Plant Alkaloids: Main Features, Toxicity, and Mechanisms of Action

Abstract

Alkaloids are one of the largest groups of plant secondary metabolites, being present in several economically relevant plant families. Alkaloids encompass neuroactive molecules, such as caffeine and nicotine, as well as life-saving medicines including emetine used to fight oral intoxication and the antitumorals vincristine and vinblastine. Alkaloids can act as defense compounds in plants, being efficient against pathogens and predators due to their toxicity. Fast perception of aggressors and unfavorable environmental conditions, followed by efficient and specific signal transduction for triggering alkaloid accumulation, are key steps in successful plant protection. Toxic effects, in general, depend on specific dosage, exposure time, and individual characteristics, such as sensitivity, site of action, and developmental stage. At times, toxicity effects can be both harmful and beneficial depending on the ecological or pharmacological context. Different strategies are used to study alkaloid metabolism and accumulation. An efficient approach is to monitor gene expression, enzyme activities, and concentration of precursors and of the alkaloid itself during controlled attacks of pathogens and herbivores or upon the simulation of their presence through physical or chemical stimulation. Detailed understanding of alkaloid biosynthesis and mechanisms of action is essential to improve production of alkaloids of interest, to discover new bioactive molecules, and to sustainably exploit them against targets of interest, such as herbivores, pathogens, cancer cells, or unwanted physiological conditions.

Full text

Plant Alkaloids: Main Features, Toxicity, and Mechanisms of Action
Hélio Nitta Matsuura and Arthur Germano Fett-Neto*
Plant Physiology Laboratory, Center for Biotechnology and Department of Botany, Federal University of Rio Grande do Sul
(UFRGS), Porto Alegre, RS, Brazil
Abstract
Alkaloids are one of the largest groups of plant secondary metabolites, being present in several econom-
ically relevant plant families. Alkaloids encompass neuroactive molecules, such as caffeine and nicotine,
as well as life-saving medicines including emetine used to fight oral intoxication and the antitumorals
vincristine and vinblastine. Alkaloids can act as defense compounds in plants, being efficient
against pathogens and predators due to their toxicity. Fast perception of aggressors and unfavorable
environmental conditions, followed by efficient and specific signal transduction for triggering alkaloid
accumulation, are key steps in successful plant protection. Toxic effects, in general, depend on specific
dosage, exposure time, and individual characteristics, such as sensitivity, site of action, and developmen-
tal stage. At times, toxicity effects can be both harmful and beneficial depending on the ecological or
pharmacological context. Different strategies are used to study alkaloid metabolism and accumulation.
An efficient approach is to monitor gene expression, enzyme activities, and concentration of precursors
and of the alkaloid itself during controlled attacks of pathogens and herbivores or upon the simulation of
their presence through physical or chemical stimulation. Detailed understanding of alkaloid biosynthesis
and mechanisms of action is essential to improve production of alkaloids of interest, to discover new
bioactive molecules, and to sustainably exploit them against targets of interest, such as herbivores,
pathogens, cancer cells, or unwanted physiological conditions.
Keywords
Alkaloid; Antioxidant; Antitumoral; Herbivory; Pathogen
Introduction
Natural products have been exploited by humans for thousands of years, used as foods, drugs, antioxi-
dants, flavors, fragrances, dyes, insecticides, and pheromones, improving our health, enhancing crop
production, unraveling complex ecological interactions, and shaping our way of life. Alkaloids are among
the largest groups of secondary metabolites, being extremely diverse in terms of structure and biosynthetic
pathways, including more than 20,000 different molecules distributed throughout approximately 20 % of
known vascular plants (Yang and Stöckigt 2010).
Alkaloids are low-molecular-weight nitrogen-containing compounds and, due to the presence of a
heterocyclic ring containing a nitrogen atom, are typically alkaline. Alkaloids are known by their
numerous pharmacological effects on vertebrates. These metabolites can be divided into different classes
according to their precursor (e.g., indole alkaloids are alkaloids derived from tryptophan), encompassing
*Email: fettneto@cbiot.ufrgs.br
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more than 20 different classes (e.g., pyrrolidine alkaloids, tropane alkaloids, piperidine alkaloids, pyridine
alkaloids, quinolizidine alkaloids, and indole alkaloids, among others) (Yang and Stöckigt 2010).
The presence of alkaloids and other secondary metabolites in plants enhances plant reproductive rates,
either by improving defenses against biotic and abiotic stresses or by affecting pollinators and seed/fruit
disperser visitation. Defensive strategies include predator repellence by toxicity or bitterness taste or
damage repair by antioxidant system (Vilariño and Ravetta 2008; Matsuura and Fett-Neto 2013). Flower
visitors can be attracted by stimulant properties of some alkaloids, whereas visit duration can be controlled
by nonlethal toxicity (Irwin et al. 2014). This and several other examples of metabolic versatility lead to
significant improvement in survival rates for plants and, at the same time, provide important pharmaco-
logical activities for the human therapeutic arsenal, such as antioxidant compounds, antitumoral drugs,
analgesics, anti-inflammatories, and stimulants (Yang and Stöckigt 2010).
The major role described for plant alkaloids in the scientific literature revolves around protection
against herbivores, for several alkaloids present characteristics such as bitter flavor, disruption of protein
function after ingestion and metabolization, and central nervous system alteration (Harborne 1993).
To minimize self-intoxication risk, defense compounds are often stored in the vacuole or apoplastic
compartment, showing limited metabolic activity (Mithöfer and Boland 2012).
