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Toxins, Medicines, or Defence Mechanisms?: The Multifaceted Nature of Plant Secondary Metabolites
With over 200,000 known compounds, plant secondary metabolites are a diverse class of biocompounds with varied properties and applications. What are their uses in plants and may humanity benefit from them too?

by Ng Yen, Tara

Plants produce a variety of metabolites, which are intermediate or final products of metabolic processes1 that are used for assorted ecological functions. Of the two main categories of plant metabolites (primary and secondary), secondary metabolites are a class of chemical compounds that are produced from the plant cell through metabolic pathways derived from the primary metabolic pathways. This concept was first defined by Albrecht Kossel, Nobel Prize winner for physiology or medicine in 1910.2 But in later definitions, such as the one by Friedrich Johann Franz Czapek,3 secondary metabolites are end-products derived from metabolic pathways involving nitrogen and that have undergone further chemical transformations to yield modified products.

The secondary metabolites that plants produce may have antibiotic, antifungal, or antiviral properties to guard against infection from pathogens or to act as repellants to deter herbivores. They may also be involved in plant signalling or used to absorb harmful ultraviolet (UV) rays.4 While these secondary metabolites serve important functions to the plants that produce them, some of them have different effects when exposed to other species, herbivores, and humans alike.

These compounds are categorised according to their chemical structures and members within each class may have similar or vastly differing properties. So far, over 50,000 distinct secondary metabolites have been discovered5 in various species in the plant kingdom with many remaining a mystery.

What Are Alkaloids?

Alkaloids are a wide category of secondary metabolites that comprise nitrogenous organic molecules,6 which may be further subdivided into classes like piperidines, pyridines, and tropanes, among others. In general, most compounds of this class are hypothesised to serve as a form of nitrogen storage in plants and act as repellents or defence mechanisms against a variety of herbivorous species like arthropods, insects, and vertebrates. They may also act as growth regulators due to their structural similarities to some pre-existing plant growth regulatory biocompounds.7

Capsaicin, commonly known as the compound that gives chillies their spicy flavour, is an alkaloid that is commonly found in tissue that directly surrounds the seeds (placental tissue), the internal membranes, and sometimes in other fleshy parts of the fruits of Capsicum spp.8

The repellent effects of capsaicin on certain animals have been documented in a 2001 study by Professor Joshua Tewksbury, at that point an associate biology professor at the University of Washington. He led a team of researchers to investigate his hypothesis that capsaicin in chilli fruits acts as a deterrent to selected species.

To investigate, two different species of plants from the Capsicum genus were used in laboratory feeding trials—one with spicy fruit from a species native to Arizona (Capsicum annuum glabrusculum, commonly known as chiltepin chilli), as well as one with non-spicy fruit (a Bolivian species of chilli, Capcisum chacoense). Fruits from both species were given to birds (curve-billed thrashers) and mammals (cactus mice and packrats), and their feeding responses were studied. The experimental results indicated that mammals were repelled by the spicy fruits, while birds like the curve-billed thrasher were unperturbed by the taste and consumed the spicy fruit in large amounts.9

Upon further inquiry, the researchers found that birds were unaffected by the capsaicin as they were unable to taste its spicy flavour. Unlike mammals, they do not have transient receptor potential (TRP) channels10—unique taste receptor channels mainly used for detecting pain that may also be triggered by capsaicin. The binding of capsaicin to these TRP channels causes calcium ions to travel into adjacent neurons, triggering nociception, the neural process of encoding and processing noxious stimuli, eliciting an unpleasant burning sensation that discourages the mammals from further consumption of the chillies.11

The researchers also sought to understand whether the deterrence of certain predators (mammals) was intentional, finding that seeds consumed by birds had rates of germination similar to the control seeds. This contrasted with the seeds consumed by mammals, which failed to germinate.

Additionally, it was also discovered that the thrashers promoted dispersal of the chilli seeds to locations with conditions favourable for their germination, particularly shaded areas, allowing for the survival of the chilli species with capsaicin content and inadvertently selecting for those species in the long run.

Saving Seeds from Fungal Infection

In further studies by Professor Tewksbury’s group to investigate the factors influencing the diversity of capsaicin content of fruits produced by different sub-populations of the C. chacoense species at different locations within Bolivia, it was also discovered that capsaicin likely had antifungal properties and was found in chilli plants in areas where they were preyed on by insects of the Hemipetra order, also known as “true bugs”.

