Issue 1, 2007
From the journal:

Molecular BioSystems

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

Meifeng Tao,a   Liyan Wang,a   Evelyn Wendt-Pienkowski,a   Nicholas P. George,b   Ute Galm,a   Guodong Zhang,a   Jane M. Coughlinc  and  Ben Shenabcde  

a Division of Pharmaceutical Sciences, University of Wisconsin-Madison, 777 Highland Ave, Madison, Wisconsin, USA

b Microbiology Doctoral Training Program, University of Wisconsin-Madison, 777 Highland Ave, Madison, Wisconsin, USA

c Department of Chemistry, University of Wisconsin-Madison, 777 Highland Ave, Madison, Wisconsin, USA

d University of Wisconsin National Drug Discovery Group, University of Wisconsin-Madison, 777 Highland Ave, Madison, Wisconsin, USA

e Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Ave, Madison, Wisconsin, USA
E-mail: bshen@pharmacy.wisc.edu
Fax: +1 (608) 262-5345
Tel: +1 (608) 263-2673

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 tlmEglycosyltransferase gene to generate a TLM non-producing mutant and by restoring TLM production to the ΔtlmE::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.

Graphical abstract: 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

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Article information

DOI
https://doi.org/10.1039/B615284H
Article type
Paper
Submitted
20 Oct 2006
Accepted
06 Nov 2006
First published
28 Nov 2006

Mol. BioSyst., 2007,3, 60-74

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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

M. Tao, L. Wang, E. Wendt-Pienkowski, N. P. George, U. Galm, G. Zhang, J. M. Coughlin and B. Shen, Mol. BioSyst., 2007, 3, 60 DOI: 10.1039/B615284H

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