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12
(S)-scoulerine is produced by the berberine bridge enzyme, which requires molecular
oxygen as oxidant and releases H 2 O 2 as by-product to form the characteristic berberine
bridge. The extra carbon atom is supplied from S-adenosylmethionine via an N-methyl
group. (S)-scoulerine can lead to the formation of sanguinarine via (S)-cheilanthifoline and
(S)-stylopine or to the formation of compounds such as berberine and noscapine via tetrahydrocolumbamine and (S)-canadine. Sanguinarine accumulates mainly in Papaveraceae,
Rutaceae and Fumariaceae. It can be extracted from the rhizome of Sanguinaria canadensis (bloodroot, Papaveraceae) and has been shown to intercalate with DNA (Croaker et al.
2016). Berberine, isolated from Berberis vulgaris and other plants, is an antiseptic and
modulates neurotransmitters. Due to the strong yellow colour of berberine, Berberis species were used to dye wool, leather and wood. Noscapine, isolated from the latex in poppy,
is used as a cough-suppressing medication. Sanguinarine is not normally present in the
latex but accumulates in roots; whereas the last steps of berberine biosynthesis are localized in the parenchyma cells of the root cortex (see . Fig. 9.1).
Two different routes for the papaverine pathway have been suggested. One pathway is initiated by the methylation of (S)-reticuline to generate (S)-laudanine (Han
et al. 2010). A second methylation at the 3′ position of laudanine leads to laudanosine
(N- methyltetrahydropapaverine); both are known alkaloids from the opium poppy.
Laudanosine is found in small amounts in opium poppy and toxic to humans by inducing epileptic seizures, bradycardia and hypotonia. In the human body, it can arise as a
degradation product of medically used drugs for muscle relaxation, including atracurium
and cisatracurium, N-demethylation, aromatization and dehydrogenation of laudanosine
yields papaverine.
The other pathway starts with (S)-coclaurine via (S)-norreticuline leading to (S)norlaudanine, (S)-tetrahydropapaverine and finally papaverine (Desgagne-Penix and
Facchini 2012). The identification of a norreticuline 7-O-methyltransferase (N7OMT),
which uses norreticuline to produce norlaudanine provides evidence for the latter pathway (Pienkny et al. 2009). Papaverine accumulates to high levels in the latex of some
poppy species and can act as a phosphodiesterase inhibitor (Han et al. 2010).
Whereas all pathways downstream of reticuline begin with the (S)-epimer, conversion
to the (R)-epimer of reticuline is a required entry step into the morphinan alkaloid biosynthetic pathway. The change in configuration is known to be achieved by an oxidationreduction process and the intermediate 1,2-dehydroreticulinium ion. Via salutaridine and
salutaridinol, thebaine is formed with the help of Cyt P450 enzymes, which catalyse C-C
bond formation, reduction and acetylation. Demethylation of thebaine leads mainly to
codeinone and further to codeine, another demethylation step yields morphine. Codeine
and morphine are the best known narcotic analgesics. The characteristics that allow these
opiates to bind strongly to the opioid receptor are defined by the “morphine rule”: (1)
tertiary nitrogen (a nitrogen atom connected by single bonds to three other atoms) with a
small alkyl group attached, (2) a quaternary carbon (a carbon attached by single bonds to
four other atoms), (3) a benzene ring or its equivalent attached to the quaternary carbon
and (4) a two-carbon chain between the quaternary carbon and the tertiary nitrogen.
In Papaver, the pathway from dopamine to thebaine takes place in the sieve element of
the phloem, and the necessary enzymes are imported from the companion cells (Ziegler
et al. 2009). The synthesis of codeine and morphine can take place either in the sieve element or in the adjoining laticifers (Weid et al. 2004). The cytoplasm of laticifers contains
many vesicles, which sequester the alkaloids. The latex in the laticifers, a milky liquid containing resins, proteins and secondary metabolites, is harvested by cuttings the capsule.
