Molecular insights on the biosynthesis of antitumour compounds by actinomycetes.
Bottom Line: The characterization of these clusters has represented, during the last 25 years, a great source of genes for the generation of novel derivatives by using combinatorial biosynthesis approaches: gene inactivation, gene expression, heterologous expression of the clusters or mutasynthesis.In addition, these techniques have been also applied to improve the production yields of natural and novel antitumour compounds.In this review we focus on some representative antitumour compounds produced by actinomycetes covering the genetic approaches used to isolate and validate their biosynthesis gene clusters, which finally led to generating novel derivatives and to improving the production yields.
Affiliation: Departamento de Biología Funcional and Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, 33006 Oviedo, Spain.Show MeSH
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Mentions: Actinomycetes have large genomes (five to nine megabases) and use 5–10% of their DNA for the production of secondary metabolites (Baltz, 2008); a good number of them are antitumour drugs (Figs 1 and 2). These belong to different structural groups: polyketides such as anthracyclines daunomycin and doxorubicin, both promoting DNA cleavage mediated by DNA topoisomerase II, or aureolic acids mithramycin and chromomycin A3 that cause DNA‐dependent inhibition of RNA synthesis and inhibit topoisomerase I causing DNA cleavage; non‐ribosomal peptides such as glycopeptide actinomycin D, which inhibits DNA‐directed RNA synthesis by binding to double stranded DNA; mixed polyketide/non‐ribosomal peptides as glycopeptide bleomycin, which inhibits DNA synthesis through a metal‐dependent oxidative cleavage of DNA; heterocyclic quinones as mitomycin C that cause intra‐ and inter‐strand DNA cross‐linking leading to selective inhibition of DNA synthesis; indolocarbazoles such as protein kinases inhibitor staurosporine and topoisomerase I‐dependent DNA‐damaging agent rebeccamycin, etc. However, even considering the enormous number of natural products discovered to date, there is still a need for generating novel drugs to be used in cancer chemotherapy due to the rapid development of resistance to multiple chemotherapeutic drugs and the high toxicity usually associated with this type of drugs and their undesirable side‐effects. In addition, there is a demand for novel antitumour drugs active against untreatable tumours, with fewer side‐effects or with greater therapeutic efficiency. To this respect, enormous efforts are under way to discover new drugs from actinomycetes by searching uncommon actinomycetes in special ecological niches, mining genomes for cryptic pathways, and applying combinatorial biosynthesis to generate novel secondary metabolites related to existing pharmacophores (Baltz, 2008).
Affiliation: Departamento de Biología Funcional and Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, 33006 Oviedo, Spain.