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The tallysomycin biosynthetic gene cluster from Streptoalloteichus hindustanus E465-94 ATCC 31158 unveiling new insights into the biosynthesis of the bleomycin family of antitumor antibiotics.
- Source :
-
Molecular bioSystems [Mol Biosyst] 2007 Jan; Vol. 3 (1), pp. 60-74. Date of Electronic Publication: 2006 Nov 28. - Publication Year :
- 2007
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Abstract
- The tallysomycins (TLMs) belong to the bleomycin (BLM) family of antitumor antibiotics. The BLM biosynthetic gene cluster has been cloned and characterized previously from Streptomyces verticillus ATCC 15003, but engineering BLM biosynthesis for novel analogs has been hampered by the lack of a genetic system for S. verticillus. We now report the cloning and sequencing of the TLM biosynthetic gene cluster from Streptoalloteichus hindustanus E465-94 ATCC 31158 and the development of a genetic system for S. hindustanus, demonstrating the feasibility to manipulate TLM biosynthesis in S. hindustanus by gene inactivation and mutant complementation. Sequence analysis of the cloned 80.2 kb region revealed 40 open reading frames (ORFs), 30 of which were assigned to the TLM biosynthetic gene cluster. The TLM gene cluster consists of nonribosomal peptide synthetase (NRPS) genes encoding nine NRPS modules, a polyketide synthase (PKS) gene encoding one PKS module, genes encoding seven enzymes for deoxysugar biosynthesis and attachment, as well as genes encoding other biosynthesis, resistance, and regulatory proteins. The involvement of the cloned gene cluster in TLM biosynthesis was confirmed by inactivating the tlmE glycosyltransferase gene to generate a TLM non-producing mutant and by restoring TLM production to the DeltatlmE::ermE mutant strain upon expressing a functional copy of tlmE. The TLM gene cluster is highly homologous to the BLM cluster, with 25 of the 30 ORFs identified within the two clusters exhibiting striking similarities. The structural similarities and differences between TLM and BLM were reflected remarkably well by the genes and their organization in their respective biosynthetic gene clusters.
- Subjects :
- Amino Acid Sequence
Antibiotics, Antineoplastic chemistry
Bleomycin chemistry
Carbohydrates biosynthesis
Cloning, Molecular
Electroporation
Escherichia coli genetics
Molecular Sequence Data
Polyketide Synthases genetics
Sequence Analysis, DNA
Sequence Homology, Amino Acid
Spores, Bacterial genetics
Streptomyces metabolism
Substrate Specificity
Antibiotics, Antineoplastic biosynthesis
Bleomycin analogs & derivatives
Bleomycin biosynthesis
Streptomyces genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1742-206X
- Volume :
- 3
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular bioSystems
- Publication Type :
- Academic Journal
- Accession number :
- 17216057
- Full Text :
- https://doi.org/10.1039/b615284h