Bleomycin Biosynthetic Genes
Bleomycins (BLMs) are a family of glycopeptide-derived anti-tumor antibiotics originally isolated from the fermentation broth of Streptomyces verticillus. BLMs exhibit strong anti-tumor activity and are one member of the family of anti-cancer drugs that is widely used for the treatment of lymphoma (particularly Hodgkin's disease), testicular tumors, various squamous cell carcinomas, and malignant effusions in ovarian and breast cancer. In the late 1970s and early 1980s, there was a great emphasis on the development of high-yield strains and the isolation of BLM biosynthetic intermediates and metabolites. More recently, there has been interest in bleomycin biosynthesis as a means of facilitating the characterization of biosynthetic enzymes with a view towards the development of improved drugs derived from the manipulation of BLM biosynthetic genes. The chief obstacle to the realization of these research objectives has been the unavailability of the BLM genes themselves. However, a University of California researcher has isolated and characterized the BLM gene cluster. The UC BLM genes can be modified in numerous ways, offering numerous potential therapeutic applications such as improved yield in recombinant organisms, improved potency, alteration of effects on the cell cycle or cell morphology (e.g. cytoskeleton), and the production of novel BLM analogs with added functionality or greater anti-tumor specificity. The BLM gene cluster also provides a key component for further research on bleomycin biosynthesis.
Patent Number: US6927286B1
Application Number: US2000477962A
Inventor: Shen, Ben | Du, Liangcheng | Sanchez, Cesar | Chen, Mei | Edwards, Daniel J.
Priority Date: 6 Jan 1999
Priority Number: US6927286B1
Application Date: 5 Jan 2000
Publication Date: 9 Aug 2005
IPC Current: C12N001552 | C12P001304 | C12P001714 | C12P001926 | C12P001944 | C12P001958
US Class: 5360232 | 4352523 | 43525235 | 43525411 | 4353201 | 435325 | 435419 | 5360231 | 5360237
Assignee Applicant: The Regents of the University of California
Title: Bleomycin gene cluster components and their uses
Usefulness: Bleomycin gene cluster components and their uses
Summary: (I) and (V) are useful for producing peptide and/or polyketide metabolites, especially bleomycin or a bleomycin analog and for chemically modifying a biological molecules to produce branched methyl groups. (VI) is useful for coupling amino acids and fatty acids. (X) may be reacted with an apo-carrier protein and coenzyme A to produce a holo-carrier protein (all claimed). The blm gene cluster or catalytic domains can be used individually or collectively to produce thiazolidine, thiazoline, bithiazoline and bithiazoline-containing microbial metabolites. The blm gene cluster may also be used to produce sugars.
Novelty: New bleomycin gene cluster components useful for peptide and/or polyketide metabolites, especially bleomycin, production and for chemically modifying biological molecules
Biomedical
DNA/Gene Engineering
6927286
Related Materials Du L, Sanchez C, Chen M, Edwards DJ, Shen B. The Biosynthetic Gene Cluster for the Antitumor Drug Bleomycin from Streptomyces Verticillus ATCC15003 Supporting Functional Interactions Between Nonribosomal Peptide Synthetases and a Polyketide Synthase. Chem Biol. 2000 Aug;7(8):623-42. Tech ID/UC Case 11399/1999-174-0 Related Cases 1999-174-0
Du L, Chen M, Sanchez C, Shen B. An Oxidation Domain in the BlmIII Non-Ribosomal Peptide Synthetase Probably Catalyzing Thiazole Formation in the Biosynthesis of the Anti-Tumor Drug Bleomycin in Streptomyces Verticillus ATCC15003. FEMS Microbiol Lett. 2000 Aug 15;189(2):171-5.
Du L, Shen B. Identification and Characterization of a Type II Peptidyl Carrier Protein from the Bleomycin Producer Streptomyces Verticillus ATCC 15003. Chem Biol. 1999 Aug;6(8):507-17.
U. Galm, B. Shen. 2007. Natural Product Drug Discovery: The Times Have Never Been Better. Chemistry & Biology, Volume 14, Issue 10, Pages 1098-1104.
USA
