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The aureolic acid family of antitumor compounds: structure, mode of action, biosynthesis, and novel derivatives

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Abstract

Members of the aureolic acid family are tricyclic polyketides with antitumor activity which are produced by different streptomycete species. These members are glycosylated compounds with two oligosaccharide chains of variable sugar length. They interact with the DNA minor groove in high-GC-content regions in a nonintercalative way and with a requirement for magnesium ions. Mithramycin and chromomycins are the most representative members of the family, mithramycin being used as a chemotherapeutic agent for the treatment of several cancer diseases. For chromomycin and durhamycin A, antiviral activity has also been reported. The biosynthesis gene clusters for mithramycin and chromomycin A3 have been studied in detail by gene sequencing, insertional inactivation, and gene expression. Most of the biosynthetic intermediates in these pathways have been isolated and characterized. Some of these compounds showed an increase in antitumor activity in comparison with the parent compounds. A common step in the biosynthesis of all members of the family is the formation of the tetracyclic intermediate premithramycinone. Further biosynthetic steps (glycosylation, methylations, acylations) proceed through tetracyclic intermediates which are finally converted into tricyclic compounds by the action of a monooxygenase, a key event for the biological activity. Heterologous expression of biosynthetic genes from other aromatic polyketide pathways in the mithramycin producer (or some mutants) led to the isolation of novel hybrid compounds.

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Acknowledgements

The authors wish to thank all the people in their laboratory involved in research on aureolic acid drugs. Research at the authors’ laboratory has been supported by grants from the Spanish Ministry of Education and Science (BMC2002-03599 and BIO2005-04115 to C. Méndez) and by a grant from the Plan Regional de Investigación del Principado de Asturias (GE-MEDO1-05 to J.A. Salas). We thank Obra Social Cajastur for financial support to F. Lombó.

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Correspondence to José A. Salas.

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Felipe Lombó and Nuria Menéndez have equally contribute to this work.

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Lombó, F., Menéndez, N., Salas, J.A. et al. The aureolic acid family of antitumor compounds: structure, mode of action, biosynthesis, and novel derivatives. Appl Microbiol Biotechnol 73, 1–14 (2006). https://doi.org/10.1007/s00253-006-0511-6

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Keywords

  • Streptomyces
  • Polyketides
  • Actinomycetes
  • Glycosylation