Getting to the bottom of Taxol biosynthesis by fungi

Abstract

Taxol (paclitaxel) is a highly-oxygenated diterpenoid natural product first isolated from the pacific yew tree (Taxus brevifolia). It is one of the most widely used anticancer drugs. Soon after the discovery of its unique mode of action and the resulting high demand, an extensive search was initiated for alternative sources to replace the slow-growing and scarce pacific yew. Thus far, however, Taxol and related compounds have only been found in the genus Taxus, which comprises a small number of slow-growing plants with a broad but generally isolated geographical distribution. In 1993, Stierle and colleagues reported the independent biosynthesis of Taxol in an endophytic fungus isolated from Taxus brevifolia, which resulted in more than 160 subsequent publications and patents addressing the biosynthesis of Taxol and related taxanes by microorganisms. The literature on fungal taxane synthesis contains numerous inconsistencies, prompting us to thoroughly re-examine Taxol biosynthesis in endophytic fungi associated with Taxus spp. Using a combination of phytochemistry, molecular biology and genome sequencing, we were unable to find any evidence for independent taxane biosynthesis in any of the endophytes, including the isolate described in the original publication (Taxomyces andreanae) and several more recent isolates from Taxus trees. Our findings therefore resolve a long-standing mystery concerning the evolution of a complex terpenoid biosynthetic pathway in two distantly-related organisms.

Investigation and Expression of the Secoisolariciresinol Dehydrogenase Gene Involved in Podophyllotoxin Biosynthesis

“…Since this fungus produces measurable amounts of PPT in culture [15], we hypothesized that it contains a similar, if not the same, PPT biosynthetic pathway as that observed in P. peltatum. Although a recent study suggests that secondary metabolite production by endophytic fungi is a consequence of carry-over from the plant host into the culture medium during fungal growth [16], we have evidence to support that this is not the case for PPE7. Our observations of increased levels of PPT production in PPE7 after multiple subculturings over several years, detection of different ratios of the PPT pathway intermediates compared to P. peltatum and our recent identification of two genes involved in PPT biosynthesis in PPE7, one of which is reported here, all support our hypothesis that the PPT biosynthetic pathway is present in this fungus.…”

Plant Bioactive Metabolites and Drugs Produced by Endophytic Fungi of Spermatophyta

“…Although a negationist point of view has been advanced concerning taxol biosynthesis by endophytes [389], taken as a whole the over 300 cases mentioned in this review concerning homologous and heterologous endophytic strains producing plant bioactive compounds represent a compelling evidence that these micorganisms and their host plants interact at some level in the biosynthetic process. The main hypothesis is that these interactions may lead to horizontal gene transfers or genetic recombinations, from the plant to its endophytic counterpart and/or vice-versa, originating novel specialized strains able to accumulate certain metabolites in the host tissues [186], which would be a good reason to explain why in the end a mutualistic relationship is established.…”

A search for antiplasmodial metabolites among fungal endophytes of terrestrial and marine plants of southern India

“…It is quite likely that survival in an alien life form may have resulted in the evolution of heightened synthetic ability of endophytes (Suryanarayanan et al 2009). The hypothesis that horizontal gene transfer events from the host plant to its endophytes being instrumental in the production of some of these metabolites has evoked considerable interest as well as great controversy (Heinig et al 2013;Sachin et al 2013). Pharmaceutically important secondary metabolites-producing endophytes, compatible with in vitro cultures offer special advantages that include cost-effective large scale production of the metabolites in industrial laboratory settings.…”