Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 16 August 2002:
Vol. 297. no. 5584, pp. 1170 - 1173
DOI: 10.1126/science.1072110
Prev | Table of Contents | Next

Reports

Biosynthesis of the Enediyne Antitumor Antibiotic C-1027

Wen Liu,1 Steven D. Christenson,3 Scott Standage,4 Ben Shen1234*

C-1027 is a potent antitumor agent with a previously undescribed molecular architecture and mode of action. Cloning and characterization of the 85-kilobase C-1027 biosynthesis gene cluster from Streptomyces globisporus revealed (i) an iterative type I polyketide synthase that is distinct from any bacterial polyketide synthases known to date, (ii) a general polyketide pathway for the biosynthesis of both the 9- and 10-membered enediyne antibiotics, and (iii) a convergent biosynthetic strategy for the C-1027 chromophore from four building blocks. Manipulation of genes governing C-1027 biosynthesis allowed us to produce an enediyne compound in a predicted manner.

1 Division of Pharmaceutical Sciences and
2 Department of Chemistry, University of Wisconsin, Madison, WI 53705, USA.
3 Biochemistry and Molecular Biology Graduate Group and
4 Department of Chemistry, University of California, Davis, CA 95616, USA.
*   To whom correspondence should be addressed. E-mail: bshen{at}pharmacy.wisc.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Detection, Distribution, and Organohalogen Compound Discovery Implications of the Reduced Flavin Adenine Dinucleotide-Dependent Halogenase Gene in Major Filamentous Actinomycete Taxonomic Groups.
P. Gao and Y. Huang (2009)
Appl. Envir. Microbiol. 75, 4813-4820
   Abstract »    Full Text »    PDF »
Structure and Catalytic Mechanism of the Thioesterase CalE7 in Enediyne Biosynthesis.
M. Kotaka, R. Kong, I. Qureshi, Q. S. Ho, H. Sun, C. W. Liew, L. P. Goh, P. Cheung, Y. Mu, J. Lescar, et al. (2009)
J. Biol. Chem. 284, 15739-15749
   Abstract »    Full Text »    PDF »
A free-standing condensation enzyme catalyzing ester bond formation in C-1027 biosynthesis.
S. Lin, S. G. Van Lanen, and B. Shen (2009)
PNAS 106, 4183-4188
   Abstract »    Full Text »    PDF »
C-1027, A Radiomimetic Enediyne Anticancer Drug, Preferentially Targets Hypoxic Cells.
T. A. Beerman, L. S. Gawron, S. Shin, B. Shen, and M. M. McHugh (2009)
Cancer Res. 69, 593-598
   Abstract »    Full Text »    PDF »
A phosphopantetheinylating polyketide synthase producing a linear polyene to initiate enediyne antitumor antibiotic biosynthesis.
J. Zhang, S. G. Van Lanen, J. Ju, W. Liu, P. C. Dorrestein, W. Li, N. L. Kelleher, and B. Shen (2008)
PNAS 105, 1460-1465
   Abstract »    Full Text »    PDF »
Biosynthesis of the enediyne antitumor antibiotic C-1027 involves a new branching point in chorismate metabolism.
S. G. Van Lanen, S. Lin, and B. Shen (2008)
PNAS 105, 494-499
   Abstract »    Full Text »    PDF »
Designer enediynes generate DNA breaks, interstrand cross-links, or both, with concomitant changes in the regulation of DNA damage responses.
D. R. Kennedy, J. Ju, B. Shen, and T. A. Beerman (2007)
PNAS 104, 17632-17637
   Abstract »    Full Text »    PDF »
Molecular Basis for Chloronium-mediated Meroterpene Cyclization: CLONING, SEQUENCING, AND HETEROLOGOUS EXPRESSION OF THE NAPYRADIOMYCIN BIOSYNTHETIC GENE CLUSTER.
