Asukamycin / Manumycin Project

Antibiotics of the manumycin family, such as asukamycin from Streptomyces nodosus ssp. asukaensis and manumycin from Streptomyces parvulus Tü 64, share the structural features of a "central" six-membered ring mC₇N moiety and a "lower" unsaturated chain with a five-membered ring C₅N unit at its terminus. The only structural variation among this group of compounds is in the "upper" unsaturated chain. Manumycin type compounds are reported to have antibacterial, antifungal and insecticidal activity, were recently recognized as inhibitors of Ras protein farnesyltransferase and human interleukin-1b converting enzyme, making them targets in anticancer drug development.

Our previous studies have shown that the C₅N unit is derived from succinic acid and glycine via 5-aminolevulinic acid (ALA), and the mC₇N unit from succinic acid, glycerol, and molecular oxygen. Our goal in this project now is to elucidate the biosynthetic pathway from these building blocks to asukamycin and manumycin, particularly the formation of the mC₇N unit, and to determine the sequence in which the different parts of the molecules are assembled. 3-Amino-4-hydroxybenzoic acid (3, 4-AHBA) has recently been identified as a key precursor for the mC₇N unit in collaboration with Professor Gould’s group at Oregon State University, and new metabolites related to the asukamycin pathway have been isolated and characterized.