Oxidative Cyclizations in Orthosomycin Biosynthesis Expand the Known Chemistry of an Oxygenase Superfamily
Oxidative cyclizations in orthosomycin biosynthesis expand the known chemistry of an oxygenase superfamily Kathryn M. McCullocha, Emilianne K. McCranieb, Jarrod A. Smithc, Maruf Sarwara, Jeannette L. Mathieua, Bryan L. Gitschlaga,YuDub, Brian O. Bachmannb,c,1, and T. M. Iversona,c,1 aDepartment of Pharmacology, Vanderbilt University, Nashville, TN 37232; bDepartment of Chemistry, Vanderbilt University, Nashville, TN 37235; and cDepartment of cBiochemistry, Vanderbilt University, Nashville, TN 37232 Edited by John T. Groves, Princeton University, Princeton, NJ, and approved July 2, 2015 (received for review January 26, 2015) Orthosomycins are oligosaccharide antibiotics that include avila- and avilamycin, which each contain two orthoester linkages (Fig. mycin, everninomicin, and hygromycin B and are hallmarked by a 1A, red) and a methylenedioxy bridge (Fig. 1A, blue). Methyl- rigidifying interglycosidic spirocyclic ortho-δ-lactone (orthoester) enedioxy bridge formation has previously been attributed to cy- linkage between at least one pair of carbohydrates. A subset of tochrome P450 enzymes (7, 8). However, orthoester linkage orthosomycins additionally contain a carbohydrate capped by a biosynthesis has not previously been described. Orthoester linkage methylenedioxy bridge. The orthoester linkage is necessary for formation is associated with especially demanding steric con- antibiotic activity but rarely observed in natural products. straints and substrates that are already highly oxygenated, and its Orthoester linkage and methylenedioxy bridge biosynthesis re- biosynthesis results in a unique trioxaspiro functional group. quire similar oxidative cyclizations adjacent to a sugar ring. We Everninomicin and avilamycin biosynthetic gene clusters en- have identified a conserved group of nonheme iron, α-ketogluta- code upwards of 50 enzymes with many lacking assigned func- rate–dependent oxygenases likely responsible for this chemistry.
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