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Abstract

Natural products are a chemically diverse group of molecules that are isolated from bacteria, fungi, or plants. Many natural products can be employed as active pharmaceutical agents, among which there is a subset bearing N-heterocycles or diazo groups in their structures. In this thesis, I have been studying the biosynthetic assembly of two types of heterocycle-containing molecules and one type of diazo compound. In the first chapter of my thesis, I review the research background of these three molecules: piperazic acid, azaserine, and azomycin. In the second chapter of my thesis, I describe my work on piperazic acid, which for the first time reveals how this cyclic hydrazine α-amino acid is activated for incorporation into diverse nonribosomal peptidyl natural products by employing a strain named Streptomyces incarnatus NRRL 8089 and its putative incarnatapeptin gene cluster. In the third chapter of my thesis, I discuss the biosynthetic studies of the diazo α-amino acid azaserine in Glycomyces harbinensis DSM46494, implicating a novel pathway for diazo group formation in nature. In the fourth chapter of my thesis, I write about my X-ray crystallographic studies on two azomycin biosynthetic enzymes from the Pseudomonas genus − RohQ and RohS − featuring a cyclodehydratase catalyzing spontaneous cyclodehydration reaction and an enzyme belonging to the emerging family of heme oxygenase-like ḏiiron oxidase/oxygenase (HDO) that catalyzes a six-electron oxidation, respectively. In the concluding chapter of my thesis, I summarize my work on these three research topics and discuss their future directions.