Toxic Alkaloids
Alkaloids are among the most important drugs in human history. The isolation of the alkaloid morphine by
Friedrich Wilhelm Sert€
urner in 1806 is regarded as the “formal”start of plant secondary metabolism
(Hartmann 2007). It is widely accepted that the main role of alkaloids in plants is toxicity against predators
and pathogens. The same toxic properties observed in the plant defense scenario can often be used in
prospection for new drugs. For example, a very specific toxicity may be used to fight certain tumor cell
types, or also be used to control specific microorganisms or pests (Yang and Stöckigt 2010; Lee
et al. 2014).
Different uses of plant alkaloids have been reported during history, including medicinal, therapeutic,
recreational, and religious. The use of plant alkaloids from distinct classes to alter senses has been known
since ancient times due to the ability of several of these molecules to modulate the human central nervous
system (CNS). The use of opium poppy (Papaver somniferum) latex has been recorded as early as 1400 to
1200 B.C. in the Eastern Mediterranean. The roots of Rauvolfia serpentina have been used in India since
approximately 1000 B.C. The Greek philosopher Socrates was executed in 399 B.C. by drinking an
extract of hemlock (Conium maculatum). The Egyptian queen Cleopatra used extracts of henbane
(Hyoscyamus), which contain atropine, to dilate pupils and appear more seductive. Tropane alkaloids
from several Solanaceae species were used in sorcery by “witches”during the Middle Ages (Croteau
et al. 2000; Evans and Hofmann 2006).
Presently used toxic or potentially toxic alkaloids include caffeine, constituent of daily foods and
beverages containing coffee (Coffea arabica), tea (mostly Camellia sinensis), or cocoa (Theobroma
cacao), consumed for mental alertness, as well as physical training enhancement; nicotine in cigars,
cigarettes, and pipes (Nicotiana tabacum), a CNS stimulant; morphine (Papaver somniferum), one of the
most powerful known analgesics; and codeine found in the same species, a sedative and cough suppres-
sant. Illicit psychoactive drugs that cause massive social and economic problems, such as cocaine
(Erythroxylum sp.) and its derivatives (Koleva et al. 2012; Senchina et al. 2014), are also contemporary
toxic alkaloids. Strychnine, from Strychnos nux-vomica, is a very powerful tetanic poison, acting as
competitive antagonist at glycine receptors. Its main current uses are as rat poison and in homeopathy
(Croteau et al. 2000).
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For crop management purposes, the presence of alkaloids of low toxicity to humans can be an
advantage by keeping herbivores away. For example, Lupinus species with higher quinolizidine content,
thus less palatable, require less pesticide application (Vilariño and Ravetta 2008). Consistently, produc-
tion of tomatoes with very low contents or lacking solanine, selected for appropriate human consumption,
requires larger amounts of pesticides. Crops that did not undergo long-term artificial selection, often
focused essentially on edible organs for human food supply, can still bear useful defensive traits, thereby
requiring less agricultural inputs to keep herbivores and competitors away. There is also evidence for
allelopathic activity of some plant alkaloids against target species mostly in laboratory assays. Inhibition
of Lactuca sativa and Lepidium sativum seedling growth by berberine, sanguinarine, and gramine, among
other alkaloids, has been recorded. Although less phytotoxic than essential oil terpenes, for instance,
quinine, cinchonidine, nicotine, boldine, lobeline, coniine, and harmaline proved phytotoxic to Lemna
gibba, causing death or chlorosis (Wink and Twardowski 1992). Whether alkaloid phytotoxicity could be
used in weed control remains to be tested.
Some animals can stock toxic alkaloids indirectly acquired from plants, as is the case of poison frogs
(Dendrobatidae) from South and Central America forests. The source of alkaloids is alkaloid-containing
arthropods that previously accumulated toxins presumably by feeding on toxic alkaloid-containing plants.
The presence of plant alkaloids chimonanthine, calycanthine, and nicotine, or its enantiomers, has been
reported in the skin of Dendrobatidae frogs (Saporito et al. 2012). Native Indians from the Amazon use the
secretion of poison frogs to contaminate the point of darts used in hunting and rapidly kill or impair birds
and little mammals. Bufonidae frogs were believed to produce alkaloids instead of accumulating them
from a food source, but recent studies showed that Bufonidae frogs also obtain alkaloids from the diet
(Hantak et al. 2013). Some species of Phyllobates (Dendrobatidae) can secrete batrachotoxins, which are
the most potent known non-peptide neurotoxins (Zhang et al. 2014). Pyrrolizidine alkaloids of species of
Crotalaria (rattlebox), which serve as hosts to the moth Utetheisa ornatrix (bella moth), can be stored by
larvae, making them poisonous and frequently repellent to predators, a feature that remains through the
pupae and adult stages. In addition, the alkaloids and biotransformation products of these are given to
females as a nuptial gift, which is transferred to eggs, presumably making these protected against
predators (Eisner 2003).
Toxicity to Humans and Other Vertebrates
Animal intoxication by alkaloids is mostly caused by accidental ingestion of food contaminated with
alkaloid-containing plants. Clearly, the amount of ingested alkaloid and the sensitivity of the target animal
are key factors leading to intoxication. Some alkaloids can be extremely harmful to mammals, which is the
case of the steroidal alkaloid cyclopamine in lambs, identified as the compound in Veratrum californicum
(Liliaceae) responsible for teratogen effects resulting in craniofacial birth defects causing a cyclops aspect
in offspring of sheep grazing V. californicum (Fig. 1). First reports on this phenomenon occurred during
the late 1960s in the western United States (Lee et al. 2014).
