Inhibition of paclitaxel and baccatin III accumulation by mevinolin and fosmidomycin in suspension cultures of Taxus baccata.
To achieve a better understanding of the metabolism and accumulation of paclitaxel and baccatin III in cell cultures of Taxus, inhibitors of the early steps in the terpenoid pathway were applied to a cell suspension culture of Taxus baccata: fosmidomycin as an inhibitor of the non-mevalonate branch of the pathway, and mevinolin as an inhibitor of the mevalonate branch. Synthesis of both taxanes in the cell suspension was first increased when cultured in the product formation medium supplemented with methyljasmonate (100 microM). The product formation medium was selected after assaying 24 different culture media. When fosmidomycin (200 microM) was added to the product formation medium together with the elicitor, the accumulation of paclitaxel and baccatin III was reduced by up to 3.0 and 1.5 times, respectively, whereas the inhibitory effect of mevinolin (1 microM) was only clearly exerted in the case of paclitaxel. Under the conditions of our experiment, we conclude that in the synthesis of both taxanes, the non-mevalonate pathway is the main source of the universal terpenoid precursor isopentenyl diphosphate (IPP).
Palazón
Javier
J
Laboratorio de Fisiologia Vegetal, Facultad de Farmacia, Universidad de Barcelona, Avda, Diagonal 643, 08028 Barcelona, Spain.
Cusidó
Rosa M
RM
Bonfill
Mercedes
M
Morales
Carmen
C
Piñol
M Teresa
MT
D000085:Acetates / Q000494:pharmacology; D000470:Alkaloids / Q000096:biosynthesis*; D002470:Cell Survival / Q000187:drug effects; D003470:Culture Media / Q000494:pharmacology; D046508:Culture Techniques / Q000379:methods; D003517:Cyclopentanes / Q000494:pharmacology; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D054883:Oxylipins; D017239:Paclitaxel / Q000096:biosynthesis*; D011786:Quality Control; D043823:Taxoids; D020946:Taxus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*
D000085:Acetates; D000470:Alkaloids; D003470:Culture Media; D003517:Cyclopentanes; D054883:Oxylipins; D043823:Taxoids; D005578:Fosfomycin; C073950:baccatin III; C024640:fosmidomycin; C072239:methyl jasmonate; D008148:Lovastatin; D017239:Paclitaxel