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: The non‐producer mutant strains generated by inactivating genes involved in the generation of starter units can be used for precursor‐directed biosynthesis of novel compounds. This approach, known as mutational biosynthesis or mutasynthesis, couples the utilization of chemical synthesis with molecular biology (Kennedy, 2008). Several non‐natural compounds derived from different metabolites such as rapamycin, borrelidin or salinosporamide have been generated following this method (Fig. 5). BC210 is a mutasynthetic derivative of rapamycin generated by feeding cyclohexane carboxylic acid to Streptomyces hygrocopicus mutant MG2‐10. This compound was found to be a better inhibitor of mTOR kinase activity and to show anticancer activity both in vivo and in vitro (Gregory et al., 2005). In addition, BC210 is not a substrate of the multidrug resistance efflux pump P‐glycoprotein, has good oral bioavailability and has a highly effective penetration of the blood–brain barrier, which makes this compound a potential therapeutic drug for the treatment of brain tumours (Zhang and Wilkinson, 2007). Six borrelidin derivatives were generated by mutasynthesis using different dicarboxylic acids as starter units (Moss et al., 2006). One of these derivatives, containing a carboxyl‐cyclobutane instead of a carboxyl‐cyclopentane moiety, was found to be 15‐fold less cytotoxic than borrelidin but sixfold more antiangiogenic (Wilkinson et al., 2006). Mutasynthesis has been used, in addition, to generate fluorosalinosporamide, a salinosporamide A analogue produced by a Sa. tropica chlorinase salL mutant that was supplemented with synthetic 5′‐fluoro‐5′‐deoxyadenosine. This compound is the most potent salinoporamide analogue showing high proteasome binding properties in which the fluoro group significantly extends its residence time on the proteasome (Eustáquio and Moore, 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.