Biosynthesis of Doxorubicin - Overview

Overview

The anthracycline skeleton of doxorubicin (DXR) is produced by a Type II polyketide synthase (PKS) in streptomyces peucetius. First, a 21-carbon decaketide chain (Fig 1. (1)) is synthesized from a single 3-carbon propionyl group from propionyl-CoA, and 9 2-carbon units derived from 9 sequential (iterative) decarboxylative condensations of malonyl-CoA. Each malonyl-CoA unit contributes a 2-carbon ketide unit to the growing polyketide chain. Each addition is catalyzed by the "minimal PKS" consisting of an acyl carrier protein (ACP), a ketosynthase (KS)/chain length factor (CLF) heterodimer and a malonyl-Coa:ACP acyltransferase(MAT). (refer to top of Figure 10.

This process is very similar to fatty acid synthesis, by fatty acid synthases and to Type I polyketide synthesis. But, in contrast to fatty acid synthesis, the keto groups of the growing polyketide chain are not modified during chain elongation and they are not usually fully reduced. In contrast to Type I PKS systems, the synthetic enzymes (KS, CLF, ACP and AT) are not attached covalently to each other, and may not even remain associated during each step of the polyketide chain synthesis.

After the 21-carbon decaketide chain of DXR is completed, successive modifications are made to eventually produce a tetracyclic anthracycline aglycone(without glycoside attached). The daunosamine amino sugar, activated by addition of Thiamine diphosphateTDP, is created in another series of reactions. It is joined to the anthracycline aglycone and further modifications are done to produce first daunorubicin then DXR. There are at least 3 gene clusters important to DXR biosynthesis: dps genes which specify the enzymes required for the linear polyketide chain synthesis and its first cyclizations, the dnr cluster is responsible for the remaining modifications of the anthracycline structure and the dnm genes involved in the amino sugar, daunosamine, synthesis. Additionally, there is a set of "self resistance" genes to reduce the toxic impact of the anthracycline on the producing organism. One mechanism is a membrane pump that causes efflux of the DXR out of the cell (drr loci). Since these complex molecules are only advantageous under specific conditions, and require a lot of energy to produce, their synthesis is tightly regulated.