have fundamentally changed the landscape of natural product research by enabling the revision of known natural product structures, the prediction of yet-to-be isolated novel compounds on the basis of gene sequences, and the systematic generation of “unnatural” natural products by manipulating genes governing their biosynthesis (also known as combinatorial biosynthesis).

Whole genome sequencing has revealed far more biosynthetic gene clusters than actual metabolites currently known for a given organism, suggesting that the biosynthetic potential for natural products in microorganisms is greatly under-explored by traditional natural product discovery methods. Among the whose genomes have been sequenced, every one of them has the potential to produce up to 30 natural products on average, and this optimism has already translated into the discovery of new natural products by fermentation optimization from strains that otherwise were not previously known as natural product producers.

Only 1% of the microbial community has been estimated to be cultivated in the lab, implying that the vast biodiversity of microbial natural products remains underappreciated. Emerging new cultivating techniques, culture-independent methods by expressing gene clusters in model heterologous hosts, and diligent effort and innovative approaches in novel microbial strain collection, identification, and classification have started to permit access to these previously inaccessible natural product resources.

The future of microbial natural product drug discovery and development remains bright. (i) Advances in DNA sequencing will greatly facilitate genome sequencing and genomics-based natural products discovery. (ii) Advances in DNA synthesis and synthetic biology will greatly facilitate natural product pathway reconstruction, engineering, and expression in model or industrial hosts for natural product production. (iii) Advances in HTS will further enable rapid screening of natural product libraries for an ever broader range of biological application. (iv) Advances in isolation technologies, analytic methods, automatic robotics, and database management will greatly facilitate natural products library construction. (v) Environmental concerns will further favor bio-based natural products drug discovery and development processes, i.e., fermentation, metabolic pathway engineering, and renewable resources.

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