Taxol: A complex diterpenoid natural product with an evolutionarily obscure origin
Taxol, a diterpenoid natural product first isolated from Taxus brevifolia, is one of today's better known anticancer drugs. Despite its clinical efficacy, the difficulty of establishing a secure and cost-effective supply of taxol has limited its use. However, its unique mode of action and efficacy against multiple forms of cancer has ensured continual efforts to achieve total and semisynthesis, as well as biotechnological production methods. Total synthesis is now possible but inefficient, so the production of taxol and related taxoids remains completely dependent on biomass derived from Taxus sp, with cell suspensions and collected plant materials as sources. The key to improving the supply of taxol and other clinically useful taxoids is the detailed elucidation of the taxoid biosynthesis pathway, which has been the subject of intense research. Many genes and enzymes in the Taxus pathway for taxoid biosynthesis have now been identified, although gaps remain. In addition to Taxus sp, taxoids are also synthesized by various endophytic fungi, which often live in association with Taxus trees, thus raising questions about the evolutionary origin of this complex diterpenoid pathway. In the future, it may be possible to improve taxoid synthesis through the genetic modification of Taxus cell cultures, by culturing endophytic fungi or by transferring the entire pathway into a heterologous expression host, such as Saccharomyces cerevisiae.