Work

Engineered Biosynthesis of Macrolide Derivatives Bearing the Non-Natural Deoxysugars 4- epi - d -Mycaminose and 3- N -Monomethylamino-3-Deoxy- d -Fucose

Year: 2007

Type: article

Abstract: Previous pathway engineering work demonstrated that the desosamine biosynthetic pathway in Streptomyces venezuelae could be converted to an efficient mycaminose biosynthesizing pathway by replacement of DesI with the hexose 3,4-ketoisomerase Tyl1a. In this work, FdtA, a ketoisomerase homologous to Tyl1a which catalyzes conversion of the Tyl1a substrate to the C-4 epimer of the Tyl1a product, was used to replace DesI. The ability of desosamine pathway enzymes DesV, DesVI, DesVII, and DesVIII to accept substrates with inverted C-4 stereochemistry in the mutant expressing FdtA resulted in formation of macrolide derivatives bearing 4- epi - d -mycaminose, a sugar heretofore unobserved in Nature. Interestingly, minor glycosylated macrolides bearing another non-natural sugar, 3- N -monomethylamino-3-deoxy- d -fucose, were also produced by this mutant. An explanation for the formation of these unexpected new compounds is presented, and the implications of this work for combinatorial biosynthesis of new antibiotics are discussed.

Source: Journal of the American Chemical Society

DOI: 10.1021/ja068254t

Authors: Charles E. Melançon, Hung-wen Liu

Institution: The University of Texas at Austin

Language: English

Topic: Microbial Natural Products and Biosynthesis

Subfield: Pharmacology

Field: Medicine

Domain: Health Sciences

Open Access status: green

Funder: National Institute of General Medical Sciences

Awards: C-C & C-N Bond Formation in Unusual Sugar Biosynthesis, G2802058731, G2973449470, MECHANISMS OF BIOSYNTHETIC FORMATION OF DEOXY SUGARS, Mechanisms of Biosynthetic Formation of Deoxy Sugars