Plants containing tropane alkaloids (TAs) are found in numerous and important plant families such as
Solanaceae, Brassicaceae, Erythroxylaceae, Convolvulaceae, and Euphorbiaceae. TAs are alkaloids
derived from ornithine, and in many parts of the world, TA-containing plants have been used for folkloric
and medicinal purposes due to their powerful anticholinergic (e.g., scopolamine) and hallucinogenic
effects (e.g., hyoscyamine and atropine), causing constipation, photophobia, pupil dilatation, vision
disturbance, and dryness of upper digestive and respiratory tract mucosa. Contaminations with TAs
often occur via ingestion of food containing Datura, which accumulates high concentrations of scopol-
amine and hyoscyamine (Koleva et al. 2012).
In Solanum plants (Solanaceae), the commonly present glycoalkaloids, solanine and chaconine, can be
found in species such as nightshades (S. nigrum), potato (S. tuberosum), tomato (S. lycopersicum),
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eggplant (S. melongena), pepper (Capsicum annuum), and petunia (Petunia sp.), carrying fungicidal and
pesticidal properties participating in plant defense mechanisms. Poisoning by solanine ingestion primarily
causes gastrointestinal and neurological disorders. The mechanism of action can be due to inhibition of
acetyl cholinesterase and calcium transport, which occur in micromolar range. A synergic effect that
increases toxicity is likely to be observed when solanine and chaconine are combined (Yamashoji and
Matsuda 2013).
The plant families Asteraceae, Boraginaceae, and Fabaceae often produce pyrrolizidine alkaloids
(PAs), which are also ornithine-derived alkaloids, estimated to be present in more than 6,000 plants and
known to be efficient against predators, including human and livestock (Shimshoni et al. 2015). PAs’
acute and chronic liver toxicity in humans and other animals is well known, and some symptoms of acute
PA poisoning are abdominal pain, nausea, vomiting, diarrhea, and edema (Koleva et al. 2012). Highly
toxic carcinogenic and genotoxic effects are reported as the main mechanism of action of PAs (Shimshoni
et al. 2015). Food contaminated with PAs, mostly esters of 1-hydroxymethyl-1,2-dehydropyrrolizidine,
include vegetables, grain-derived products, eggs, honey, offal, and milk, due to contamination of the
grains by seeds and/or plant fragments from PA-containing weeds growing in the crops used for animal
feeding or human consumption (Koleva et al. 2012). Grazing animals will generally avoid PA-containing
plants; however, in unfavorable conditions, such as overgrazed pastures and favored toxic weed devel-
opment caused by drought, a behavior of PA-containing weed consumption can be observed (Shimshoni
et al. 2015). A screening of 350 plant-derived PAs showed that approximately half of them were
hepatotoxic and several were carcinogenic (Cushnie et al. 2014). In addition to PAs, iridoid glycoside
(IG) presence also confers plant resistance, and a combined defense is often common and most effective
for plants to increase protection (Shimshoni et al. 2015).
Some quinolizidine alkaloids, as the case of lupin alkaloids, are toxic to humans in acute doses, which
may occur when consuming lupin beans that were not previously debittered, causing dry mouth, blurry
vision, facial flushing, and confusion (Koleva et al. 2012).
Fig. 1 (a) Structure of the toxic alkaloid cyclopamine from Veratrum californicum;(b,c) lambs with cyclops phenotype due to
alkaloid ingestion by their mother (Adapted with permission from Lee et al. (2014). Copyright (2014) American Chemical
Society)
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To adult livestock animals, piperidine alkaloids (derived from lysine) can be acutely toxic causing
musculoskeletal deformities in neonatal individuals. Signs of acute intoxication by piperidine alkaloids in
livestock include frequent urination and defecation, muscle weakness, tachycardia, ataxia, muscle
fasciculations, collapse, and death by respiratory failure. The teratogenic effect of some piperidine
alkaloids, such as ammodendrine, N-acetylhystrine, anabaseine, coniine, and g-coniceine, include mul-
tiple congenital contracture deformities and cleft palate in pigs, goats, cattle, and sheep. Poisonous plants
containing teratogenic piperidine alkaloids include some Lupinus sp., Laburnum sp., N. tabacum,
N. glauca, and Conium maculatum (Green et al. 2012).
Taxines are a mixture of active alkaloids from yew trees (Taxus sp., Taxaceae), which have been
implicated in several animal and human poisonings with predominant cardiovascular effects. Although
some taxines are related to the antitumor drug Taxol, they are distinct molecules. Toxicity of the yew
genus has been known since the second century B.C., particularly among Celts and related cultures
(Wilson et al. 2001).
Excess of daily-consumed metabolites such as caffeine can also be considerably toxic. Some overdose
symptoms include tachycardia, arrhythmia, convulsions, vomiting, and eventually coma and death. The
average caffeine content in a cup of coffee or tea is between 40 and 150 mg, and medicinal/fitness
supplements may contain some 100–400 mg. Lethal caffeine overdoses are typically in excess over 5 g in
adults and are relatively rare, generally occurring by accidental causes (Kerrigan and Lindsey 2005).
