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      Accessing low-oxidation state taxanes: is taxadiene-4(5)-epoxide on the taxol biosynthetic pathway?†

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          Abstract

          We report the first synthesis of taxadiene-4(5)-epoxide, which rearranges upon acid treatment to produce products of relevance to taxol biosynthesis.

          Abstract

          We have shown for the first time that taxadiene ( 3) can be epoxidised in a regio- and diastereoselective manner to provide taxadiene-4(5)-epoxide ( 12) as a single diastereoisomer, and that this epoxide can be rearranged to give taxa-4(20),11(12)-dien-5α-ol ( 4). Furthermore, the epoxide 12 rearranges under acidic conditions to give taxa-4(20),11(12)-dien-5α-ol ( 4), the known bridged ether OCT ( 5) and the new oxacyclotaxane (OCT2) 15. Contrary to previous speculation, taxadiene-4(5)-epoxide ( 12) is susceptible to rearrangement when exposed to an iron III porphyrin, and these observations justify consideration of epoxide 12 as a chemically competent intermediate on the taxol biosynthetic pathway.

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          Total synthesis of taxol.

          K Nicolaou, Z. Yang, J. J. Liu … (1994)
          Taxol, a substance originally isolated from the Pacific yew tree (Taxus brevifolia) more than two decades ago, has recently been approved for the clinical treatment of cancer patients. Hailed as having provided one of the most significant advances in cancer therapy, this molecule exerts its anticancer activity by inhibiting mitosis through enhancement of the polymerization of tubulin and consequent stabilization of microtubules. The scarcity of taxol and the ecological impact of harvesting it have prompted extension searches for alternative sources including semisynthesis, cellular culture production and chemical synthesis. The latter has been attempted for almost two decades, but these attempts have been thwarted by the magnitude of the synthetic challenge. Here we report the total synthesis of taxol by a convergent strategy, which opens a chemical pathway for the production of both the natural product itself and a variety of designed taxoids.
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            Metabolic engineering of taxadiene biosynthesis in yeast as a first step towards Taxol (Paclitaxel) production.

            Benedikt Engels, Pia Dahm, Stefan Jennewein (2008)
            Metabolic engineering in microbes could be used to produce large amounts of valuable metabolites that are difficult to extract from their natural sources and too expensive or complex to produce by chemical synthesis. As a step towards the production of Taxol in the yeast Saccharomyces cerevisiae, we introduced heterologous genes encoding biosynthetic enzymes from the early part of the taxoid biosynthetic pathway, isoprenoid pathway, as well as a regulatory factor to inhibit competitive pathways, and studied their impact on taxadiene synthesis. Expression of Taxus chinensis taxadiene synthase alone did not increase taxadiene levels because of insufficient levels of the universal diterpenoid precursor geranylgeranyl diphosphate. Coexpression of T. chinensis taxadiene synthase and geranylgeranyl diphosphate synthase failed to increase levels, probably due to steroid-based negative feedback, so we also expressed a truncated version of 3-hydroxyl-3-methylglutaryl-CoA reductase (HMG-CoA reductase) isoenzyme 1 that is not subject to feedback inhibition and a mutant regulatory protein, UPC2-1, to allow steroid uptake under aerobic conditions, resulting in a 50% increase in taxadiene. Finally, we replaced the T. chinensis geranylgeranyl diphosphate synthase with its counterpart from Sulfolobus acidocaldarius, which does not compete with steroid synthesis, and codon optimized the T. chinensis taxadiene synthase gene to ensure high-level expression, resulting in a 40-fold increase in taxadiene to 8.7+/-0.85mg/l as well as significant amounts of geranylgeraniol (33.1+/-5.6mg/l), suggesting taxadiene levels could be increased even further. This is the first demonstration of such enhanced taxadiene levels in yeast and offers the prospect for Taxol production in recombinant microbes.
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              Taxadiene Synthase Structure and Evolution of Modular Architecture in Terpene Biosynthesis

              Mustafa Köksal, Yinghua Jin, Robert M. Coates … (2010)
              With more than 55,000 members identified to date in all forms of life, the family of terpene or terpenoid natural products represents the epitome of molecular biodiversity. A particularly eminent member of this family is the polycyclic diterpenoid Taxol (paclitaxel), which promotes tubulin polymerization1 and exhibits remarkable efficacy in cancer chemotherapy2. The first committed step of Taxol biosynthesis in the Pacific yew (Taxus brevifolia)3 is the cyclization of the linear isoprenoid substrate geranylgeranyl diphosphate (GGPP) to form taxa-4(5),11(12)diene4, which is catalyzed by taxadiene synthase5. The full-length form of this diterpene cyclase contains 862-residues, but an ~80-residue N-terminal transit sequence is cleaved upon maturation in plastids6. We now report the X-ray crystal structure of a truncation variant lacking the transit sequence and an additional 27 residues at the N-terminus, henceforth designated TXS. Specifically, we have determined structures of TXS complexed with 13-aza-13,14-dihydrocopalyl diphosphate (ACP, 1.82 Å resolution) and 2-fluorogeranylgeranyl diphosphate (FGP, 2.25 Å resolution). The TXS structure is the first of a diterpene cyclase and reveals a modular assembly of three α-helical domains. The C-terminal catalytic domain is a class I terpenoid cyclase, which binds and activates substrate GGPP with a three-metal ion cluster. Surprisingly, the N-terminal domain and a third "insertion" domain together adopt the fold of a vestigial class II terpenoid cyclase. A class II cyclase activates the isoprenoid substrate by protonation instead of ionization, and the TXS structure reveals a definitive connection between the two distinct cyclase classes in the evolution of terpenoid biosynthesis.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Chem Sci
                Journal ID (iso-abbrev): Chem Sci
                Title: Chemical Science
                Publisher: Royal Society of Chemistry
                ISSN (Print): 2041-6520
                ISSN (Electronic): 2041-6539
                Publication date (Print): 1 May 2016
                Publication date (Electronic): 26 January 2016
                Volume: 7
                Issue: 5
                Pages: 3102-3107
                Affiliations
                [a ] School of Chemistry , University of Nottingham , University Park , NG7 2RD , Nottingham , UK
                [b ] Division of Plant and Crop Sciences , School of Biosciences , University of Nottingham , Sutton Bonnington , LE12 5RD , Loughborough , UK . Email: chris.hayes@ 123456nottingham.ac.uk ; Fax: +44 (0)115 951 3564 ; Tel: +44 (0)115 951 3045
                Author information
                http://orcid.org/0000-0003-1692-3646
                Article
                Publisher ID: c5sc03463a
                DOI: 10.1039/c5sc03463a
                PMC ID: 6005263
                PubMed ID: 29997802
                SO-VID: a2b5e07b-39ea-41e9-988c-eb7c410f3455
                Copyright © This journal is © The Royal Society of Chemistry 2016
                License:

                This article is freely available. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (CC BY 3.0)

                History
                Date received : 14 September 2015
                Date accepted : 26 January 2016
                Categories
                Subject: Chemistry

                Notes

                †Electronic supplementary information (ESI) available: Full experimental procedures and copies of 1H and 13C NMR spectra. CCDC 1030909. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5sc03463a


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