Looking Back and Building Forward: Natural Products Biosynthesis

Natural products are organic secondary metabolites produced by all forms of life. In their native environment, natural products mediate intra- and interspecies communication. Bioinhibitory activities of natural products make them medicinally attractive– majority of clinically used drugs and pharmaceuticals are or are derived from natural products. The Agarwal laboratory seeks to understand how gene encoded enzymes construct natural product organic structures starting from simple biologically available starting materials. With the underlying motivation to reconstitute natural product biosynthetic pathways in the laboratory, we use a multidisciplinary approach involving metabolomics, (meta)genomics, enzymological assays, and structural biology to query the intricate enzymological chemistry which underlies natural product biosynthesis, and the metabolomic and genomic complexity of multi-organismal ecological niches in which natural products are produced. This seminar will highlight recent progress in three research directions: mass spectrometry-based identification of intermediates to reconstruct cryptic biosynthetic schemes, total in vitro reconstitution of polyketide synthases to reveal gatekeeping selectivity of ketosynthase domains, and the discovery and synthetic biological elaboration of an exceptionally widely distributed biosynthetic gene loci encoding brominated ribosomally synthesized and post-translationally modified peptide natural products.