Cyclization of geranylgeranyl diphosphate to taxa-4(5),11(12)-diene is the committed step of taxol biosynthesis in Pacific yew.
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.
Koepp
A E
AE
Institute of Biological Chemistry, Washington State University, Pullman 99164-6340, USA.
Hezari
M
M
Zajicek
J
J
Vogel
B S
BS
LaFever
R E
RE
Lewis
N G
NG
Croteau
R
R
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*
D000475:Alkenes; D004224:Diterpenes; D011106:Polyisoprenyl Phosphates; C093125:taxa-4(5),11(12)diene; C002963:geranylgeranyl pyrophosphate; D017239:Paclitaxel