Biosynthetic pathway of 24-membered macrolactam glycoside incednine

Incednine was isolated from Streptomyces sp. ML694-90F3 as an inhibitor of anti-apoptotic function of Bcl-2/Bcl-xL oncoproteins. The structure of incednine is quite unique with a characteristic 24-membered macrocyclic lactam aglycone and two unusual aminosugars. To understand its biosynthetic pathway, the incorporation studies were carried out with [1-13C]acetate, [1,2-13C2]acetate, [1-13C]propionate, l-[13C5,15N]glutamate, [1,2,3-13C3]glycerol, d-[6,6-2H2]glucose, and l-[CH3-13C]methionine. As a result, acetate, propionate, and glycerol were well incorporated into the elongation units of the macrolactam moiety, which indicates that its basic skeleton could be constructed by standard polyketide synthase, whereas all atoms of the starter unit were labeled by [13C5,15N]glutamate suggesting that glutamate is somehow decarboxylated and rearranged into 3-aminobutyrate as the unique starter unit. The origins of the sugar moieties and methyl groups were also clarified. Based on the incorporation pattern, a plausible biosynthetic pathway for incednine is proposed.

The unique 3-aminobutyrate starter unit of incednine is derived from glutamate.