Chemistry Reference
In-Depth Information
9.3 TERPENOID INDOLE ALKALOIDS
The terpenoid indole alkaloids have a variety of chemical structures and a wealth
of biologic activities (Fig. 9.2a) (59, 60). Terpenoid indole alkaloids are used as
anticancer, antimalarial, and antiarrhythmic agents. Although many biosynthetic
genes from this pathway remain unidentified, studies have correlated terpenoid
indole alkaloid production with the transcript profiles of
Catharanthus roseus
cell
cultures (61).
9.3.1 Early Steps of Terpenoid Indole Alkaloid Biosynthesis
All terpenoid indole alkaloids are derived from tryptophan and the iridoid terpene
secologanin (Fig. 9.2b). Tryptophan decarboxylase, a pyridoxal-dependent
enzyme, converts tryptophan to tryptamine (62, 63). The enzyme strictosidine
synthase catalyzes a stereoselective Pictet-Spengler condensation between
tryptamine and secologanin to yield strictosidine. Strictosidine synthase (64)
has been cloned from the plants
C. roseus
(65),
Rauwolfia serpentine
(66),
and,
Ophiorrhiza pumila
(67). A crystal structure of strictosidine synthase from
R. serpentina
has been reported (68, 69), and the substrate specificity of the
enzyme can be modulated (70).
Strictosidine then is deglycosylated by a dedicated
β
-glucosidase, which con-
verts it to a reactive hemiacetal intermediate (71-73). This hemiacetal opens to
form a dialdehyde intermediate, which then forms dehydrogeissoschizine. The
enol form of dehydrogeissoschizine undergoes 1,4 conjugate addition to produce
the heteroyohimbine cathenamine (74-76). A variety of rearrangements subse-
quently act on deglycosylated strictosidine to yield a diversity of indole alkaloid
products (77).
9.3.2 Ajmaline Biosynthesis
The biosynthetic pathway for ajmaline in
R. serpentina
is one of the best-
characterized terpenoid indole alkaloid pathways. Much of this progress has been
detailed in an extensive review (78). Like all other terpenoid indole alkaloids,
ajmaline, an antiarrhythmic drug with potent sodium channel-blocking properties
(79), is derived from deglycosylated strictosidine (Fig. 9.2c).
A membrane-protein fraction of an
R. serpentina
extract transforms labeled
strictosidine (80, 81) into sarpagan-type alkaloids. The enzyme activity is depen-
dent on NADPH and molecular oxygen, which suggests that sarpagan bridge
enzyme may be a cytochrome P450 enzyme. Polyneuridine aldehyde esterase
hydrolyzes the polyneuridine aldehyde methyl ester, which generates an acid
that decarboxylates to yield epi-vellosamine. This enzyme has been cloned from
a
Rauwolfia
cDNA library, heterologously expressed in
E. coli
, and subjected to
detailed mechanistic studies (82, 83).
In the next step of the ajmaline pathway, vinorine synthase transforms
the sarpagan alkaloid epi-vellosamine to the ajmalan alkaloid vinorine (84).
