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The synthesis of bleomycins  has been shown to be the product of a megasynthase that uses the combination  of non-ribosomal peptide synthase(NRPS) and a polyketide synthesis (PKS) pathways according to B Shen et al.[2] The starting units of bleomycin are the L- amino acids: L-Ser, L-Asn, L-Asn, L-His, L-Ala. These amino acids are sequentially added via the NRPS modules and are transferred to a PKS system where malonyl CoA is added along with a methyl group followed by a reduction, and then is passed back to another NRPS system where further amino acids are loaded onto the molecule.



Bleomycin Aglycone

Bleomycin (Blm) aglycone is known to be a product of a megasynthase that utilizes a non-ribosomal peptide synthase (NRPS) and polyketide synthase (PKS) hybrid system (1, 2). NRPS/PKS hybrid systems employ multi-modular catalytic domains that elongate, or modify a growing polypeptide chain by the addition of amino acid monomers and acyl groups in specific sequences following a template like construction (1). Nine amino acids, an acetate, and two S-adenosy methionine (AdoMet) is believed to be the precursors towards the construction of the bleomycin  aglycone (2, 3). The amino acid substrates that have been biochemically identified are Asn, His, Thr, Cys. Other amino acids yet to be confirmed are Ala, Ser, β-Ala; however their structures are evidenced in the BLM structure (2, 3).

Catalytic domains contained within NRPS modules are: AL, acyl CoA ligase; ACP, acyl carrier protein,; C and C’, Condensation; A, adenylation; PCP, peptidyl carrier protein; Cy, Condensation/cyclization; and Ox, oxidation (2,3). The PKS domains are: KS, ketosynthase; AT, acyltransferase; MT, methyl transferase; KR, ketoreductase; ACP, acyl carrier proteins (2, 3). A linear arrangement of NRPS/PKS/ NRPS domains has been proposed that elucidates the construction organization of the BLM glycone (2, 3).




(1) Belshaw, P. J.; Walsh, C. T.; Stachelhaus, T. Aminoacyl-CoAs as Probes of Condensation Domain Selectivity in Nonribosomal Peptide Synthesis. Science 1999, 284, 486-489.

(2) Shen, B Du, L Sanchez, C Edwards, D J Chen, M Murrell,J M. The Biosynthetic Gene Cluster for the Anticancer Drug Bleomycin from Streptomyces Verticillus ATCC15003 as a Model for Hybrid Peptide-Polyketide Natural Product Biosynthesis. Journal of industrial microbiology biotechnology 2001, 27, 378.

(3) Shen, Ben Du, Liangcheng Sanchez, Cesar Edwards, Daniel J Chen, Mei Murrell,Jeffrey M. Cloning and Characterization of the Bleomycin Biosynthetic Gene Cluster from Streptomyces Verticillus ATCC15003. Journal of natural products 2002, 65, 422.

[1] Shen Ben, et al. Cloning and characterization of the Bleomycin Biosynthetic Gene Cluster from Streptomyces verticillus ATCC150003.

[2] Shen B., et al. The biosynthetic gene cluster for the anticancer drug bleomycin from strptomyces verticillus ATCC15003 as a model for hybrid peptide-polyketide natural product biosynthesis. Journal of Microbiology and Biotechnology (2001) 27, 378-385 © Nature Publishing Group 1367-5435/01





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