CAREER: Enzymatic Sulfur Incorporation and Modification in the Biosynthesis of Natural Products

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With the support of the Chemistry of Life Processes Program in the Chemistry Division, Jie Li from the University of South Carolina is studying how nature uses enzymes to incorporate and modify sulfur centers in microbial secondary metabolites. These natural products provide a competitive advantage to the producing microbes while also conferring significant fundamental value in medicinal, manufacturing, agricultural applications. In contrast to extensively studied sulfur incorporation in primary metabolism (e.g., nucleotides and amino acids), there is a gap in the general understanding of the installation of sulfur in secondary metabolites. Thus, this study seeks to develop a molecular-level understanding of this life process, which will provide not only valuable sulfur-containing natural products but also opportunities to employ relevant enzymes in practical applications, including synthetic biology and green chemistry. Furthermore, this research synergizes with education and outreach activities aimed at conveying the importance of the chemistry of living systems to diverse groups of students, particularly members of underrepresented minority communities including students at historically black colleges and universities in South Carolina. An important outreach activity will involve a Backyard Chemists program, through which backyard microbial samples will be collected in the larger community, thereby engaging community members in the discovery of new natural products.This research project is directed at the investigation of the enzymology of sulfur incorporation and modification in the biosynthesis of microbial natural products, with initial efforts focused on two unique types of sulfur-containing natural products: sulfenic acids and sulfonolipids. The goal of the research includes understanding how a sulfur center is transferred, incorporated, and modified in sulfenic acids and/or sulfonolipids through a series of enzymatic steps, as part of both primary and secondary metabolism and from both organic and inorganic sulfur sources. A flavoprotein and two pyridoxal phosphate-dependent enzymes and their mechanisms will be studied. A combination of in vivo genetic manipulation, in vitro enzymatic reconstitution, site-directed mutagenesis, enzyme kinetics, and protein crystallography will be employed. Considering the remarkable diversity of sulfur reactivity, this work is expected to both facilitate discovery of sulfur-containing natural products and advance fundamental understanding of enzymatic sulfur incorporation and modification in natural products biosynthesis. This work has the potential to yield new strategies to unleash the power of enzymatic reactions in natural products chemistry.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.