*3.3. Biosynthesis of Hedamycin*

Hedamycin is a pluramycin antitumor antibiotic, produced by *Streptomyces griseoruber*. This aromatic polyketide has a planar anthrapyrantrione chromophore, two amino sugars in its structure (α-l-*N,N*-dimethylvancosamine and β-d-angolosamine), and a bisepoxide-containing a side chain. The compound could inhibit 50% of human cancer cell growth at a subnanomolar concentration in three days. It is a monofunctional DNA alkylating agent, and because of its low therapeutic index, hedamycin is not clinically used [81,85].

Biosynthesis of hedamycin uses twelve malonyl-CoAs and two amino sugars, vancosamine and an angolosamine moiety. The minimal type II PKSs of hedamycin biosynthesis consist of HedC (KSα), HedD (CLF), and HedE (ACP). Uniquely, the initial process involves type I PKSs (HedT and HedU proteins) that produce the 2,4-hexadienyl primer unit from three malonyl-CoAs, and then, it is transferred to the minimal type II PKSs of hedamycin biosynthesis. After that, a dodecaketide structure is formed by processing nine malonyl-CoAs. The structure then is modified with keto reductase, aromatase/cyclase, and oxygenase into the aglycone compound. In the last step, two glycosyltransferases are used for incorporating two amino sugars to produce hedamycin [80,81].