Insects from this order puncture the chilli fruits to obtain their juice, wounding the plant tissue in the process. This increases the exposure of the mesocarp of fruit to Fusarium moulds, increasing the chances of fungal infection of the seeds, which damages and hampers their ability to germinate.

Through experiments conducted on artificial fruit media with the chemical composition created to resemble the flesh of the C. chacoense fruit, which was treated with varying concentrations of capsaicin and exposed to Fusarium mould, researchers found strong, conclusive evidence that capsaicin resulted in less mould growth, verifying its antifungal activity. Populations of C. chacoense that grew in areas with a greater presence of Hemipetra order insects had fruits with higher capsaicin content, resulting in the greater survivability of plants with spicier fruits.12

In conclusion, this example highlights the use of secondary metabolites in plants as repellents to unwanted predators, as well as their uses in combatting fungal infections.

Cyanogenic Glycosides: As Deadly As the Name Sounds

Besides repellents, some secondary metabolites are precursors to potent toxins. Cyanogenic glycosides are a class of compounds that produces hydrogen cyanide (HCN) upon enzyme-mediated hydrolysis of the compounds.

Hydrogen cyanide (HCN) is a fatal toxin to most mammals or any animal that is reliant on the enzyme, cytochrome oxidase, for the electron transport chain during aerobic respiration.13 HCN’s toxicity works by binding to cytochrome oxidase, disabling the electron transport chain from transporting electrons to oxygen during aerobic cellular respiration, stopping aerobic respiration entirely, eventually causing the death of the organism due to the lack of energy.

Usually, the cyanogenic glycosides and the enzymes responsible for their hydrolysis are kept separate from each other and are only released when cell structures are damaged, allowing the mixture of cyanogenic glycoside with its specific β‐glucosidase enzyme, and in the presence of water, releases a cyanohydrin that spontaneously decomposes at a pH higher than 514 to hydrogen cyanide (HCN) and other by-products.

In nature, hydrolysis of these cyanogenic glycosides mostly occurs when the plant tissues are chewed up by herbivores during feeding. It may also occur during the processing of foods, like grinding, pounding, and fermentation. This is because plant tissues are physically broken down into smaller particles, degraded, or exposed to water,15 allowing for the mixing of the cyanogenic glycosides with their hydrolysis enzymes, causing the deadly HCN gas to evolve. Depending on whether the HCN gas is allowed to escape into the atmosphere, or is produced in situ, its toxicity to the mammal varies. If produced in situ, it is highly toxic but is harmless when allowed to escape into the atmosphere before ingestion.

Linamarin: Making Cassava Deadly

One of the most common food crops behind human health issues caused by widespread cyanide poisoning is cassava (Manihot esculenta). It is an edible tuberous root, widely grown and consumed in tropical regions in Asia and Africa. It is particularly drought-, disease- and pest-resistant due to the presence of linamarin, a cyanogenic glycoside.

However, linamarin has been found to cause a paralytic disease, commonly known as konzo, in rural populations in Africa, which have been exposed to high amounts of linamarin due to the lack of proper processing and consumption of cassava as the main staple food. According to the World Health Organization’s guidelines for diagnosis,16 its symptoms include a symmetric spastic abnormality of gait while walking or running, an onset of less than one week in an otherwise healthy person, and exaggerated ankle or knee jerks on both sides. This disease hampers the walking ability of patients, who may require walking sticks to move about, or in severe cases render them immobile.17

Preventing Cyanide Poisoning Paralysis Through Food Processing

Fortunately, this disease may be prevented by processing the cassava to ensure that its hydrogen cyanide content remains below levels safe for consumption. In cassava flour, the WHO safe level of HCN or its equivalents is 10 parts per million (ppm) or 10 mg of HCN equivalents per kilogram of flour.18

The cyanogenic glycoside content of cassava flour is usually reduced via heap fermentation and sun drying in eastern and southern Africa, but these methods alone do not lower the levels of cyanogenic glycosides to sufficiently safe levels as evidenced by the persistence of konzo. This issue is exacerbated during drought seasons as the cyanogenic glycogen content in cassava increases with increasing environmental stresses.18

The main reason behind the lack of effectiveness of the above processing methods is due to the lack of the mixing of linamarin, which is located in the cell, and linamarase, which is located in the cell walls, for the hydrolysis and liberation of hydrogen cyanide from the cassava. For mixing to occur, the cell walls must be disrupted, which occurs minimally in sun drying as the roots are merely sliced along their lengths and dried. Heap fermentation offers a slightly better outcome as more linamarase-producing microbes, for example, a species of lactic acid bacteria Lactobacillus fermentum,20 is present to help break down the cyanogenic glycosides to cyanohydrins, after which it further decomposes to hydrogen cyanide gas which then escapes into the surroundings.

