Michael Wink Quinolizidine and Pyrrolizidine Alkaloid Chemical Ecology - a Mini-Review on Their Similarities and Differences
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Quinolizidine and Pyrrolizidine Alkaloid
Chemical Ecology – a Mini-Review on
Their Similarities and Differences
Michael Wink
Journal of Chemical Ecology
ISSN 0098-0331
Volume 45
Number 2
J Chem Ecol (2019) 45:109-115
DOI 10.1007/s10886-018-1005-6
1 23Your article is protected by copyright and all rights are held exclusively by Springer Science+Business Media, LLC, part of Springer Nature. This e-offprint is for personal use only and shall not be self-archived in electronic repositories. If you wish to self- archive your article, please use the accepted manuscript version for posting on your own website. You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com”. 1 23
Author's personal copy
Journal of Chemical Ecology (2019) 45:109–115
https://doi.org/10.1007/s10886-018-1005-6
REVIEW ARTICLE
Quinolizidine and Pyrrolizidine Alkaloid Chemical
Ecology – a Mini-Review on Their Similarities and Differences
Michael Wink 1
Received: 27 February 2018 / Revised: 13 July 2018 / Accepted: 30 July 2018 / Published online: 6 August 2018
# Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
This mini-review summarizes over 40 years of research on quinolizidine (QAs) and pyrrolizidine alkaloids (PAs). Emphasis is on
the chemical ecology of both groups of alkaloids, which serve as general defense compounds against herbivores for the plants
producing them. For QAs and PAs, a number of insects (aphids, moths, beetles) have acquired tolerance. These specialists store
the alkaloids and use them as defense chemicals against predators. In some PA sequestering moths, the adaptation is even more
intricate and advanced. PAs can function as a morphogen to induce the formation of male coremata, inflatable organs that
dissipate pheromones. In these insects, PAs are additionally used as a precursor for male pheromones. Female moths utilize
their own PAs and those obtained from males via the spermatophore as nuptial gift, to transfer them to the eggs that thus become
chemically protected. Novel genomic technologies will allow deeper insights in the molecular evolution of these two classes of
alkaloids in plant-insect interactions.
Keywords Quinolizidine alkaloids . Pyrrolizidine alkaloids . Chemical ecology . Lupins . Insect herivores . Plant-herbivore
interactions
Introduction Flowering plants and insects are closely connected.
With the beginning of the Tertiary, we see a phylogenetic
It is a trivial observation that plants cannot run away when radiation of flowering plants and concomitantly of in-
they are attacked by an herbivore. Neither do they have an sects. Many insects are pollinators, others are herbivo-
immune system to defend themselves against invading mi- rous. Within the herbivorous insects, we can distinguish
crobes (Wink 1988). However, over the course of more between polyphagous herbivores, which feed on many
than 400 million years of evolution, plants evolved com- plant species; oligophagous species, which select a few
plex bioactive defence and signalling molecules in order to host plants; and monophagous species, which are closely
survive in an environment with a multitude of enemies and adapted to individual hostplants which produce a certain
competitors (Wink 2003). The compounds conferring these class of PSM (Ali and Agrawal 2012; Mason and Singer
defence functions are often referred to as Plant Secondary 2015). The fact that polyphagous species are not adapted
Metabolites (PSM; Hartmann 2007). PSM not only serve as to a single class of PSM, does not mean they do not
defence molecules; some of them are used by plants to possess mechanisms to deal with plant toxins. Common
attract pollinating and fruit-dispersing animals. In addition, mechanisms found in many polyphagous insect herbi-
some PSM are of direct use for plants as nitrogen storage vores are detoxification by generic detoxification en-
compounds, antioxidants and UV protectants (Hartmann zymes, e.g. Cytochrome P450 (CYP) enzymes, or direct
2007; Harborne 2014). elimination of PSM by excretion via so-called ABC-
transporters. Some herbivores harbour or even cultivate
symbiotic intestinal microorganisms, which can degrade
or inactivate toxic PSM (Pennisi 2017). A number of
* Michael Wink monophagous insects not only tolerate the toxic PSM
wink@uni-heidelberg.de of their host plant, but actively store them in their bodies
1 (Boppré 1984; Cogni et al. 2012; Hartmann 2004;
Heidelberg University, Institute of Pharmacy and Molecular
Biotechnology, INF 364, D-69120 Heidelberg, Germany Laurent and Braekman J-C Daloze 2005; Macel 2011;Author's personal copy
110 J Chem Ecol (2019) 45:109–115
Trigo 2011; Wink 1992). These specialists use the ac- tigloyl transferase have been identified. Presently, we analyse
quired toxins for their own defence against predators transcriptomes from QA producing plants, generated by
(Mason and Singer 2015; Petschenka and Agrawal RNASeq, to identify additional genes involved in QA synthe-
2016). Such specialists, often adorned with aposematic sis, storage and transport.