Chapter 12 · Alkaloids
12
(S)-scoulerine is produced by the berberine bridge enzyme, which requires molecular
oxygen as oxidant and releases H 2 O 2 as by-product to form the characteristic berberine
bridge. The extra carbon atom is supplied from S-adenosylmethionine via an N-methyl
group. (S)-scoulerine can lead to the formation of sanguinarine via (S)-cheilanthifoline and
(S)-stylopine or to the formation of compounds such as berberine and noscapine via tetrahydrocolumbamine and (S)-canadine. Sanguinarine accumulates mainly in Papaveraceae,
Rutaceae and Fumariaceae. It can be extracted from the rhizome of Sanguinaria canadensis (bloodroot, Papaveraceae) and has been shown to intercalate with DNA (Croaker et al.
2016). Berberine, isolated from Berberis vulgaris and other plants, is an antiseptic and
modulates neurotransmitters. Due to the strong yellow colour of berberine, Berberis species were used to dye wool, leather and wood. Noscapine, isolated from the latex in poppy,
is used as a cough-suppressing medication. Sanguinarine is not normally present in the
latex but accumulates in roots; whereas the last steps of berberine biosynthesis are localized in the parenchyma cells of the root cortex (see . Fig. 9.1).
Two different routes for the papaverine pathway have been suggested. One pathway is initiated by the methylation of (S)-reticuline to generate (S)-laudanine (Han
et al. 2010). A second methylation at the 3′ position of laudanine leads to laudanosine
(N- methyltetrahydropapaverine); both are known alkaloids from the opium poppy.
Laudanosine is found in small amounts in opium poppy and toxic to humans by inducing epileptic seizures, bradycardia and hypotonia. In the human body, it can arise as a
degradation product of medically used drugs for muscle relaxation, including atracurium
and cisatracurium, N-demethylation, aromatization and dehydrogenation of laudanosine
yields papaverine.
The other pathway starts with (S)-coclaurine via (S)-norreticuline leading to (S)norlaudanine, (S)-tetrahydropapaverine and finally papaverine (Desgagne-Penix and
Facchini 2012). The identification of a norreticuline 7-O-methyltransferase (N7OMT),
which uses norreticuline to produce norlaudanine provides evidence for the latter pathway (Pienkny et al. 2009). Papaverine accumulates to high levels in the latex of some
poppy species and can act as a phosphodiesterase inhibitor (Han et al. 2010).
Whereas all pathways downstream of reticuline begin with the (S)-epimer, conversion
to the (R)-epimer of reticuline is a required entry step into the morphinan alkaloid biosynthetic pathway. The change in configuration is known to be achieved by an oxidationreduction process and the intermediate 1,2-dehydroreticulinium ion. Via salutaridine and
salutaridinol, thebaine is formed with the help of Cyt P450 enzymes, which catalyse C-C
bond formation, reduction and acetylation. Demethylation of thebaine leads mainly to
codeinone and further to codeine, another demethylation step yields morphine. Codeine
and morphine are the best known narcotic analgesics. The characteristics that allow these
opiates to bind strongly to the opioid receptor are defined by the “morphine rule”: (1)
tertiary nitrogen (a nitrogen atom connected by single bonds to three other atoms) with a
small alkyl group attached, (2) a quaternary carbon (a carbon attached by single bonds to
four other atoms), (3) a benzene ring or its equivalent attached to the quaternary carbon
and (4) a two-carbon chain between the quaternary carbon and the tertiary nitrogen.
In Papaver, the pathway from dopamine to thebaine takes place in the sieve element of
the phloem, and the necessary enzymes are imported from the companion cells (Ziegler
et al. 2009). The synthesis of codeine and morphine can take place either in the sieve element or in the adjoining laticifers (Weid et al. 2004). The cytoplasm of laticifers contains
many vesicles, which sequester the alkaloids. The latex in the laticifers, a milky liquid containing resins, proteins and secondary metabolites, is harvested by cuttings the capsule.
Chapter 12 · Alkaloids