To reduce the instance of konzo, a simple and effective method of processing cassava flour has been devised and implemented in various rural villages in Tanzania.21 The cassava flour is soaked in water and spread out in a thin layer and left out to sit for at least five hours in the shade or two hours in the sun.22 It allows ample time for the water to soak into the crushed grains of cassava for hydrolysis of the cyanogenic glycoside to take place, allowing the hydrogen cyanide gas to escape into the surroundings and be removed from the cassava, after which it is safe to be made into a stiff porridge for consumption.

While the study acknowledged its limitations, such as the lack of sufficient logistics to conduct the intervention programme, it was noted that it was a highly effective yet feasible solution to such a devastating problem. It is clear that the toxic effects of some secondary plant metabolites should not be underestimated as they have the potential to adversely affect the quality of life of humans.

Terpenes and Terpenoids: Biologically Active Molecules

Besides alkaloids and cyanogenic glycosides, another important class of secondary metabolites are the terpenes and terpenoids. Terpenes are simple hydrocarbons that contain only carbon and hydrogen. They are made up of isoprene “building blocks” arranged in different configurations and are classified into subcategories according to the number of isoprene units they contain.23

The most common subclasses of terpenes are the monoterpenes (two isoprene units), sesquiterpenes (three isoprene units), and diterpenes (four isoprene units).24 Terpenoids, on the other hand, refer to terpenes that contain oxygen, or other functional groups substituted on the original terpene and may be grouped using the same conventions as the regular terpenes.

The terpenes and terpenoids produced by plants are involved in many important plant functions, for example, in primary metabolism as antioxidants and hormones. They also make up parts of the electron transport chain required for aerobic respiration.25 Besides general uses, some of them are also volatile and are released by plants to attract pollinators or to repel herbivores.26 Furthermore, a great majority of terpenes and terpenoids are also biologically active in humans and may be used for pharmacological purposes.

Signaling for Help with Terpenes For Indirect Defence

One of the more interesting uses of terpenes in plants is their role in attracting predators of herbivores as indirect defences. Maize has been found to release a mixture of volatile terpenes that attract the parasitic wasp Cotesia marginiventris, which feeds on herbivores, upon plant tissue injury. This wasp then preys on the lepidopteran larvae like Spodoptera littoralis (a type of caterpillar) that feed on the maize plants, eliminating their threat to the plants.

To check if the particular mixture of volatiles was indeed responsible for the attraction of the predatory wasps, the tps10 gene—a gene that codes for the enzymes responsible for the conversion of farnesyl diphosphate into several sesquiterpenes and seven other minor products, which constitutes the volatile mixture released when maize plant tissues are wounded by herbivores—was inserted and overexpressed in model plants Arabidopsis thaliana. The behaviour of the C. marginiventris predatory wasps in response to the released mixture of sesquiterpenes was observed, and it was found that for wasps with prior knowledge that the particular mixture of sesquiterpenes was an indicator of an abundance of Spodoptera littoralis caterpillars on the plants, they were indeed attracted to them.27 Other studies have also verified that other terpene synthase (TPS) genes produce unique blends of terpenes that are recognised by other predatory insects that help control herbivore populations, further verifying the role of terpenes in indirect defence, where plants protect themselves from excess damage from herbivores by attracting their natural predators.

Terpenes in Medicine

Besides their original uses in plant defence, some terpenes also have pharmacological uses. For example, tea tree oil and the main medicinal component terpinen-4-ol is anti-inflammatory. One might already have previous encounters with this common ingredient in cosmetics as it is often marketed to have anti-inflammatory and anti-microbial properties that can resolve mild to moderate acne outbreaks.Research has brought some truth to the claim, as it has been tested to be successful in reducing skin oedema, the swelling caused by the buildup of fluid in the tissues, which may be caused by allergies or histamine injections.28 Furthermore, terpenes and terpenoids, like linalool,29 are also being studied for their potential uses in treating neurodegenerative diseases like Alzheimer’s and Parkinson’s disease, as they have been observed to have the potential to suppress microglia-mediated inflammation in acute or chronic neurodegenerative diseases.30

One of the more notable highlights of the medicinal effects of terpenoids is that of the sesquiterpene lactone, artemisinin. This terpenoid was discovered by Tu Youyou in 1972, a cumulation of her efforts to understand the effects of malaria in situ and a means to cure it.

