184
12
Strictosidine β-D-glucosidase (SGD) is the next important enzyme generating the
strictosidine aglycone (Stockigt and Panjikar 2007). From Catharanthus roseus, it is known
that SGD accumulates in highly stable supramolecular aggregates within the nucleus
(Guirimand et al. 2011) or as a soluble enzyme that associates with the cytoplasmic face
of the endoplasmic reticulum (Stevens et al. 1993). This means that strictosidine, the aglycone, is formed outside of the vacuole. The aglycone is toxic for the cell as it can lead
to protein cross-linking and precipitation; therefore the sequestration of the glycosylated
form in the vacuole is a protective measure. However, if the tonoplast is disrupted by herbivoral or microorganismal attack, the vacuolar pool of strictosidine glucoside is exposed
to the glucosidase, leading to a massive production of the toxic aglycone, a defence mechanism. Under normal conditions, upon hydrolysis of the glycoside one ring opens, leading
to the exposure of an aldehyde group (Barleben et al. 2007). This destabilizes the aglycone,
and it is rapidly processed by a three-enzyme system to generate the strychnos alkaloid
scaffold (Tatsis et al. 2017).
One branch downstream of strictosidine, mainly in Catharanthus, proceeds via DielsAlder reactions (see . Fig. 9.2e) through tabersonine (named the Aspidosperma type),
leading to vindoline. Another branch leads to catharanthine (the Iboga type). Coupling of
the monomeric alkaloids catharanthine and vindoline leads to the bisindoles vinblastine
and vincristine, which both interfere with microtubule dynamics and are therefore used
for chemotherapy, especially in leukaemia. Catharanthine is secreted to the waxy cuticle,
where it acts as an insect poison and inhibits fungal growth on the surface of the leaf. In
animals, it has been shown to act as an inhibitor of voltage-operated calcium channels.
In contrast, vindoline is transported to laticifers and idioblasts and distributed within the
mesophyll of leaves (Guirimand et al. 2011; Courdavault et al. 2014; Zhu et al. 2015).
In addition to the fact that in Catharanthus roseus the vindoline pathway is spread over
several cell types, internal phloem parenchyma of aerial organs (geraniol 10-hydroxylase),
epidermis of aerial organs, the apical meristem of roots (e.g. secologanin synthase) and
laticifers and idioblasts of leaves and stems, the enzymes are also localized in different
subcellular compartments (vacuole, cytoplasm, ER). This demonstrates the necessity of
spatial separation to avoid toxicity and to provide adequate transport mechanisms.
Another iboga type alkaloid is ibogaine from the bark of African shrubs such as
Tabernanthe iboga, Voacanga africana and Tabernaemontana undulata (Apocynaceae).
Ibogaine has psychedelic activity and has been used in the treatment of substance dependence (Brown 2013). After indigestion ibogaine is modified in the gut of animals resulting
in 12-hydroxyibogamine, a 5HT analogue, which can serve as a selective serotonin reuptake inhibitor. Noribogaine is also extracted from Tabernanthe iboga with slightly different
activities in comparison with ibogaine.
A third pathway, mainly in Rauwolfia, leads to cathenamine (also called the Corynanthe
type) and further to vinorine (cytotoxic), ajmalicine (raubasine), ajmaline and serpentine.
Ajmaline is an antiarrhythmic agent, whereas ajmalicine is used to treat high blood pressure, acting as an adrenergic antagonist. Serpentine possesses antihistamine activity and
is used in the treatment of snakebites.
