Engineering multifunctional enzymes and investigating versatility of enzymatic halogenation for nonribosomal peptide synthesis

Nonribosomal peptides are natural products biosynthesized by multi-modular enzymatic assembly-lines comprised of domains performing varied activities. Adenylating enzymes play a key role in dictating the identity of building blocks to be incorporated in growing peptides during nonribosomal peptide biosynthesis. To increase the structural diversity of the products it generates, Nature has evolved unique interrupted adenylating enzymes capable of performing both adenylation and methylation reactions. We will present our biochemical and structural work towards understanding the mechanism by which these unique enzymes function and our efforts towards engineering novel interrupted enzymes with adenylating and methylating activities. Additionally, we will discuss halogenation, an important biotransformation and a highly promising transformation in medicinal chemistry, which could lead to improvement in pharmacological and pharmaceutical properties of compounds or enabling further modifications by using the halogen as a reactive handle. In the last decade, halogenases have emerged as highly promising tools that may serve as an alternative or the only route to halogenating some molecules, especially natural products. Our biochemical and structural study of two halogenases will be presented.