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J. Biol. Chem., Vol. 275, Issue 43, 33443-33448, October 27, 2000
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From the Departments of Chemical Engineering and ¶ Chemistry
and Biochemistry, Stanford University, Stanford, California
94305-5025
R1128 substances are anthraquinone natural
products that were previously reported as non-steroidal estrogen
receptor antagonists with in vitro and in vivo
potency approaching that of tamoxifen. From a biosynthetic viewpoint,
these polyketides possess structurally interesting features such as an
unusual primer unit that are absent in the well studied anthracyclic
and tetracyclic natural products. The entire R1128 gene cluster was
cloned and expressed in Streptomyces lividans, a
genetically well developed heterologous host. In addition to R1128C, a
novel optically active natural product, designated HU235, was isolated.
Nucleotide sequence analysis of the biosynthetic gene cluster revealed
genes encoding two ketosynthases, a chain length factor, an acyl
transferase, three acetyl-CoA carboxylase subunits, two cyclases, two
oxygenases, an amidase, and remarkably, two acyl carrier proteins.
Feeding studies indicate that the unusual 4-methylvaleryl side chain of
R1128C is derived from valine. Together with the absence of a dedicated
ketoreductase, dehydratase, or enoylreductase within the R1128 gene
cluster, this suggests a functional link between fatty acid
biosynthesis and R1128 biosynthesis in the engineered host.
Specifically, we propose that the R1128 synthase recruits four subunits
from the endogenous fatty acid synthase during the biosynthesis of this
family of pharmacologically significant natural products.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF293442.
Cloning, Nucleotide Sequence, and Heterologous Expression of the
Biosynthetic Gene Cluster for R1128, a Non-steroidal Estrogen Receptor
Antagonist
INSIGHTS INTO AN UNUSUAL PRIMING MECHANISM*
,
*
This research was supported in part by Grant CA77248 from
the National Institutes of Health.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of postdoctoral fellowships from the Swiss National
Science Foundation, the Roche Research Foundation, and the Novartis Foundation.
§
Recipient of National Institutes of Health Postdoctoral Fellowship
1 F32 GM19540.
To whom correspondence should be addressed. Tel./Fax:
650-723-6538; E-mail: ck@chemeng.stanford.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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