Due to stimulatory and addictive effects of nicotine from tobacco, the popularity of tobacco products
and their widespread use remain, causing billions of people around the world to use it, despite the fact that
almost all users are aware of the numerous negative health and economic impacts of smoking (Dewey and
Xie 2014). Nicotine is also important as a treatment to help quit smoking, in the form of skin patches
and gums.
Cocaine and its derivatives are extremely addictive and harmful drugs, with devastating effects in
health and behavior of users, carrying economical and social disorders to society. Chewing coca leaves
has been a centuries-old practice of Andean native people. The presumed effects of this practice are
related to improved physical performance; in fact, this information has found some support in controlled
experiments involving physical exercises. However, the beneficial effects may not be related to the minute
amounts of cocaine ingested by leaf chewing, but rather to flavonoids or other constituents that could
function as adaptogens (Casikar et al. 2010).
Adaptations of some animals to tolerate plant alkaloids, and even store these compounds, such as
alkaloid-accumulating poison frogs, require specialized strategies including storage of the defensive
compound in specialized structures (dermal granular glands, located at the dorsum), conversion of the
metabolite into a less toxic form prior to storage (e.g., conversion of pyrrolizidine alkaloids to N-oxides),
and changes at molecular level in ion channel sites or receptors to avoid self-intoxication (Saporito
et al. 2012).
Anti-herbivory and Pollinator Interactions (Focus on Insects)
Plant arsenals to cope with herbivores include repellent, antinutritive, and toxic compounds. Some
examples are alkaloids, cyanogenic glycosides, glucosinolates, terpenoids, and also macromolecules
such as proteinase inhibitors and cyclotides, solid inclusions (raphides and druses), resins, and latex.
Alkaloid-mimicking sugars are efficient inhibitors of several sugars and glycosidases metabolizing
enzymes by inhibition of trehalase in some tissues and sucrose in the midgut, leading to toxic effects and
affecting growth once the insect becomes disabled to use threalose or uptake sucrose. Colchicine from
Colchicum autumnale (Colchicaceae) is toxic to honey bee (Apis mellifera) and inhibits microtubule
polymerization by binding to tubulin and inhibiting mitosis (Mithöfer and Boland 2012). Pollinators are
exposed to a diverse array of alkaloids, similar to grazing animals, since secondary metabolites can also be
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present in plant reproductive tissues, as well as in nectar and pollen. Some negative consequences, such as
reduced ovary development, mobility, and survivorship, are documented for several pollinators visiting
alkaloid-containing plants, but, in some cases, secondary compounds present in nectar can be beneficial to
the pollinator, reducing gut pathogens. In fact, low concentrations of some alkaloids can attract pollinators
(Irwin et al. 2014). A strategy of accumulating both attractant (e.g., sugars and volatile phenolics) and
repellent (e.g., alkaloids) compounds in the nectar observed in N. attenuata results in benefits to the plant
by decreasing pollinator visitation time and increasing the number of visited flowers (Brandenburg
et al. 2009). The presence of low concentrations of caffeine in nectar (below its bitterness threshold) of
some Rubiaceae and Rutaceae has been shown to potentiate the pollinator memory of reward by acting as
an adenosine receptor antagonist, stimulating more visits to the same flower (Wright et al. 2013).
Plant alkaloid toxicity can be quite diversified, but often involves neurotoxicity or cell signaling
disruption (Mithöfer and Boland 2012). Sanguinarine from Sanguinaria canadensis (Papaveraceae)
presents multiple toxic effects. This alkaloid inhibits choline acetyltransferase, affecting neurotransmis-
sion; it also affects several other neuroreceptors and DNA synthesis. Caffeine found in C. arabica
(Rubiaceae) and various other plant species is often toxic and paralyzes insects feeding on the plant.
Caffeine inhibits phosphodiesterase activity and promotes increase in intracellular cyclic AMP level. In
vertebrates, the interaction of the alkaloid with adenosine receptors of the nervous system is responsible
for stimulating effects. Nicotine effect lies on the ability of some alkaloids to bind various neuroreceptors
and block or displace endogenous neurotransmitters. Nicotine acts as an agonist or antagonist targeting
nicotinic acetylcholine receptors in insects, which are the most abundant excitatory postsynaptic recep-
tors, causing continual neuronal excitation, leading to insect paralysis and death (Dewey and Xie 2014).
Nicotine accumulation is triggered by herbivore attack, which leads to increased jasmonic acid (JA) levels
in wounded leaves, signaling for nicotine synthesis in roots, and subsequent transport of the alkaloid to
aerial parts (Mithöfer and Boland 2012).
“Friendly”Toxicity
The alkaloid mechanism of action is complex, meaning that toxicity observed in insects, for example, is
not necessarily the same to other animals. Key aspects related to toxicity symptoms include the amount of
active metabolite, the organ that it is in contact with, and particular characteristics of the target organism.
Understanding alkaloid metabolism and action can lead to useful molecules for human health and crop
production.
Some important drugs of the therapeutic arsenal that are plant alkaloids include morphine to treat severe
pain; emetine and cephaeline as antidotes for intoxication; caffeine with its stimulant properties; quinine
used due to its antimalarial properties and bitter taste; the antitumorals vincristine, vinblastine, and
camptothecin; anti-arrhythmic ajmaline; antihypertensives serpentine and ajmalicine; antimicrobials
berberine and sanguinarine; antitussive noscapine; vasodilator papaverine; and the muscle relaxant
tubocurarine (Yang and Stöckigt 2010).