warning colours, are known for sequestering toxic cardi- According to our experimental data, the QA biosynthe-
ac glycosides, aristolochic acids, cyanogenic glucosides, sis takes place in the chloroplast, which is also the site of
iridoid glucosides and several toxic alkaloids, such as lysine formation (Wink and Hartmann 1982b). QA synthe-
aconitine, pyrrolizidine, and quinolizidine alkaloids sis is regulated by light and follows a diurnal rhythm. After
(Dobler 2001; Kelly and Bowers 2016; Petschenka and synthesis, QAs are exported from the chloroplast into the
Agrawal 2016; Wink 1992; Zagrobelny and Moller cytoplasm and are actively sequestered in the vacuole. The
2011). The ability to sequester toxins also requires spe- necessary transport across the tonoplast is catalysed by an
cific adaptations making the specialist insensitive to the ATP-dependent proton antiporter (Mende and Wink 1987).
biological effect of the PSM. For example, insects which Since plants have several hundred of ABC transporter
store cardiac glycosides, which target the Na+,K+-ATPase genes it needs to be analysed if our QA transporter is a
enzyme, possess a target site modification in the genes true H + antiporter or an ABC transporter. Apparently,
coding for these proteins (Aardema and Andolfatto ABC transporters play a role for the transport of QAs from
2016). This allows them to tolerate high concentrations the phloem to the seeds (Frick et al. 2017).
of cardiac glycosides, which would kill any poly- or After synthesis, QAs are exported from the leaves to
oligophagous species (Dobler et al. 2012; Holzinger et other organs, such as stems, flowers and fruits. In stems
al. 1992; Holzinger and Wink 1996). and leaves, alkaloids are mainly stored in epidermal
In this mini -review I will focus on quinolizidine (QA) and cells. The transport takes place in the phloem and not
pyrrolizidine alkaloids (PA). These are two main classes of the xylem (review in Wink 1992). We had postulated that
alkaloids whose chemical-ecological functions have been the transfer from the phloem into the growing seeds also
researched for over 40 years now (Hartmann and Witte requires an alkaloid transporter, which was identified re-
1995). The review will address their biosynthesis, allocation, cently (Frick et al. 2017). If such a transporter would be
and, in particular, the similarities and differences in their genetically inactivated, the breeding of lupin varieties
chemical ecology in insect-plant interactions. with high alkaloid levels in the green parts, but low
levels in the seeds, would be become feasible. Such lu-
pins would retain their resistance against herbivores (see
Biosynthesis and Accumulation below), but would produce sweet seeds, suitable for an-
of Quinolizidine Alkaloids imal and human nutrition.
Transport and accumulation occur in a diurnal cycle (Wink
Starting with the amino acid lysine, the first step of QA bio- 1992). Alkaloid levels are highest during flowering and fruit
synthesis (Fig. 1) is the decarboxylation of lysine (catalysed formation. In annual species, most of the alkaloids are
by lysine decarboxylase, LDC) to the diamine cadaverine. The translocated into the seeds whereas the senescent aerial parts
next step involves a desamination of cadaverine either by a have very low levels. In wild lupins, seed alkaloid contents
transaminase or more like an oxidase into 5-aminopentanal. In can be between 2 and 8% of dry weight (Wink 1992). After
a complex reaction, in which the amino group of 5- germination, QA levels drop, because QAs are metabolized
aminopentanal forms a Schiff’s base with the aldehyde func- and their nitrogen serves to build amino acids. Therefore, one
tion of a second and third molecule of 5-aminopentanal, a additional function of QAs is that of a nitrogen storage.
