Biosynthesis of Doxorubicin - Conversion To 12-deoxyalkalonic Acid

Conversion To 12-deoxyalkalonic Acid

The 21-carbon decaketide is converted to 12-deoxyalkalonic acid (5), the first free easily isolated intermediate in DXR biosynthesis, in 3 steps. These steps are catalyzed by the final 3 enzymes in the dps gene cluster and are considered part of the polyketide synthase.

While the decaketide is still associated with the KS/CLF heterodimer the 9-carbonyl group is reduced by Dps E, the 9-ketoreductase, using NADPH as the reducing agent/hydride donor. Dps F, the “1st ring cyclase” /aromatase, is very specific and is in the family of C-7/C-12 cyclases that require prior C-9 keto-reduction. These two reactions are felt to occur while the polyketide chain is still partially in the KS/CLF tunnel and it is not known what finally cleaves the chain from its covalent link to the KS or ACP. If the Dps F cyclase is inactivated by mutations or gene deletions, the chain will cyclize spontaneously in random fashion. Thus, Dps F is thought to “chaperone” or help fold the polyketide to ensure non-random cyclization, a reaction that is energetically favorable and leads to subsequent dehydration and resultant aromatization.

Next, Dps Y regioselectively promotes formation of the next two carbon-carbon bonds and then catalyzes dehydration leading to aromatization of one of the rings to give (5).