Insights into Taxol® biosynthesis by endophytic fungi

Abstract

There have been two hundred reports that endophytic fungi produce Taxol®, but its production yield is often rather low. Although considerable efforts have been made to increase Taxol/taxanes production in fungi by manipulating cocultures, mutagenesis, genome shuffles, and gene overexpression, little is known about the molecular signatures of Taxol biosynthesis and its regulation. It is known that some fungi have orthologs of the Taxol biosynthetic pathway, but the overall architecture of this pathway is unknown. A biosynthetic putative gene homology approach, combined with genomics and transcriptomics analysis, revealed that a few genes for metabolite residues may be located on dispensable chromosomes. This review explores a number of crucial topics (i) finding biosynthetic pathway genes using precursors, elicitors, and inhibitors; (ii) orthologs of the Taxol biosynthetic pathway for rate-limiting genes/enzymes; and (iii) genomics and transcriptomics can be used to accurately predict biosynthetic putative genes and regulators. This provides promising targets for future genetic engineering approaches to produce fungal Taxol and precursors. Key points • A recent trend in predicting Taxol biosynthetic pathway from endophytic fungi. • Understanding the Taxol biosynthetic pathway and related enzymes in fungi. • The genetic evidence and formation of taxane from endophytic fungi.

Production and bioprocessing of Taxol from Aspergillus niger, an endophyte of Encephalartos whitelockii, with a plausible biosynthetic stability: antiproliferative activity and cell cycle analysis

“…Despite the fungal fast growth, resistance to mechanical stress, and feasibility of genetic manipulation, the commercial production of Taxol by fungi has been halted by the rapid loss of Taxol productivity with the storage and subculturing [ 14 , 18 , 22 , 59 ]. Thus, screening for a novel endophytic fungal isolate inhabiting the plants of ethnopharmacological uses, could have relatively stable Taxol-producing machinery.…”

Paclitaxel – a Product of Fungal Secondary Metabolism or an Artefact?#

“…3 ) 7 , 32 or from cell cultures created from meristematic cells of the yew cambium 7 , 8 , 9 . In principle, it seems that there are no longer any fundamental problems in meeting the demand for this proven anti-cancer drug, although this is sometimes assessed differently 33 , 34 , 35 . Reliable data that would allow the assessment of the coverage of demand are not available.…”

“…Also, no published efforts to reproduce the original research results could be observed. It is striking that the seminal publication by Heinig, Scholz, and Jennewein was mostly – and even in broad review articles – ignored 34 , 43 , 44 , 47 , 48 , 61 , 62 , 63 , sometimes dutifully cited, but nevertheless ignored in substance 33 , 44 , 64 . In some cases, the article is correctly summarized in one sentence, but the negative findings have not prompted the researchers to question their own assumptions or, at least, to discuss them in more detail 8 , 45 , 48 .…”

Research Advances in Clinical Applications, Anticancer Mechanism, Total Chemical Synthesis, Semi-Synthesis and Biosynthesis of Paclitaxel

“…In 1993, the endophytic fungus Taxomyces andreanae from T. brevifolia was discovered by Stierle et al to produce paclitaxel in vitro [88]. Since then, more and more researchers have been engaged in isolating and characterizing paclitaxel-producing endophytic fungi [89][90][91]. To date, more than 20 genera of endophytic fungi have been identified in Taxus species and non-Taxus species such as sycamore and ginkgo (Table 4) .…”