Biosynthetic pathways are rich in enzymatic transformations that produce structurally diverse natural products, such as secondary metabolites, modified nucleic acids, and modified peptides. Discovering and understanding the molecular basis for these transformations underpins efforts towards development of deep insights into factors that either belie many disease processes, or their use in development of therapeutic agents. The two major NIGMS-funded research areas in the Bandarian lab at the University of Utah focus on (1) discovering the molecular basis of biogenesis of the pyrrolopyrimidine core structure found in a variety of secondary metabolites, as well as in the hypermodified base, queuosine, and (2) elucidating the mechanism of enzymes involved in the biosynthetic pathways of ribosomally synthesized posttranscriptionally modified polypeptides (RiPPs), which are emerging as a new group of natural products with substantial potential as therapeutic agents. These pathways often utilize complex radical- mediated enzymatic transformations whose mechanisms are not known. The discovery and mechanistic studies of these enzymes are proposed as part of this R35 application. !
All organisms produce a bevy of small molecules, many of which are not required for primary metabolic processes but confer selective advantage to the producing organism in complex biological environments. The biosynthetic pathways to these molecules often involve complex enzymatic transformations, which in many cases remain to be discovered. Understanding the biosynthetic pathways to these small molecule natural products is an important step in gleaning their role in physiology, with an ultimate goal of introducing them in the clinic.! !
|Grell, Tsehai A J; Kincannon, William M; Bruender, Nathan A et al. (2018) Structural and spectroscopic analyses of the sporulation killing factor biosynthetic enzyme SkfB, a bacterial AdoMet radical sactisynthase. J Biol Chem 293:17349-17361|
|Wilcoxen, Jarett; Bruender, Nathan A; Bandarian, Vahe et al. (2018) A Radical Intermediate in Bacillus subtilis QueE during Turnover with the Substrate Analogue 6-Carboxypterin. J Am Chem Soc 140:1753-1759|
|Young, Anthony P; Bandarian, Vahe (2018) TYW1: A Radical SAM Enzyme Involved in the Biosynthesis of Wybutosine Bases. Methods Enzymol 606:119-153|
|Lewis, Julia K; Bruender, Nathan A; Bandarian, Vahe (2018) QueE: A Radical SAM Enzyme Involved in the Biosynthesis of 7-Deazapurine Containing Natural Products. Methods Enzymol 606:95-118|
|Bandarian, Vahe (2018) Preface. Methods Enzymol 606:xv-xvi|
|Dowling, Daniel P; Miles, Zachary D; Köhrer, Caroline et al. (2016) Molecular basis of cobalamin-dependent RNA modification. Nucleic Acids Res 44:9965-9976|