tetracyclic quinolizidine ring skeleton is generated which Alkaloid levels are not static but are regulated by environmen-
can be converted into sparteine or lupanine (Wink and tal influences, such as heat, drought, high temperatures and
Hartmann 1978; Wink et al. 1979). After lupanine has been herbivory. Artificial wounding can enhance QA contents by a
hydroxylated to 13-hydroxylupanine, ester alkaloids can be factor of four with a couple of hours (Wink 1992). In lupins,
generated by a tigloyl-CoA: 13-hydroxylupanine O-tigloyl growing along altitudinal gradients in the Rocky Mountains,
transferase (Wink and Hartmann 1982a). An S-adenosyl-L- lupins from high altitudes have lower alkaloid contents than
methionine: N-methyltransferase can transfer methyl groups those of lower elevations (Wink et al. 1995).
to free nitrogen atoms in some QA, such as cytisine (Wink
1984). At that time, our evidence came from enzyme assays
but failed to identify the corresponding genes. Now, 30 years Quinolizidine Alkaloid Diversity in Lupins
later, we have genomic and transcriptomic tools to address the
old questions again (Frick et al. 2017). So far, genes for LDC, QAs are typical PSM of papilionoid legumes (Wink et al.
cadaverine oxidase, and tigloyl-CoA: 13-hydroxylupanine O- 2010), among them the species-rich genus Lupinus. The genusAuthor's personal copy J Chem Ecol (2019) 45:109–115 111 Fig. 1 Biosynthesis of quinolizidine alkaloids. A = lysine decarboxylase, B = cadaverine oxidase; C = quinolizidine synthase; D = tigloyl-CoA: 13-hydroxylupanine O-tigloyl transferase; E = S- adenosyl-L-methionine: N- methyltransferase Lupinus belongs to the tribe Genisteae within the subfamily Using GLC-MS we were able to profile the alkaloid com- Papilionoideae of the family Fabaceae. More than 300 position of more than 70 lupins and several other legumes Lupinus species are known. We have used DNA sequences from Europe, North America, Mexico and South America so of chloroplast genes (rbcL) and nuclear genes (ITSI, ITSII) to far (Wink et al. 1995). It has been argued by chemotaxono- reconstruct the molecular phylogeny of the genus Lupinus mists that the chemical profiles of plants could help to recon- (Käss and Wink 1997). About 13 species occur in southern struct their evolutionary relationships. Knowing the molecular Europe, northern and eastern Africa, where this genus proba- phylogeny of lupins, we could show that similarity of QA bly evolved. From the Old World two emigrations into the profiles are a poor indicator of a common descent. The genes New World took place less than 15 million years ago. About of QA formation appear to be present in all legumes and it 35 species now colonize the eastern lowlands of South seems to be a matter of gene regulation which genes are America whereas more than 250 species evolved after several switched on or off (Wink 2003; Wink et al. 2010). radiations in the Rocky Mountains and the Andes (Käss and Furthermore, QA profiles often differ more between organs Wink 1997; Nevado et al. 2016). than between species, which would make the profiles an even Lupins employ QAs, saponins, isoflavones and protease more ambiguous taxonomic marker. inhibitors against herbivores and saponins, phenolics and ter- penoids against microbial infections. We developed a solid- liquid extraction procedure using Extrelut columns and di- The Role of Quinolizidine Alkaloids in Plants chloromethane as a solvent to obtain QA extracts suitable for further analyses (Wink 1993). QAs (and PAs) are volatile Lupin alkaloids are toxic to a number of insects, slugs and as free bases, thus the complex mixtures can be separated by vertebrates. Furthermore, they are active against fungi (mil- high resolution capillary gas-liquid chromatography (GLC). dew), bacteria and even viruses and could be used as a natural For the identification of the individual alkaloids, the combi- pesticide (Wink 1992). QAs should thus be important for lu- nation of GLC with mass spectrometry (GLC-MS) is the pins as defence chemicals against herbivorous animals; in method of choice. Kovats retention indexes and mass spectral nature, alkaloid-rich lupins are usually left untouched by gen- data allow the identification of most QAs (details in Wink eral herbivores (Wink 1992). QAs have evolved as neuro- 1993; Wink et al. 1995). toxins, which target acetylcholine receptors and Na+/K+ ion