Other pathways lead to yohimbine in Rubiaceae, an antagonist of the adrenoreceptor and acting as an aphrodisiac, and to reserpine in Rauwolfia, a substance blocking the
“vesicular transporter for monoamine storage” (VMAT, SLC18a) irreversibly, thereby
depleting neurons of norepinephrine, epinephrine, dopamine, serotonin and histamine
containing neuronal granules. Reserpine therefore acts as a sympatholytic agent (see
7 Sect. 5.2). In Strychnos nux-vomica (Loganiaceae) strychnine and the less toxic brucine
(a dimethoxy analogue) are formed. The non-tryptamine portion of these compounds is
Chapter 12 · Alkaloids
12
Strictosidine β-D-glucosidase (SGD) is the next important enzyme generating the
strictosidine aglycone (Stockigt and Panjikar 2007). From Catharanthus roseus, it is known
that SGD accumulates in highly stable supramolecular aggregates within the nucleus
(Guirimand et al. 2011) or as a soluble enzyme that associates with the cytoplasmic face
of the endoplasmic reticulum (Stevens et al. 1993). This means that strictosidine, the aglycone, is formed outside of the vacuole. The aglycone is toxic for the cell as it can lead
to protein cross-linking and precipitation; therefore the sequestration of the glycosylated
form in the vacuole is a protective measure. However, if the tonoplast is disrupted by herbivoral or microorganismal attack, the vacuolar pool of strictosidine glucoside is exposed
to the glucosidase, leading to a massive production of the toxic aglycone, a defence mechanism. Under normal conditions, upon hydrolysis of the glycoside one ring opens, leading
to the exposure of an aldehyde group (Barleben et al. 2007). This destabilizes the aglycone,
and it is rapidly processed by a three-enzyme system to generate the strychnos alkaloid
scaffold (Tatsis et al. 2017).
One branch downstream of strictosidine, mainly in Catharanthus, proceeds via DielsAlder reactions (see . Fig. 9.2e) through tabersonine (named the Aspidosperma type),
leading to vindoline. Another branch leads to catharanthine (the Iboga type). Coupling of
the monomeric alkaloids catharanthine and vindoline leads to the bisindoles vinblastine
and vincristine, which both interfere with microtubule dynamics and are therefore used
for chemotherapy, especially in leukaemia. Catharanthine is secreted to the waxy cuticle,
where it acts as an insect poison and inhibits fungal growth on the surface of the leaf. In
animals, it has been shown to act as an inhibitor of voltage-operated calcium channels.
In contrast, vindoline is transported to laticifers and idioblasts and distributed within the
mesophyll of leaves (Guirimand et al. 2011; Courdavault et al. 2014; Zhu et al. 2015).
In addition to the fact that in Catharanthus roseus the vindoline pathway is spread over
several cell types, internal phloem parenchyma of aerial organs (geraniol 10-hydroxylase),
epidermis of aerial organs, the apical meristem of roots (e.g. secologanin synthase) and
laticifers and idioblasts of leaves and stems, the enzymes are also localized in different
subcellular compartments (vacuole, cytoplasm, ER). This demonstrates the necessity of
spatial separation to avoid toxicity and to provide adequate transport mechanisms.
Another iboga type alkaloid is ibogaine from the bark of African shrubs such as
Tabernanthe iboga, Voacanga africana and Tabernaemontana undulata (Apocynaceae).
Ibogaine has psychedelic activity and has been used in the treatment of substance dependence (Brown 2013). After indigestion ibogaine is modified in the gut of animals resulting
in 12-hydroxyibogamine, a 5HT analogue, which can serve as a selective serotonin reuptake inhibitor. Noribogaine is also extracted from Tabernanthe iboga with slightly different
activities in comparison with ibogaine.
A third pathway, mainly in Rauwolfia, leads to cathenamine (also called the Corynanthe
type) and further to vinorine (cytotoxic), ajmalicine (raubasine), ajmaline and serpentine.
Ajmaline is an antiarrhythmic agent, whereas ajmalicine is used to treat high blood pressure, acting as an adrenergic antagonist. Serpentine possesses antihistamine activity and
is used in the treatment of snakebites.
Other pathways lead to yohimbine in Rubiaceae, an antagonist of the adrenoreceptor and acting as an aphrodisiac, and to reserpine in Rauwolfia, a substance blocking the
“vesicular transporter for monoamine storage” (VMAT, SLC18a) irreversibly, thereby
depleting neurons of norepinephrine, epinephrine, dopamine, serotonin and histamine
containing neuronal granules. Reserpine therefore acts as a sympatholytic agent (see
7 Sect. 5.2). In Strychnos nux-vomica (Loganiaceae) strychnine and the less toxic brucine
(a dimethoxy analogue) are formed. The non-tryptamine portion of these compounds is
Chapter 12 · Alkaloids