Alkaloids are also consumed to improve immune functions, nutrition, and physical performance, being
present in daily foods, beverages, and supplements. Some examples include the caffeine from coffee
(or guaranine and mateine from other plants) with antioxidant, anti-inflammatory, and stimulatory
properties; theobromine and paraxanthine from cocoa as antioxidants; and gingerol and shogaols
(phenolic alkanones) present in ginger bearing antioxidant, anti-inflammatory, antimicrobial, and
antitumoral properties (Senchina et al. 2014; Han et al. 2015). Mitochondria are the major intracellular
sources of reactive oxygen species (ROS) in animal cells. Conjugates of the plant alkaloids berberine and
palmatine with the antioxidant plastoquinone can be used as a strategy in therapies focusing
mitochondria-targeted antioxidant activity (Apostolova and Victor 2015). Various alkaloids display
antioxidant properties, some of which being effective skin sunscreens (Machowinski et al. 2006; Ahsan
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et al. 2007). Some alkaloids may have a major role in plants as antioxidants rather than as toxins for
herbivores, thereby helping the detoxification of reactive oxygen species generated by different stresses
(Matsuura et al. 2014; Porto et al. 2014).
Antibacterial activity is reported for various alkaloid classes, including aaptamine, indole, indolizidine,
isoquinoline, piperazine, quinoline, quinolone, agelasine, polyamine, aaptamine-indole, bisindole,
indole-quinoline, pyridoacridine, bispyrrole, and pyrrole-imidazole alkaloids (Cushnie et al. 2014). In
addition, natural xenobiotics, such as gramine, can prevent cyanobacterial and algal growth, being useful
tools in freshwater quality management and ecology (Laue et al. 2014).
Alkaloids previously known as exclusively harmful have often found new uses. Protective and
therapeutic effects of solanine treatment were observed in animal breast cancer models, with reduction
in tumor size and weight, apoptosis induction, as well as an inhibition of angiogenesis and cell
proliferation (Mohsenikia et al. 2013). Cyclopamine has displayed potential as antitumor agent.
Cyclopamine teratogenic properties lie on inhibition of the sonic hedgehog (Shh) signaling pathway,
which plays a critical role in development of embryos; interestingly, the very same inhibition of Shh
signaling is a promising treatment method for several cancer types. Human patients carrying basal cell
carcinomas treated with a topical cream containing cyclopamine showed tumor regression and no adverse
effects (Lee et al. 2014).
Mechanisms of Action
Alkaloids affect different metabolic systems in animals, and the toxic mechanism of action of alkaloids
may vary considerably. Toxicity may arise by enzymatic alterations affecting physiological processes,
inhibition of DNA synthesis and repair mechanisms by intercalating with nucleic acids, or affecting the
nervous system. Several alkaloids may affect multiple functions (Mithöfer and Boland 2012).
Taxines are calcium channel antagonists, increasing cytoplasmic calcium (Wilson et al. 2001).
Pyrrolizidine alkaloid toxic effects are mainly due to their biotransformation into strong reactive pyrrole
structures by oxidases from the mammalian liver. The reactive pyrroles act by alkylating nucleic acids and
proteins (Cushnie et al. 2014). Alkaloid mechanisms of action as antibacterial agents differ among
alkaloid classes. Synthetic quinolone alkaloids may have respiratory inhibition effects; isoquinolines,
such as berberine, sanguinarine, protoberberine, and benzophenanthridine, inhibit cell division by
perturbing the Z-ring; the phenanthridine isoquinoline alkaloid ungeremine acts by inhibiting nucleic
acid synthesis; pergularinine and tylophorinidine, which are indolizidine alkaloids, inhibit nucleic acid
synthesis as well, by targeting dihydrofolate reductase (Cushnie et al. 2014).
Plant Alkaloid Accumulation Strategies and Dynamics
Accumulation of defense compounds in plants, originating either from primary (e.g., toxic peptides) or
secondary (e.g., alkaloids) metabolism, is closely related to the survival strategy of the organism in the
environment by ensuring adequate maintenance of basic primary metabolism activity. In stressful
environments, such as those with extreme temperatures, floods, and/or droughts, mechanisms to tolerate
freezing and dormancy periods, to prevent loss of water or to deal with anoxia, may also require
modifications/specializations in metabolism, besides morphological and anatomical adaptations.
Several biotic and abiotic stressing conditions modulate the induction of alkaloids as well as other
secondary metabolites. The presence of herbivores and pathogens; wounding; hormones mimicking
herbivore/pathogen attacks, such as JA and salicylic acid (SA); changes in irradiance intensities and
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qualities [e.g., high red/far-red ratio and ultraviolet-B radiation (UV-B)]; temperature; drought; and soil
nutrient composition can affect alkaloid concentrations in plants. As for most secondary metabolites,
alkaloid accumulation is also often responsive to developmental signals, such as changes associated with
flowering and fruit setting (Nascimento and Fett-Neto 2010), as well as with leaf growth (Roepke
et al. 2010). The elucidation of alkaloid biosynthetic pathways and the influence of external and
developmental signals on them may not only help in understanding the ecological roles of these
compounds but also assist in defining strategies to improve their production for pharmacological or
agrochemical purposes.
Catharanthus roseus together with Rauwolfia serpentina (Apocynaceae) produce a range of important
alkaloids such as vincristine, vinblastine, reserpine, ajmaline, ajmalicine, and serpentine and are model
plants in MIA (monoterpene indole alkaloid) biosynthesis. Relatively detailed physiological and ecolog-
ical aspects of MIA production are known for C. roseus.
