193
12
to produce N-acyl nornicotine, which is more toxic than nicotine. This compound can be
secreted to coat the leaf surface (Laue et al. 2000).
Arecoline is found in the fruit of the Areca catechu palm (Palmae/Arecaceae), used
for betel quids and is a tetrahydronicotinic acid derivative. The nuts are chewed for their
stimulating effect on alertness; continued usage is a major risk for cancer of the mouth and
oesophagus (Horenstein et al. 2017). Ricinine (from Ricinus communis, Euphorbiaceae,
castor bean) contains a nitrile group as a side group to the pyridine ring and is probably
formed by dehydration of a nicotinamide derivative. The castor oil plant is toxic due to the
presence of ricin (a protein) and the ricinine alkaloid.
Condensation of the N-methyl-Δ 1 -pyrrolium cation with acetoacetic acid is proposed
to yield hygrine (found mainly in coca leaves), a pyrrolidine alkaloid. Hygrine cyclization
or alternative routes lead to tropinone, a branch point for two pathways, which both lead
to tropane alkaloids (Drager 2006). They depend on the stereochemistry of the reduction.
In the first pathway tropinone reductase I produces tropine, which is then fused with phenylalanine-derived (R)-phenyllactyl-CoA to the bicyclic littorine and further to hyoscyamine. Hyoscyamine 6β-hydroxylase, an α-ketoglutarate-dependent dioxygenase, converts
hyoscyamine to its epoxy derivative, scopolamine, in two sequential steps (Hashimoto
et al. 1993). Scopolamine forms atropine upon racemization (. Fig. 12.5). Atropine, hyoscyamine and scopolamine can be found in many members of the Solanaceae family, such
as Atropa belladonna and several Datura species. Some enzymes needed to catalyse the
steps to yield scopolamine are localized at the pericycle in the roots of Atropa belladonna
and Hyoscyamus muticus, whereas others are localized in the endodermis or cortical cells,
which means that intermediates of this pathway have to traffic between different cell types
(Pramod et al. 2010). Hyoscyamine and scopolamine can then be translocated to the aerial
parts of the plant, but the hyoscyamine 6β-hydroxylase is also found in leaves of Duboisia
myoporoides and Hyoscyamus senecionis, suggesting that scopolamine biosynthesis could
be taking place mainly in leaves at least in some plant species (Dehghan et al. 2013;
Kohnen et al. 2018). The synthesis of N-demethylated tropane alkaloids such as norlittorine and norhyoscyamine is induced under stress conditions, which could be a detoxification mechanism for cells (Al Balkhi et al. 2012). Atropine, hyoscyamine and scopolamine
are strong antagonists of the human muscarinic acetylcholine receptor (see 7 Sect. 5.1).
The second pathway from tropinone is via tropinone reductase II, leading to
pseudotropines from which calystegines (selective glucosidase inhibitors) are synthesized
(Scholl et al. 2001). Calystegines are nortropane alkaloids bearing between three and five
hydroxyl groups at various positions and in various orientations. They function as selective
glucosidase inhibitors due to their structural similarity with monosaccharides and occur
mainly in the Solanaceae and Convolvulaceae. This pathway has been shown to localize
to the companion cells of sieve elements in the phloem of potato (Petersson et al. 2013).
Epibatidine alkaloids are also compounds with a nortropane ring system, but their
biosynthesis and biological source are not yet clearly understood. They have been first
isolated from poison frogs, Epipedobates. Epibatidine has an analgesic effect 200 times that
of morphine, yet it targets a specific subset of nicotinic acetylcholine receptors (NAchRs)
rather than opioid receptors. Frogs eat this poison with their diet (mainly insects, like
ants and beetles) before depositing it in their skin. One amino acid replacement, which
evolved three times in poison frogs, decreases epibatidine sensitivity of the frog nicotinic
acetylcholine receptor. This comes at the cost of acetylcholine sensitivity of this receptor,
suggesting a mechanism how the frog protects itself from the poison (Tarvin et al. 2017).
12.7 · Pyridine Alkaloids (e.g. Nicotine), Pyrrolidine Alkaloids (e.g. Hygrine) and....