Her discovery drew on insights gained from an ancient Chinese medicinal text, A Handbook of Prescriptions for Emergencies by Ge Hong (Jin Dynasty, 284-346 AD), which reflected that in ancient times, Artemisia annua, also known as sweet wormwood, had been used to treat intermittent fevers, a characteristic symptom of malaria.31 In one of their earlier attempts to isolate the active compound in sweet wormwood, they found that the extract had reduced activity. Hypothesising that the heating process in the conventional extraction of the active compound from wormwood was responsible for the reduced activity, she attempted the extraction again, using an ether-based solvent with a lower boiling point.32

From further testing, she discovered that the most effective extracts came from the wormwood leaves as it was extremely effective in the inhibition of the parasite, Plasmodium berghei, responsible for malaria in mice. Despite its effectiveness, it was also discovered to be toxic to the mice, so further separation of the extract was required.

Thankfully, after much trial and error, she managed to separate the extract into an acidic and a neutral portion, of which the latter was shown to be less toxic and exhibited better antimalarial activity than the original extract. Due to the Cultural Revolution, there was a lack of resources to conduct proper clinical trials with the extracts, thus Tu and her team tested the extract on themselves, before trialling the extract as a cure for malaria in humans caused by other Plasmodium parasites in heavily-hit Hainan32.

The trials were a success, with the extracts able to cure fever quickly and eliminate parasites from the blood of the infected as compared to the common treatment for malaria at that time, chloroquine. Through further experimentation, the key compound with antimalarial activity was revealed to be a terpenoid, a sesquiterpene lactone, named artemisinin. Its chemical structure was later published in 1977 and was quickly adopted as the preferred malaria treatment within China.

Its use in antimalarial treatment became accepted worldwide with the World Health Organization’s recommendation of artemisinin-combination treatments as the best scientifically-backed remedy for malaria in 2005. In recognition of her contributions to finding an effective malaria cure, Tu Youyou was awarded the Nobel Prize for Physiology or Medicine in 2015, making her the first Chinese woman to receive such an honour.

What Does the Future Hold?

While terpenoids lead the way for their uses in treating various types of inflammatory conditions in humans, the significance of the other two classes of secondary plant metabolites should not be overlooked as they either pose important health risks or have other potentially useful applications.

Despite being one of the most successful plant defences, cyanogenic glycosides remain a significant health risk to humans and are hard to repurpose due to their lethal toxicity to many different species, including humans. Thus, their presence must be closely monitored in foods to reduce the incidences of cyanide poisoning from foods with cyanogenic glycoside content, like improperly treated almonds, bamboo shoots, cassava, and kirch, an alcohol made from cherries.33 Thankfully, a reduction of the toxicity in such crops may be achieved through various food processing methods like soaking, cooking, and fermentation, tailored to each species.

Potential methods for the detoxification of linamarin may be potentially adapted from nature, especially with emerging research on species with natural cyanogenic glycoside tolerance. For example, it was recently discovered that a species of whitefly, Bemisia tabaci, produces enzymes that add more groups to linamarin. This changes its chemical structure and properties, which prevents it from undergoing linamarase-mediated hydrolysis as the modified linamarin compound can no longer fit into the active site of linamarase, preventing the release of hydrogen cyanide gas.34 In the future, perhaps novel fermentation methods with genetically modified bacteria that produce the detoxifying enzymes found in B. tabaci could be designed to reduce the accessible cyanide content, provided that the products have been confirmed to be non-toxic to humans.

Like terpenoids, alkaloids are a large class of bioactive molecules, many of which possess pharmacological properties. In particular, research is currently underway to identify alkaloids suitable for the treatment of neglected tropical diseases (NTDs), which are common in tropical underdeveloped areas lacking the proper infrastructure for a clean water supply and proper sanitation. For example, isoquinoline alkaloids from Berberis glaucocarpa (a common weed) have been highlighted as possible candidates to treat Leishmaniasis, one of the most common and deadly NTDs caused by parasites of the genus Leishmania.35

In conclusion, secondary plant metabolites are a fascinatingly large class of varied compounds with different tailored uses within the plants that produce them and secondary uses to improve the quality of human lives. The untapped potential of the undiscovered secondary metabolites emphasises the importance of diversity in nature and by extension, provides us with the reasons to place a greater emphasis on the conservation of nature and the abundance of secondary metabolites it provides.

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