C. roseus has specialized alkaloid accumulation strategies, with an elaborate compartmentalization
system involving at least four cell types and further subcellular distribution in various organelles. As
expected, such morpho-metabolic organization is seamed together by tight regulated mechanisms of
intracellular and extracellular translocation events. This complex spatial organization regulates metabolic
fluxes and allows efficient plant defense. C. roseus leaf protection is likely ensured by accumulation of
toxic MIAs (Courdavault et al. 2014).
At non-stressful physiological conditions, strictosidine (first MIA engaged in the biosynthetic pathway)
concentrations remain low in C. roseus. High concentrations of strictosidine may be triggered, for
example, after hormonal treatment mimicking the attack of herbivores and/or microorganisms.
Catharanthus alkaloids and enzymes involved in biosynthetic pathways are compartmentalized, being
strictosidine accumulated in vacuoles of epidermal cells. Biosynthesis of strictosidine precursors, how-
ever, is restricted to the cytosol of epidermal cells. An ER-anchored P450 secologanin synthase (SLS) and
two soluble enzymes, tryptophan decarboxylase (TDC) and loganic acid methyltransferase (LAMT),
involved in strictosidine precursor synthesis, are found in the cytosol compartment and operate as
homodimers, preventing enzyme passive diffusion into the nucleus. Further strictosidine accumulation
in the vacuole occurs via internalization of precursors and strictosidine synthase (STR) activity within this
organelle. b-D-Glucosidase (SGD) is the first downstream enzyme after first MIA formation
(strictosidine), leading to aglycone biosynthesis and subsequent generation of all other Catharanthus
MIAs, including the well-known catharanthine, tabersonine, and vindoline. SGD is restricted to the
nucleus, and strictosidine exportation from the vacuole must be tightly controlled to avoid accumulation
of the aglycone, which is highly reactive and induces strong protein cross-linking. During an herbivore
attack, sudden break of substrate (strictosidine) and loss of enzyme (SGD) compartmentalization lead to
cellular disruption and massive production of reactive aglycone, readily conferring deterrent/toxic
properties to the plant (Courdavault et al. 2014; Fig. 2).
Catharanthine is derived directly from strictosidine, by a currently unknown mechanism, and accu-
mulates in the surface of both below- and aboveground parts of the plant, with almost all content on leaf
surfaces. An active transport of catharanthine secretion in wax exudates is mediated by TPT2
[catharanthine transporter pleiotropic drug resistance (PDR) family of ABC transporters], the first
characterized MIA transporter. This very specific alkaloid accumulation forces bio-aggressors to face
fungicidal and insecticidal properties of catharanthine as the first protection barrier of C. roseus (Roepke
et al. 2010). The external barrier strength is enhanced by wax exudate enrichment with other active
compounds (Courdavault et al. 2014).
One of the most abundant MIAs in C. roseus leaves is vindoline, resulting from a six-step modification
of tabersonine, and accumulated in laticifers/idioblasts. While only traces of dimeric MIAs are present in
plant leaves under physiological conditions, formation of dimeric MIAs, such as vincristine or
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anhydrovinblastine, also toxic to bio-aggressors by their microtubule disassembly properties, could result
from a mixture of secreted catharanthine with alkaloids released from specialized cells in the presence of a
vacuolar class III peroxidase (PRX1) in injured leaves (Courdavault et al. 2014).
MIAs from some South Brazilian Psychotria (Rubiaceae) species have also been studied focusing on
the influence of environmental factors. Brachycerine, GPV (N,b-D-glucopyranosyl vincosamide), and
psychollatine, from the understory species P. brachyceras,P. leiocarpa, and P. umbellata, respectively,
are the major alkaloids in these plants. Some common features of these three alkaloids in adult plants
include shoot-specific accumulation, high levels of alkaloids in leaves (0.1 % DW to 4 % DW –dry
weight), higher content of alkaloids in inflorescences and lower in fruits, broad and strong antioxidant
properties, and relatively simpler structures, comparable to that of strictosidine, including the retention of
Fig. 2 A simplified version of the main steps of monoterpene indole alkaloid biosynthesis in leaves of Catharanthus roseus,
indicating the cell types and subcellular compartments involved, and the changes deployed upon herbivory or pathogen attack
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one or two glucose residues. GPV seems to be derived directly from strictosidine, whereas brachycerine
and psychollatine accumulation may depend on an STR-like enzyme. The monoterpene moiety pre-
cursors are not secologanin, but likely epiloganin for brachycerine and a geniposide-derived terpene for
psychollatine (Pasquali et al. 2006).
Whereas the leaf concentrations of GPV in P. leiocarpa and psychollatine in P. umbellata remain
constitutively high, not changing under the effect of various stress factors, the concentration of the
alkaloid brachycerine (of P. brachyceras) is highly responsive to various signals. These include JA
application, mechanical wounding, drought, heavy metal exposure, high temperature, and UV-B radia-
tion. The latter stimulus increases its content by approximately 10 times compared to basal levels.
Accumulation of brachycerine occurs only in the damaged site, not becoming systemic to the whole
plant (Matsuura and Fett-Neto 2013). For seedlings, light presence and developmental stage affect GPV
levels, indicating a regulation of alkaloid dynamics by photoautotrophic activity and developmental
regulation (higher contents in older seedlings). At least for psychollatine, a tight regulation mechanism
involving compartmentalization in specialized cells and organelles may be required; the alkaloid is absent
in undifferentiated cell cultures or in rhizogenic calli, even if greened under light, but is accumulated again
as soon as embryos start to regenerate from the calli (Paranhos et al. 2005). In P. brachyceras leaves,
epidermis analysis revealed enrichment of brachycerine in epidermal cells, also indicating specialized
compartmentalization.