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112 J Chem Ecol (2019) 45:109–115
channels (Schmeller et al. 1997). QAs can bind to either the Arctiid moths are known to sequester PAs and cardiac
nicotinic acetylcholine receptor or the muscarinic acetylcho- glycosides. I personally came into contact with this topic
line receptor, probably as agonists (Wink 2000). Some indi- through Dietrich Schneider, who had discovered the
vidual QA interfere with dopamine, GABA, NMDA and strange relationship between Creatonotus moths and PAs
alpha-2 neuroreceptors. Sparteine and lupanine are inhibitors (Schneider et al. 1982; Boppré 1986). The hairy caterpil-
of sodium and potassium channels (Wink et al. 1998). Both lars of Creatonotus gangis and C. transiens prefer plant
interactions with neuroreceptors and ion channels qualify material with PAs. They even appear to be ‘addicted’ to
these alkaloids as potent neurotoxins. PAs, because they will eat filter paper impregnated with
However, a few specialists have evolved counter adapta- pure PAs, when offered. We suggested that PAs induce a
tions, such as the lupin aphid, Macrosiphon albifrons, which very strong feeding stimulus, similar to the behaviour of
loves alkaloid-rich lupins (Wink 1992). This aphid is appar- humans towards addictive drugs (Wink 2018).
ently able to tolerate and to store QA- although we do not For a couple of years, PAs were studied in Braunschweig
know the underlying mechanisms. Aphids rich in QA are by the Hartmann lab (Lindigkeit et al. 1997) and our lab in
apparently protected against predators (Wink and Römer Munich, Mainz or Heidelberg (von Nickisch-Rosenegk et
1986). Aposematically coloured larvae of the pyralid moth al. 1990; von Nickisch-Rosenegk and Wink 1993; Wink and
Uresiphita reversalis feeds on QA-rich Teline plants. Larvae Schneider 1988, 1990). Studies implied that PAs actively
actively take up QAs and store them in their integument. QAs enter the larval body. In most plants, PAs are present as polar
are not transferred to pupae and imagines but end up in the PA N-oxides that cannot pass biomembranes by simple dif-
cocoon silk of the pupae (Wink et al. 1991). As expected, non- fusion. We discovered that epithelial transporter proteins
specialised aphids avoid QA-rich lupins but select alkaloid- can transport the polar PAs into the haemolymph (Wink
poor sweet lupin cultivars. Also other animals discriminate and Schneider 1988). An alternative mechanism is also
between bitter and sweet lupins and prefer the latter (Wink plausible: In the gut, PAs are reduced to the more lipophilic
1992). This illustrates the role of QAs as defences against a free base, which can pass the membranes by simple diffu-
broad range of herbivores. sion. In the haemolymph, however, PAs must be re-oxidised
to PA N-oxides to avoid them from diffusing back
(Lindigkeit et al. 1997; Wang et al. 2012). The PAs do not
Occurrence and Biosynthesis of Pyrrolizidine remain in the haemolymph but are sequestered into the lar-
Alkaloids val integument (Egelhaaf et al. 1990; von Nickisch-
Rosenegk et al. 1990; von Nickisch-Rosenegk and Wink
PAs occur in several families and are the main group of alka- 1993), where they apparently serve for chemical defence
loids in Boraginaceae, in the subtribe Senecioninae against predators (Martins et al. 2015).