12
to produce N-acyl nornicotine, which is more toxic than nicotine. This compound can be
secreted to coat the leaf surface (Laue et al. 2000).
Arecoline is found in the fruit of the Areca catechu palm (Palmae/Arecaceae), used
for betel quids and is a tetrahydronicotinic acid derivative. The nuts are chewed for their
stimulating effect on alertness; continued usage is a major risk for cancer of the mouth and
oesophagus (Horenstein et al. 2017). Ricinine (from Ricinus communis, Euphorbiaceae,
castor bean) contains a nitrile group as a side group to the pyridine ring and is probably
formed by dehydration of a nicotinamide derivative. The castor oil plant is toxic due to the
presence of ricin (a protein) and the ricinine alkaloid.
Condensation of the N-methyl-Δ 1 -pyrrolium cation with acetoacetic acid is proposed
to yield hygrine (found mainly in coca leaves), a pyrrolidine alkaloid. Hygrine cyclization
or alternative routes lead to tropinone, a branch point for two pathways, which both lead
to tropane alkaloids (Drager 2006). They depend on the stereochemistry of the reduction.
In the first pathway tropinone reductase I produces tropine, which is then fused with phenylalanine-derived (R)-phenyllactyl-CoA to the bicyclic littorine and further to hyoscyamine. Hyoscyamine 6β-hydroxylase, an α-ketoglutarate-dependent dioxygenase, converts
hyoscyamine to its epoxy derivative, scopolamine, in two sequential steps (Hashimoto
et al. 1993). Scopolamine forms atropine upon racemization (. Fig. 12.5). Atropine, hyoscyamine and scopolamine can be found in many members of the Solanaceae family, such
as Atropa belladonna and several Datura species. Some enzymes needed to catalyse the
steps to yield scopolamine are localized at the pericycle in the roots of Atropa belladonna
and Hyoscyamus muticus, whereas others are localized in the endodermis or cortical cells,
which means that intermediates of this pathway have to traffic between different cell types
(Pramod et al. 2010). Hyoscyamine and scopolamine can then be translocated to the aerial
parts of the plant, but the hyoscyamine 6β-hydroxylase is also found in leaves of Duboisia
myoporoides and Hyoscyamus senecionis, suggesting that scopolamine biosynthesis could
be taking place mainly in leaves at least in some plant species (Dehghan et al. 2013;
Kohnen et al. 2018). The synthesis of N-demethylated tropane alkaloids such as norlittorine and norhyoscyamine is induced under stress conditions, which could be a detoxification mechanism for cells (Al Balkhi et al. 2012). Atropine, hyoscyamine and scopolamine
are strong antagonists of the human muscarinic acetylcholine receptor (see 7 Sect. 5.1).
The second pathway from tropinone is via tropinone reductase II, leading to
pseudotropines from which calystegines (selective glucosidase inhibitors) are synthesized
(Scholl et al. 2001). Calystegines are nortropane alkaloids bearing between three and five
hydroxyl groups at various positions and in various orientations. They function as selective
glucosidase inhibitors due to their structural similarity with monosaccharides and occur
mainly in the Solanaceae and Convolvulaceae. This pathway has been shown to localize
to the companion cells of sieve elements in the phloem of potato (Petersson et al. 2013).
Epibatidine alkaloids are also compounds with a nortropane ring system, but their
biosynthesis and biological source are not yet clearly understood. They have been first
isolated from poison frogs, Epipedobates. Epibatidine has an analgesic effect 200 times that
of morphine, yet it targets a specific subset of nicotinic acetylcholine receptors (NAchRs)
rather than opioid receptors. Frogs eat this poison with their diet (mainly insects, like
ants and beetles) before depositing it in their skin. One amino acid replacement, which
evolved three times in poison frogs, decreases epibatidine sensitivity of the frog nicotinic
acetylcholine receptor. This comes at the cost of acetylcholine sensitivity of this receptor,
suggesting a mechanism how the frog protects itself from the poison (Tarvin et al. 2017).
12.7 · Pyridine Alkaloids (e.g. Nicotine), Pyrrolidine Alkaloids (e.g. Hygrine) and....