The main reason for these Psychotria MIAs’accumulation seems not directly related to protection
against herbivores, as shown by the lack of deterrence or other toxic effects in tests with both specialist
and generalist herbivores. Allelopathic effects of the alkaloids in target plant species were also lacking.
Because of their efficient antioxidant properties against most types of reactive oxygen species, they may
assist in general oxidative stress detoxification (Matsuura and Fett-Neto 2013). P. brachyceras and
P. leiocarpa are resistant to acute UV-B doses, and this protection is mainly caused by brachycerine
and GPV presence, which has been shown to improve UV-B tolerance in UV-B-sensitive plants, being
this protection linked to the antioxidant properties of these alkaloids (Matsuura and Fett-Neto 2013; Porto
et al. 2014). Similarly, the indole alkaloid pityriacitrin (Machowinski et al. 2006) and benzylisoquinoline
alkaloid sanguinarine (Ahsan et al. 2007) have been shown to be very efficient in UV-B protection when
applied on skin.
P. somniferum (Papaveraceae), one of oldest medicinal plants in the world, is considered the model
plant in the study of benzylisoquinoline alkaloids (BIAs) and remains as the only commercial source of
morphine and codeine. Other important alkaloids produced by P. somniferum include papaverine,
noscapine, and sanguinarine. BIAs are also found in plants from the order Ranunculales, in particular
Ranunculaceae, Berberidaceae, and Menispermaceae families. BIA production in P. somniferum occurs in
sieve elements and specialized laticifers; in the latter structures, most BIAs are stored. Phloem tissues are
not always involved in BIA biosynthesis, as seen in Thalictrum flavum (Ranunculaceae). Phthalide
isoquinoline, morphinan, and benzylisoquinoline alkaloids, such as noscapine and papaverine, are
major compounds in latex from aerial parts of the plants, whereas benzophenanthridine alkaloids (e.g.,
sanguinarine) are predominant in roots (Hagel and Facchini 2013; Beaudoin and Facchini 2014).
Defensive roles for BIAs include anti-herbivory, antifungal, and antibacterial properties; in addition to
the presence of defensive compounds in the latex, its glue-like consistency per se seems to act as a defense
mechanism against foraging herbivores. Mechanically damaged P. somniferum was shown to rapidly
increase incorporation of bismorphine into the cell wall, decreasing susceptibility to hydrolysis by
pectinases, which are often present in salivary secretion of herbivores and are also produced by fungi
(Beaudoin and Facchini 2014).
Nicotiana sp. (Solanaceae) contains high levels of the pyridine alkaloid nicotine, playing a role in
protection against insect herbivores. Nicotine biosynthesis occurs in the roots of Nicotiana plants and is
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transported via xylem to leaves and other parts of the plant by a multidrug and toxic compound extrusion
(MATE) transporter; nicotine is primarily stored in the cell vacuoles of aerial parts. Removal of shoot tips
and attack by herbivores quickly increase nicotine levels in Nicotiana. Auxins are negative regulators of
nicotine accumulation, whereas abscisic acid may have a dual effect. Ethylene response factors (ERFs),
which are involved in nicotine level regulation, were identified in Nicotiana and are positively regulated
by abscisic acid. Downregulating ARF1, an auxin response factor, increased nicotine basal concentration,
whereas silencing of NbERF1 had the opposite effect on both basal and stimulated nicotine accumulation
(Todd et al. 2010; Wang and Bennetzen 2015). JA is well known as a positive regulator of nicotine
biosynthesis, via activation of MYC2-like bHLH (basic helix-loop-helix) transcription factors (TFs) in
Nicotiana, which directly regulate alkaloid production by transactivating alkaloid biosynthetic genes
bearing G-boxes in their promoters. JA also indirectly regulates nicotine accumulation by activating the
production of B-locus ERF transcription factors, which bind to GCC-boxes in promoters of genes
encoding biosynthetic enzymes. The F-box protein COI1 (coronatine-insensitive protein 1) is an impor-
tant regulator of JA signaling, acting as a receptor, which interacts with JA-Ile, (+)-7-iso-Jasmonoyl-
L-isoleucine, targeting the transcriptional repressor protein JAZ (jasmonic acid ZIM domain) for degra-
dation in the proteasome, so that MYC2 TFs are released for action (Dewey and Xie 2014). The role of JA
and JA-Ile has also been established in the regulation of MIA production in C. roseus through the control
of TFs such as the ORCA family, involved in the coordinated transactivation of biosynthetic genes in both
primary and secondary metabolism (Wasternack and Hause 2013).
Signaling for Alkaloid Biosynthesis in Plants
The success of plants is significantly based on their ability to rapidly recognize specific environmental
signals and biotic attacks and promote signal transduction pathways that lead to the biosynthesis of
defensive compounds (Okada et al. 2015). Recognition of herbivores and pathogens in plants can be
conceptually separated in three distinct responses, which are recognition of oviposition, leading to
herbivory-induced immunity (HTI), perception of damage or herbivore via DAMPs (damage-associated
molecular patterns) and HAMPs (herbivore-associated molecular patterns) leading to HTI, and mechan-
ical wounding, generating wound-induced resistance (WIR). JA is the most important signaling molecule
in plant defense triggered by herbivores and mechanical wounding, leading to elicitation of several
metabolites including alkaloids. JA biosynthesis can be regulated by different ways. Control of JA
biosynthesis is done by a positive feedback loop and also specificity of tissue and substrate availability.
