Bleomycin is a glycopeptide-derived antibiotic, isolated from several Streptomyces species. It exhibits strong antitumor activity and is currently used clinically in combination with a number of other agents for the treatment of several types of tumors. Bleomycin is thought to act through a sequence selective, metal-dependent oxidative cleavage of DNA and RNA in the presence of oxygen. Bleomycin does not cause myelosupression, which makes it unique among anticancer drugs and promotes their wide application in combination chemotherapy.

Biosynthesis of Bleomycin:

Bleomycin is a nonribosomal peptide that is a hybrid peptide-polyketide natural product.  The peptide/polyketide/peptide backbone of the bleomycin alycon is assembled by the bleomycin megasynthetase, which is made of both nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) modules. Nonribosomal peptides and polyketides are synthesized from amino acids and short carboxylic acids by NRPSs and PKSs, respectively. These NRPSs and PKSs use similar strategies for the assembly of these two distinct classes of natural products. Both NRPs and type I PKSs are organized into modules. The structural variations of the resulting peptide and polyketide products are determined by the number and order of modules on each NRPS and PKS protein.

The biosynthesis of the bleomycin aglycon can be easily visualized in three stages (see Figure 2):

1. NRPS-mediated formation of P-3A from Ser, Asn, His, and Ala
2. PKS-mediated elongation of P-3A by malonyl CoA and AdoMet to yield P-4
3. NRPS-mediated elongation of P-4 by Thr to P-5 that is further elongated by b-Ala, Cys, and Cys to get P-6m.

On the basis of the bleomycin structure and the deduced functions of individual NRPS and PKS domains and modules, a linear model for the bleomycin megasynthetase-templated assembly of the bleomycin peptide/polyketide/peptide aglycon was proposed from nine amino acids and one acetate.  

References:

[1] Murrell et. al., Journal of Natural Products, 2002, 65, 422-431

[2] Murrell et. al., Journal of Industrial Microbiology & Biotechnology, 2001, 27, 378-385

[3] Edwards et. al., Bioorganic Chemistry, 1999, 27, 155-171

[4] Chen J., Stubbe, J.; Nature, 2005, 5, 102-112