Biosynthesis of Macrolide Antibiotics. 6. Late Steps in Brefeldin A Biosynthesis

Article abstract of DOI:10.1021/ja00294a045

Brefeldin A (1), a macrolide antibiotic produced by several fungi,contains a cyclopentanol rings as part of its 16-membered lactone.The role that the oxygen and double bond functionality at positions 2,3,4,7,10, and 11 play in the mechanism of 5-membered ring formation is examined by comparing the efficiency of incorporation of several isotopically labeled compounds into 1 which are putative intermediaties of the late part of the biosynthetic pathway.Brefeldin C (7-deoxybrefeldin A,3) and 7-oxobrefeldin A(2) were efficiently metabolized to 1,4-deoxibrefeldin C (8) was inneficiently metabolized to 1, but the 3,4-double bond isomers of 4-deoxybrefeldin C and 2,3,10,11-tetrahydrobrefeldin C were not metabolized to 1 by intact cells of Eupenicillium brefeldianum. 7-Oxobrefeldin A was found in the fungal cells,and a small amount of exogenously added brefeldin A was converted to 2 in vivo.These results support the intermediacy of 3 in the biosynthetic pathway of 1 and suggest that 1 and 2 can be interconverted by a biochemical redox process.The low conversion of 8 to1, however, suggests that it is not an intermediate of the main biosinthetic pathway to 1 but possibly only metabolized to 1 by a shunt pathway or by a nonspecific hydroxylase