Abstract 2362 A myo-inositol dehydrogenase involved in aminocyclitol biosynthesis of hygromycin A

Hygromycin A is a broad-spectrum antibiotics synthesized by the soil bacterium Streptomyces hygroscopicus. It is composed of three distinct moieties: furanose, cinnamic acid, and aminocyclitol. The cinnamic acid and aminocyclitol moieties are essential for bioactivity. Although the biosynthesis of the aminocyclitol has been proposed through six enzymatic steps, biochemical investigations of individual enzyme activity are lacking. Here, we verify the activity of one enzyme in the pathway, Hyg17. Through bioinformatics and biochemical analysis, we show that Hyg17 is a myo-inositol dehydrogenase with an optimum pH of 10.5-11, preference for NAD+ as a cofactor, and unique promiscuity with scyllo-inositol. Additionally, we show that certain members of this protein family are involved in different natural product biosynthetic pathways and suggest these sequences can be used as specialized genome-mining targets for discovering novel natural products. Our findings not only verify a critical step in the biosynthesis of the aminocyclitol moiety from hygromycin A but will also set the stage for identifying new compounds with therapeutic potential. Research was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R35GM151137