title: Cyclization of geranylgeranyl diphosphate to taxa-4(5),11(12)-diene is the committed step of taxol biosynthesis in Pacific yew.
abstract: The biosynthesis of taxol (paclitaxel) and related taxoids in Pacific yew (Taxus brevifolia) is thought to involve the cyclization of geranylgeranyl diphosphate to a taxadiene followed by extensive oxygenation of this diterpene olefin intermediate. A cell-free preparation from sapling yew stems catalyzed the conversion of [1-3H]geranylgeranyl diphosphate to a cyclic diterpene olefin that, when incubated with stem sections, was converted in good radiochemical yield to several highly functionalized taxanes, including 10-deacetyl baccatin III and taxol itself. Addition of the labeled olefin to a yew bark extract, followed by radiochemically guided fractionation, provided sufficient product to establish the structure as taxa-4(5),11(12)-diene by two-dimensional NMR spectroscopic methods. Therefore, the first dedicated step in taxol biosynthesis is the conversion of the universal diterpenoid precursor geranylgeranyl diphosphate to taxa-4(5),11(12)-diene, rather than to the 4(20),11(12)-diene isomer previously suggested on the basis of the abundance of taxoids with double bonds in these positions. The very common occurrence of taxane derivatives bearing the 4(20)-ene-5-oxy functional grouping, and the lack of oxygenated derivatives bearing a 4(5)-double bond, suggest that hydroxylation at C-5 of taxadiene with allylic rearrangement of the double bond is an early step in the conversion of this olefin intermediate to taxol.
authors.affiliation: Institute of Biological Chemistry, Washington State University, Pullman 99164-6340, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Koepp
authors.forename: M
authors.initials: M
authors.lastname: Hezari
authors.forename: J
authors.initials: J
authors.lastname: Zajicek
authors.forename: B S
authors.initials: BS
authors.lastname: Vogel
authors.forename: R E
authors.initials: RE
authors.lastname: LaFever
authors.forename: N G
authors.initials: NG
authors.lastname: Lewis
authors.forename: R
authors.initials: R
authors.lastname: Croteau
mesh_terms: D000475:Alkenes / Q000378:metabolism*; D004224:Diterpenes / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D017239:Paclitaxel / Q000096:biosynthesis*; D011106:Polyisoprenyl Phosphates / Q000737:chemistry / Q000378:metabolism*; D014197:Trees / Q000378:metabolism*
chemical_list: D000475:Alkenes; D004224:Diterpenes; D011106:Polyisoprenyl Phosphates; C093125:taxa-4(5),11(12)diene; C002963:geranylgeranyl pyrophosphate; D017239:Paclitaxel