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Antimicrobial Agents and Chemotherapy, February 2000, p. 382-392, Vol. 44, No. 2
Department of Chemistry, University of
California, Davis, California 95616,1 and
Institute of Medicinal Biotechnology, The Chinese Academy of
Medical Sciences, Beijing, 100050 China2
Received 2 August 1999/Returned for modification 28 October
1999/Accepted 10 November 1999
C-1027, the most potent member of the enediyne antitumor antibiotic
family, is produced by Streptomyces globisporus C-1027 and
consists of an apoprotein (encoded by the cagA gene) and a nonpeptidic chromophore. The C-1027 chromophore could be viewed as
being derived biosynthetically from a benzoxazolinate, a deoxyamino hexose, a
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Copyright © 2000, American Society for Microbiology. All rights reserved.
Genes for Production of the Enediyne Antitumor
Antibiotic C-1027 in Streptomyces globisporus Are Clustered
with the cagA Gene That Encodes the C-1027
Apoprotein
-amino acid, and an enediyne core. By adopting a strategy for cloning of the C-1027 biosynthesis gene cluster by mapping a
putative dNDP-glucose 4,6-dehydratase (NGDH) gene to cagA,
we have localized 75 kb of contiguous DNA from S. globisporus. DNA sequence analysis of two regions of the cloned
gene cluster revealed two genes, sgcA and sgcB,
that encode an NGDH enzyme and a transmembrane efflux protein,
respectively, and confirmed that the cagA gene resides
approximately 14 kb upstream of the sgcAB locus. The
involvement of the cloned gene cluster in C-1027 biosynthesis was
demonstrated by disrupting the sgcA gene to generate
C-1027-nonproducing mutants and by complementing the sgcA
mutants in vivo to restore C-1027 production. These results represent
the first cloning of a gene cluster for enediyne antitumor antibiotic
biosynthesis and provide a starting point for future genetic and
biochemical investigations of C-1027 biosynthesis.
*
Corresponding author. Mailing address: Department of
Chemistry, University of California, One Shields Ave., Davis, CA 95616. Phone: (530) 754-9382. Fax: (530) 752-8995. E-mail:
shen{at}chem.ucdavis.edu.
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