Moreover, the synthesis of JA is regulated by different branches in the upstream lipoxygenase (LOX)
pathway; hydroperoxide lyase (HPL) branch is known for oxylipins, both volatiles (green leaf
volatiles –GLVs) and nonvolatiles, which are leaf aldehydes and alcohols involved in plant defense
against herbivores and long-distance signaling (Wasternack and Hause 2013).
GLVs are a class of volatile organic compounds (VOCs) and are involved in indirect plant protection by
signaling to distal parts of the attacked plant and to neighbor plants the incoming danger. GLVs also attract
carnivorous arthropods, as well documented for lima beans (Kautz et al. 2014). At belowground, VOCs
are also important players in plant defense; the quality of VOCs emitted from roots is altered when the
hybrid Festuca pratensis Lolium perenne is in symbiosis with the fungus Neotyphodium uncina
colonizing aerial parts, enhancing production of insect-toxic alkaloids in the whole plant (Rostás
et al. 2015).
Another regulation point of JA biosynthesis occurs via Ca
2+
and MAPK cascades. During JA
accumulation induced by herbivory or wounding in Nicotiana attenuata, activation of wound-induced
protein kinase (WIPK) occurs in the wound site, activating JA biosynthesis. The Ca
2+
-dependent protein
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kinases CDPK4 and CDPK5 negatively regulate the process. In response to many biotic and abiotic
conditions, Ca
2+
acts as a second messenger; Ca
2+
is involved in modulating the response against
herbivores through a calmodulin-like protein CLM42, which acts in decreasing COI1-mediated JA
sensitivity downstream of damage-induced Ca
2+
increase. Calcium may also increase resistance to
necrotrophic pathogens and regulate SA levels (Wasternack and Hause 2013).
The mechanisms of perception of the environment and transduction of these external signals to activate
alkaloid biosynthetic pathways are of great importance to define and exploit the ecological roles of these
compounds, as well as to define strategies to increase their production. Among the strategies to produce
alkaloids, plant cultivation and management techniques to improve the content of the metabolite of
interest prior to extraction are important tools. Several bioactive plant alkaloids are very complex
molecules of difficult and expensive chemical syntheses. Plant cell cultures, both in suspension and
immobilized, may also represent a very interesting source of bioactive alkaloids due to the features of
cleaner extraction, production independent of weather conditions, and amenability to scale up. Organ
cultures are another interesting strategy, particularly roots, which retain a good degree of cellular
differentiation, sometimes required for alkaloid biosynthesis, and can be cultivated in large scale
(Pasquali et al. 2006). R. serpentina hairy root cultures, induced by Agrobacterium rhizogenes, are a
promising system for production of alkaloids and are considered an experimental model for metabolic
engineering in plants due to biochemical stability, fast growth rates, and easy manipulation (Yang and
Stöckigt 2010). Hairy roots of R. serpentina can yield twice as much of the medicinal alkaloid reserpine
compared to field-grown plants (Mehrotra et al. 2015).
For larger scale production of complex plant alkaloids, molecular strategies would be a preferred tool.
Some key points for genetic manipulation involve the knowledge of plant interspecific diversity,
elucidation of biosynthetic pathways, technology for gene knockout, silencing or overexpression of key
points of biosynthetic routes, or master regulator TFs, both with constitutive or inducible promoters in
plants or cell cultures (Yang and Stöckigt 2010; Nascimento and Fett-Neto 2010). Major research efforts
have also been focused on introducing plant alkaloid biosynthetic pathways in bacteria or yeasts in order
to take advantage of the numerous biochemical engineering tools for large-scale production of metabo-
lites in microorganisms (Hagel and Facchini 2013).
Conclusions and Future Directions
Alkaloids are a large and diverse group carrying a broad range of biological activities of great importance
to plants, animals, and humans, with highly significant pharmaceutical properties. The study of alkaloid
biosynthesis by dissecting the key enzymes of high metabolic flux control, TFs, their encoding genes, and
the regulatory controls of metabolism can be used to improve alkaloid production. It may also provide a
better understanding of the complex ecological roles of alkaloids and foster the discovery of new drugs or
toxins. On the alkaloid supply front, it appears that future efforts will focus on the use of synthetic biology
approaches to engineer metabolic pathways leading to plant alkaloids in microorganisms.
Often alkaloids once viewed as “villains,”due to their high toxicity, may be reassessed as holding the
cues for combating specific diseases. New emerging ecological roles for alkaloids are also surfacing, such
as their activity as antioxidants and general stress protectants, for example, in the case of Psychotria
MIAs. The primary functions of alkaloids may differ in the various plant species, and their metabolic
profiles can be linked to specific environmental factors and developmental signals, often conferring a clear
adaptive value. Such dynamic profiles of plant alkaloid metabolism and accumulation are key factors to be
considered regarding toxicity to other organisms or bioactive metabolite production for therapeutic
purposes.
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Acknowledgments
This work was elaborated with the support of the Brazilian agencies: National Council for Scientific and
Technological Development (CNPq), Coordination for the Improvement of Higher Education Personnel
(CAPES), and Rio Grande do Sul State Foundation for Research Support (FAPERGS).
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