Abstract
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.
Highlights
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
Building on the pioneering studies of Malpartida and Hopwood [14], recent studies have successfully demonstrated the ability of the model organism, S. lividans, to produce heterologous aromatic polyketides [15, 16]
Because the site-specific integrative plasmids used in such efforts could not be readily recovered from transformants of interest, genomic libraries had to be prescreened for candidate cosmids carrying putative polyketide genes prior to their transfer into S. lividans
Summary
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. The isolation, fermentation, structures, and properties of R1128 A–D (Fig. 1) were described in 1993 [5, 6] These molecules, which were identified as potent ER antagonists, had IC50 values in the range of 0.1– 0.3 M. These activities were approximately 7–17-fold less than that of tamoxifen, their selectivity (50-fold better binding to ER as compared with the androgen receptor) and low toxicity (significant inhibition of tumor volume in a subrenal capsule assay at 100 mg/kg; no acute toxicity in mice or rats at 500 mg/kg) profiles were promising [7]. The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF293442
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