*3.1. Biosynthesis of Doxorubicin*

Doxorubicin was isolated from *Streptomyces peucetius* in the early of 1960s. It belongs to anthracyclines that have a tetracyclic ring containing quinone and a hydroquinone group in their structure. Doxorubicin is one of the important drugs for the treatment of cancer such as breast cancer, childhood solid tumors, soft tissue sarcomas, and aggressive lymphomas. There are some proposed mechanisms for how doxorubicin kills the cancer cells: (i) intercalation of DNA and interference of topoisomerase-II-mediated DNA repair; and (ii) formation of free radicals and their deterioration of cell components such as cellular membranes, DNA, and proteins [61–63].

Daunorubicin (DNR)-doxorubicin (DXR) type II PKSs, encoded by *dps* genes in *Streptomyces peucetius*, are involved in the formation of doxorubicin. The biosynthesis of doxorubicin requires one propionyl-CoA as the starter unit and nine malonyl-CoAs as the extender units. The process involves two "minimal PKSs" (DpsC-DpsD-DpsG and DpsA-DpsB-DpsG) to produce a 21-carbon decaketide as an intermediate compound. The repetitive process is conducted by KSα (DpsA), KSβ (DpsB), and ACP (DpsG). The next process employs several enzymes such as ketoreductase (DpsE), cyclases (DpsF, DpsY, and DnrD), oxygenase (DnrG and DnrF), and methyl transferase (DnrC) to produce ε-rhodomycinone, an important intermediate of doxorubicin biosynthesis. The remaining steps to synthesize doxorubicin utilize glycosyltransferase (DnrS) with the thymidine-diphospho (TDP) derivative of l-daunosamine, methyl esterase (DnrP), oxygenase (DoxA), and methyl transferase (DnrK) (Figure 6) [60,64–68].

**Figure 6.** Biosynthesis of doxorubicin. Adapted with permission of The Royal Society of Chemistry 2009, from Chan, Y.A.; Podevels, A.M.; Kevany, B.M.; Thomas, M.G. Biosynthesis of polyketide synthase extender units. *Nat. Prod. Rep.* **2009**, *26*, 90–114 [60]; permission conveyed through Copyright Clearance Center, Inc.


#### *3.2. Biosynthesis of Medermycin*

Medermycin is a benzoisochromanequinone (BIQ) antibiotic, isolated from *Streptomyces* sp. K73. It has high activity against some Gram-positive bacteria such as *Staphylococcus aureus*, *Staphylococcus epidermidis*, *Sarcina lutea*, *Bacillus subtilis*, and *Bacillus cereus*. Besides antibiotic activity, medermycin

also has potent activity as a platelet aggregation inhibitor. Because of its unique ability to give different colors in acidic and alkaline aqueous solution, medermycin is considered as an indicator type antibiotic [69,70,84].

Biosynthesis of medermycin requires eight malonyl-CoAs and a sugar molecule, angolosamine, which is derived from the deoxyhexose (DOH) pathway. In the first step of biosynthesis, the minimal PKS that consists of ACP (encoded by the *med*-ORF23 gene), KS<sup>α</sup> (encoded by *med*-ORF1), and KS<sup>β</sup> (encoded by *med*-ORF2) forms an octaketide moiety. The next process employs several enzymes such as keto reductase, aromatase, cyclase, enoyl reductase, and oxygenase/hydroxylase to produce the aglycone compound dihydrokalafungin. The aglycone structure then is combined by C-glycosyl transferase with an angolosamine structure to yield the final structure medermycin [69].
