Natural Product Biosynthesis, Engineering and Drug Discovery
Microorganisms produce a large variety of biologically active substances representing a vast diversity of fascinating molecular architecture not available in any other systems. Our research centers on the chemistry, biochemistry, and genetics of the biosynthesis of these natural products. Blending organic chemistry, biochemistry, and molecular biology, we take a multidisciplinary approach to study the secondary metabolism by asking the following questions: what reactions are available in nature, what are the enzymatic mechanisms of these reactions, how are these reactions linked to produce complex structures, what are the regulatory mechanisms of these pathways, and, ultimately, how can we leverage the large actinobacterial strain collection and develop enabling genome mining and synthetic biology technologies for natural product discovery and production, and manipulate nature’s biosynthetic machinery for the discovery and development of new drugs. Members of our group gain broad training spanning organic chemistry, biochemistry, microbiology and molecular biology, a qualification that is becoming essential for the modern bioorganic chemists who seek career opportunity in both academia and pharmaceutical and biotechnology industry (https://shen.scripps.ufl.edu/).
Natural Products Discovery Center at UF Scripps
Natural products have been exquisitely tailored via evolution to elicit potent and unique biological activities, rendering them unrivaled in structural complexity and diversity. Of the FDA-approved small molecule therapeutics, 67% of anti-infective and 83% of anti-cancer drugs are natural products, natural product derivatives, or inspired by natural products. UF Scripps houses one of the world’s largest actinobacterial strain collections, totaling 125,127 strains. These strains were isolated over the last eight decades, with the majority acquired between 1940s to the 2010s. The wide time range of collection has allowed for capture of chemical diversity based on evolution and environmental cues, which change over time and are impossible to reproduce in laboratory settings today. Spanning at least 88 different genera, these strains were isolated from 69 different countries with different climate and ecology factors that further increase natural product structural diversity. The ~125K strains in the collection are estimated to produce more than 3.75 million natural products. In reference to the ~20,000 natural products that have been isolated from actinobacteria, the current number of known natural products is only ~1% of this value, leaving millions of compounds to be discovered. The strain collection therefore provides an unprecedented source of rich and unique natural product chemotypes to target emerging biology and accelerate drug discovery (https://scripps.ufl.edu/departments/centers-and-specialties/natural-products-discovery-center/).
We are excited to have launched the NPDC Genome Portal from which investigators across the world can access the Actinobacterial Strain Collection. The initial release includes 8,490 assembled genomes, a mere 7% of the total collection, and each of these strains are immediately available upon request. This remarkable resource has the potential to revolutionize natural product discovery and related fields. In our portal, users can see data on each strain’s taxonomy, view associated biosynthetic gene clusters (BGCs), and download the genome as desired. We have also implemented an easy-to-use BLASTP system, from which users can search for proteins (or a set of co-occurring proteins) of interest in both genomes and BGCs as we continue to sequence the collection. We hope that the unique aspect of our collection, namely the dual availability of both genome and strain, will allow investigators to realize their most ambitious objectives and usher in a new Golden Age of Natural Products.