426
Antitumor Agents: Taxol and Taxanes – Production by Yew Cell Culture
OPP
Geranylgeranyl diphosphate
1
H
H
13
14
5
19
10
9
12
Taxa-4(5), 11(12)-diene
2
H
H
Taxa-4(20),11(12)-dien-5
a
-ol
OH
3
H
H
O
O
4
H
H
O
O
HO
5
HO
H
O
O
HO
HO
O
OH
O
O
O
10-Deacetyl Baccatin III (10-
DAB III)(3)
6
HO
H
O
O
O
HO
O
OH
O
O
O
O
+
OH
OH
NH
2
O
Phenylisoserine
Baccatin III
7
HO
H
O
O
O
O
OH
O
O
O
O
O
NH
2
O
OH
8
HO
H
O
O
O
O
OH
O
O
O
O
O
O
OH
NH
O
Taxol
TM
Fig. 3
AschemeofTaxo
l
biosynthesis.
1
. Taxadiene synthase,
2
. Cytochrome P450
taxane-13
α
-hydroxylase,
3
. Taxa-4(20),
11(12)-dien-5
α
-
o
-acetyl transferase,
4
. Cytochrome P450 taxane-10
β
-hydroxylase,
5
. Multiple steps,
6
. 10-deacetyl baccatin III
acetyl transferase,
7
. C-13 side chain addition,
8
.
N
-benzoylation.
the
α
-acetoxy group from C-5 to C-4, with
oxirane-to-oxetane ring expansion. The at-
tachment of the C-13 side chain to the
taxane ring seems to involve initial es-
teriFcation with phenylisoserine, followed
by
N
-benzoylation. Phenylisoserine would
be generated by an aminomutase reac-
tion of phenylalanine to
β
-phenylalanine,
followed by
α
-hydroxylation (±ig. 3).
5
General Characteristics of Taxol
Yield and
Growth in
Taxus
Cell Culture
This
section
focuses
on
the
detailed
analysis of a set of cell lines of
T. cuspidata
developed in the early and mid 90s at
the University of Toronto to characterize
the
relationships
and
general
features
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