FIGURE 2.

Biosynthetic pathway of doxorubicin and modifications required for biosynthesis of N,N-dimethylated daunorubicin and doxorubicin. Doxorubicin biosynthesis occurs in three stages: biosynthesis of TDP-l-daunosamine from D-glucose-1-phosphate, biosynthesis of ɛ-rhodomycinone (16) from one propionyl-CoA and nine malonyl-CoA units, followed by tailoring steps of the aglycone. For biosynthesis of N,N-dimethylated daunorubicin and doxorubicin, the pathway should be modified in three steps: 1) N,N-dimethylation of TDP- l-daunosamine to TDP-l-rhodosamine, 2) glycosylation of ɛ-rhodomycinone (16) with l-rhodosamine instead of l-daunosamine, and 3) the further tailoring steps should be performed when l-rhodosamine is attached.