Synthetic biological approaches to natural product biosynthesis

Abstract

Small molecules produced in Nature continue to be an inspiration for the development of new therapeutic agents. These natural products possess exquisite chemical diversity, which gives rise to their wide range of biological activities. In their host organism, natural products are assembled and modified by dedicated biosynthetic pathways that Nature has meticulously developed. Often times, the complex structures or chemical modifications instated by these pathways are difficult to replicate using traditional synthetic methods. An alternative approach for creating or enhancing the structural variation of natural products is through combinatorial biosynthesis. By rationally reprogramming and manipulating the biosynthetic machinery responsible for their production, unnatural metabolites that were otherwise inaccessible can be obtained. Additionally, new chemical structures can be synthesized or derivatized by developing the enzymes that carry out these complicated chemical reactions into biocatalysts. In this review, we will discuss a variety of combinatorial biosynthetic strategies, their technical challenges, and highlight some recent (since 2007) examples of rationally designed unnatural metabolites, as well as platforms that have been established for the production and modification of clinically important pharmaceutical compounds.

Production of Bioactive Diterpenoids in the Euphorbiaceae Depends on Evolutionarily Conserved Gene Clusters

“…Alternatively, drugs can be produced in heterologous species such as Escherichia coli or Saccharomyces cerevisiae. The advent of synthetic biology has proven particularly beneficial in this latter approach (Paddon et al, 2013), and this could also be exploited to produce novel compounds by combinatorial biochemistry (Winter and Tang, 2012). However, our understanding of diterpenoid biosynthesis within the Euphorbiaceae is limited at present.…”

Diversity-oriented combinatorial biosynthesis of benzenediol lactone scaffolds by subunit shuffling of fungal polyketide synthases

“…Natural polyketides from diverse microorganisms also deliver novel scaffolds that can be exploited in drug discovery programs by semisynthetic modification and combined chemical and biosynthetic approaches (4,5) and as inspiration for total synthesis and combinatorial chemistry (6,7). A complementary approach is combinatorial biosynthesis, which strives to reengineer biosynthetic pathways to generate novel polyketide scaffolds by one-pot, onestep synthesis via fermentation of recombinant microorganisms.…”

An Overview on Marine Sponge-Symbiotic Bacteria as Unexhausted Sources for Natural Product Discovery

“…Discovery of cryptic pathways may not only be used to activate silent gene clusters and detect novel compounds but may also improve the production of compounds that are already expressed [225]. These new techniques and discoveries in heterologous gene expression could therefore potentially eliminate the supply problem from the marine macro-organisms and can be used for the production of these compounds not only for clinical trials but also for subsequent commercial uses [231].…”

“…The draft genome may be used to identify cryptic pathways by analyzing the genome using bioinformatics [221][222][223]. Combinatorial biosynthesis is a technique that exploits this gene cluster organization within the pathway through genetic manipulation (addition, deletion, and reorganization of genes and amino acids) of these clusters with the aim of creating new pathways responsible to produce novel compounds [57,224,225]. Pathways could also be genetically altered to produce structurally novel analogs with improved pharmacological profiles [226].…”