Submitted to: Journal of Antibiotics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/12/2007
Publication Date: 7/23/2007
Citation: Price, N.P., Tsvetanova, B. 2007. Biosynthesis of the Tunicamycins: a review. Journal of Antibiotics. 60(8):485-491. Interpretive Summary: The carbohydrate-based natural products tunicamycin are produced by soil-dwelling bacteria, Streptomyces, and have potent antifungal and antibacterial activity. Although this is well established, how the tunicamycin are bio-synthesized is only recently becoming understood. This paper reviews the metabolic processes leading to the biosynthesis of the tunicamycins, with particular emphasis on the biosynthetic pathways established by the authors in previous publications. An understanding of these pathways allows the possibility for their manipulation to produce novel, and potentially more useful antimicrobial agents based on the parent structure of the tunicamycins. This information will be valuable to researchers in the area of antifungal agents and, more generally, to the U.S. pharmaceutical and agrochemical industry.
Technical Abstract: Tunicamycins are nuclueotide sugar analogs produced by several Streptomyces species. In eukaryotes, tunicamycins inhibit UDP-N-acetylglucosamine:dolichol phosphate GlcNAc-1-P transferase (GPT) that catalyzes the first step in protein glycosylation. In bacteria they inhibit UDP-N-acetylmuramoyl-pentapeptide:undecaprenol phosphate MurNAc-pentapeptide-1-P transtransferase (MraY) that catalyzes an early stage in peptidoglycan cell wall assembly. Tunicamycins are substrate analog of GPT and MraY, such that the alpha beta-1",11'-linked GlcNAc residue of the tunicamycins mimics the transferred GlcNAc-1-phosphate. The unusual structure of tunicamycins, particularly the unique 11-carbon sugar, tunicamine, and the alpha beta-1",11'-O-glycosidic linkage, suggest its biosynthesis to be unique. This review discusses potential biosyntheses for tunicamycins via the synthesis and conjugation of uridine-5'-aldehyde and UDP-4-keto-N-acetylgalactosamine-5,6-ene and the subsequent formation of the alpha beta-1",11' glycosidic linkage.