J. M. Winter, M. C. Moffitt, E. Zazopoulos, J. B. McAlpine, P. C. Dorrestein, and B. S. Moore (2007)
J. Biol. Chem. 282, 16362-16368
   Abstract »    Full Text »    PDF »
Single Chemical Modifications of the C-1027 Enediyne Core, a Radiomimetic Antitumor Drug, Affect Both Drug Potency and the Role of Ataxia-Telangiectasia Mutated in Cellular Responses to DNA Double-Strand Breaks.
D. R. Kennedy, L. S. Gawron, J. Ju, W. Liu, B. Shen, and T. A. Beerman (2007)
Cancer Res. 67, 773-781
   Abstract »    Full Text »    PDF »
Substrate Specificity of the Adenylation Enzyme SgcC1 Involved in the Biosynthesis of the Enediyne Antitumor Antibiotic C-1027.
S. G. Van Lanen, S. Lin, P. C. Dorrestein, N. L. Kelleher, and B. Shen (2006)
J. Biol. Chem. 281, 29633-29640
   Abstract »    Full Text »    PDF »
Utilization of the Methoxymalonyl-Acyl Carrier Protein Biosynthesis Locus for Cloning the Oxazolomycin Biosynthetic Gene Cluster from Streptomyces albus JA3453.
C. Zhao, J. Ju, S. D. Christenson, W. C. Smith, D. Song, X. Zhou, B. Shen, and Z. Deng (2006)
J. Bacteriol. 188, 4142-4147
   Abstract »    Full Text »    PDF »
Chemoenzymatic and Template-Directed Synthesis of Bioactive Macrocyclic Peptides.
J. Grunewald and M. A. Marahiel (2006)
Microbiol. Mol. Biol. Rev. 70, 121-146
   Abstract »    Full Text »    PDF »
Evolutionary Implications of Bacterial Polyketide Synthases.
H. Jenke-Kodama, A. Sandmann, R. Muller, and E. Dittmann (2005)
Mol. Biol. Evol. 22, 2027-2039
   Abstract »    Full Text »    PDF »
Tryptophan 7-Halogenase (PrnA) Structure Suggests a Mechanism for Regioselective Chlorination.
C. Dong, S. Flecks, S. Unversucht, C. Haupt, K.-H. van Pee, and J. H. Naismith (2005)
Science 309, 2216-2219
   Abstract »    Full Text »    PDF »
Dichlorination of a pyrrolyl-S-carrier protein by FADH2-dependent halogenase PltA during pyoluteorin biosynthesis.
P. C. Dorrestein, E. Yeh, S. Garneau-Tsodikova, N. L. Kelleher, and C. T. Walsh (2005)
PNAS 102, 13843-13848
   Abstract »    Full Text »    PDF »
Cloning, Sequencing, and Functional Analysis of an Iterative Type I Polyketide Synthase Gene Cluster for Biosynthesis of the Antitumor Chlorinated Polyenone Neocarzilin in "Streptomyces carzinostaticus".
M. Otsuka, K. Ichinose, I. Fujii, and Y. Ebizuka (2004)
Antimicrob. Agents Chemother. 48, 3468-3476
   Abstract »    Full Text »    PDF »
Evidence for a Symbiosis Island Involved in Horizontal Acquisition of Pederin Biosynthetic Capabilities by the Bacterial Symbiont of Paederus fuscipes Beetles.
J. Piel, I. Hofer, and D. Hui (2004)
J. Bacteriol. 186, 1280-1286
   Abstract »    Full Text »    PDF »
Rapid PCR amplification of minimal enediyne polyketide synthase cassettes leads to a predictive familial classification model.
W. Liu, J. Ahlert, Q. Gao, E. Wendt-Pienkowski, B. Shen, and J. S. Thorson (2003)
PNAS 100, 11959-11963
   Abstract »    Full Text »    PDF »
Polyketide and non-ribosomal peptide synthases: Falling together by coming apart.
C. R. Hutchinson (2003)
PNAS 100, 3010-3012
   Full Text »    PDF »
C-O Bond Formation by Polyketide Synthases.
H.-J. Kwon, W. C. Smith, A. J. Scharon, S. H. Hwang, M. J. Kurth, and B. Shen (2002)
Science 297, 1327-1330
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)