(Asteraceae) and in the tribe Crotalarieae (Fabaceae) The PA story becomes more complex, if we look closer
(Hartmann and Witte 1995; El-Shazly and Wink 2014). The into male and female larvae of Creatonotus after metamor-
precursors of PAs are the amino acids ornithine and arginine, phosis into adult insects: In female caterpillars, PAs will be
which produce the diamine putrescine. One unit of putrescine stored partly in the integument, but a larger proportion is
and spermidine are converted to homospermidine by transferred to the eggs, which thus gain chemical defence
homospermidine synthase. Homospermidine is deaminated (von Nickisch-Rosenegk et al. 1990). PAs thus function as
and via a reactive aldehyde converted to the necine base skel- a nuptial gift for the defense of the eggs; this phenomenon
eton. The necine base forms esters with small organic acids has also been described for other arctiids Utetheisa ornatrix
and generates cyclic PAs (retronecine and otonecine type) and and Cosmosoma myrodora (Bezzerides and Eisner 2002;
open-ringed PAs (heliotridine type) (Fig. 2) (Hartmann and Cogni et al. 2012; Conner et al. 2000; Gonzalez et al.
Witte 1995). 1999). Male moths of Creatonotus show impressive
coremata (hairy, inflatable sacks at the abdomen). They
are inflated during courtship to dissipate pheromones
Chemical Ecology of Pyrrolizidine Alkaloids attracting female partners. Dietary PAs exhibit morphogen-
ic properties, i.e., they induce the formation of coremata. If
PAs are among the alkaloids, which are often stored by a male caterpillar is reared on a PA-free diet, it will form
specialised insects. The role and fate of PAs have been most only very small coremata as adult male (Boppré 1986;
widely explored, thanks to the curiosity of Thomas Hartmann Schneider et al. 1982). The more PAs were ingested by a
and Tom Eisner who explored dozens of PA sequestering ar- male caterpillar, the larger the corema become (von
thropods (Eisner et al. 2007; Hartmann 1999; Hartmann and Nickisch-Rosenegk et al. 1990). Co-evolution was appar-
Witte 1995). As compared to QAs, the chemical ecology of ently even more intricate in this system (Schneider et al.
PAs is far more intricate and advanced. 1982). As mentioned before, the corema releasesAuthor's personal copy J Chem Ecol (2019) 45:109–115 113 Fig. 2 Biosynthesis of pyrrolizidine alkaloids pheromones to attract females. The pheromones of PA- react to serotonin receptor agonists (Wink 2018). Possibly, sequestering arctiids consist of hydroxydanadial (and this may explain the ‘addictive’ behaviour of arctiid moths others), which originate from dietary PAs (Boppré 1986; towards PAs, described above. This is an open question, Schulz et al. 1993, 1998; Wink et al. 1988). Apparently, which needs to be addressed experimentally. female moths are attracted by males with a fragrant PA perfume. And for good reason: the spermatophore of males contains dietary PAs, which were donated as a nuptial gift Conclusion during copulation to the female. These nuptial PAs also end up in the eggs. Males can thus enhance the fitness of their Both QAs and PAs are neurotoxins which are used by the offspring by transferring chemical defences. plants producing them as chemical defense compounds Hydroxydanaidal, occurring in many PA plants is also a against predators. However, a few insects have developed signal for other PA insects (Bogner and Boppré 1989). It resistance to QAs and PAs. In fact, they do not only tolerate was demonstrated that arctiid caterpillars have taste receptor them, but store and utilize them as acquired defence chemicals neurons which are dedicated to the perception of PAs and PA- against predators. In some moths, the interrelationship be- N oxides (Bernays et al. 2002, 2003). In vertebrates, PAs bind tween PAs and insects is more complex and advanced. In to serotonin receptors (Schmeller et al. 1997). We do not these specialist species, PAs serve as morphogens for corema know, if this is also the case of insect serotonin receptors, induction, as precursors for pheromones and as nuptial gifts. which are involved in the regulation of feeding, food choice Despite many years of research by Thomas Hartmann, his and sleep. Serotonin receptors are expressed in the brain but students and colleagues, many details of the biochemistry also in the intestinal tract of animals. Serotonin is involved in and molecular biology of these adaptations need to be ex- the regulation of appetite, mood and emotion, sleep, sexual plored in future studies. New technologies, such as Next activity, pain, learning and memory (Vleugels et al. 2015). As Generation Sequencing of DNA and RNA may open novel serotonin agonist often induce euphoria and hallucinations in possibilities to gain a better understanding of the evolution vertebrates, we can only speculate that maybe also insects and chemical ecology of these alkaloids.
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