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Plant Secondary Metabolites

Contents

• Alkaloids.
• Terpenes.
• Phenolics.
• Miscellaneous.

Alkaloids

Plants, by their nature, are unable to run away from their predators. Consequently, they have evolved a large battery of toxic chemicals (secondary metabolites), the purpose of which is to make them unpalatable, toxic, or lethal to would-be herbivores. Many of these chemicals are useful as drugs because in smaller-than-lethal doses, they have useful pharmacological properties, e.g. many of the alkaloid toxins can be used as drugs because they mimic neurotransmitters. About a quarter of all the pharmaceuticals sold are derivatives of chemicals found in plants; the rest are mostly from bacteria and fungi (notably penicillin). The most popular pharmaceutical in the world, aspirin, is an acetylated derivative of salicylic acid, which was originally isolated from willow bark.

Alkaloids are derivatives of amino acids, whose main role is to make the tissues of an organism toxic to would-be predators. Alkaloids are generally nitrogen heterocycles, i.e. they contain nitrogen in a ring, and most of them are synthesised by plants from ornithine, lysine, tyrosine or tryptophan. However, some are produced by fungi and other sessile organisms such as corals; some are non-heterocyclic amines (technically termed 'protoalkaloids'), like colchicine; and some are synthesised from precursors of biological significance that are not amino acids ('pseudoalkaloids'), like caffeine. Many also contain structures derived from other biosynthetic pathways - capsaicin (the heat in chillis) is both an alkaloid and a terpene. Purines and pyrimidines are extremely important classes of (pseudo)alkaloid: as well as providing the basic structure of toxins, they are also the compounds upon which the nucleobases of DNA are RNA are based.

The alkaloids are classified according to their underlying structure.

Group	Structure	Examples
Pyrrolidine		Nicotine, tetrapyrroles
Tropane		Cocaine, atropine
Piperidine		Coniine
Pyrrolizidine		Retrosine
Quinolizidine		Lupinine
Isoquinoline		Codeine, morphine, heroin
Indole		Strychnine, vinblastine, lysergamide, psilocybin

Atropine

Atropine (and the related compound scopolamine) are tropane alkaloids extracted from Atropa belladonna. Atropos was the goddess who cut the thread of life, and belladonna means 'beautiful lady', i.e. one with wide pupils, due to the use of nightshade juice to dilate pupils in Renaissance Italy. Atropine is found in many members of the potato family (Solanaceae), and is capable of causing delirium: the angel trumpet and thorn apple (Brugmansia and Datura) are ornamental plants, but gradually being banned in the US as a result of teenagers getting high - and small children getting dead - from ingesting the leaves. Other members of the group include mandrake and henbane, both used allegedly by witches in the middle ages to 'fly'.

Atropine was widely used in eye surgery to dilate the pupil, and in surgery as a premed. It is now mostly used as a travel sickness medicine and treatment for nerve-gas victims.

Atropine's mode of action involves attacking the parasympathetic nervous system. The sympathetic nervous system controls the fight-or-flight response by secreting adrenaline. The parasympathetic nervous system does the opposite. Its secretion of acetylcholine:

• Slows heart rate.
• Increases gut motion.
• Constricts bronchioles and pupils.

Atropine blocks (is an antagonist of) the parasympathetic ACh receptors, so mimics the sympathetic response:

• Speeds heart rate.
• Reduces gut motion.
• Dilates bronchioles and pupils.

Cocaine

Cocaine is a stimulant and anaesthetic extracted from Erythroxylon coca. Like atropine, it is a tropane alkaloid. Originally used as a local anaesthetic, and as a stimulant by Incas attempting high altitude climbs in Peru; it is now public enemy number two after heroin. The coca leaf contains only about 1% cocaine, and is usually chewed with limestone to aid release from its base. Crack is the modern 'scientific' way of freebasing this tropane alkaloid.

Morphine

Opiates are isoquinoline alkaloids and are the most important group of strong analgesics. This group include codeine (methylmorphine), morphine and heroin (diacetylmorphine). Morphine is a is extracted from the opium poppy (Papaver somniferum), principally from the unripe seed capsules where it probably serves to make the seeds unpalatable to marauding herbivores.

Depending on the country in which you live, it is either extremely illegal to grow, quantum-illegal to grow (if you know it's an opium poppy you can get in trouble, but otherwise it's OK), or fully legal as long as you don't try doing anything more than look at the pretty flowers.

Morphine acts at endorphin receptors in the brain. Endorphins are small peptide hormones secreted in the brain to deaden pain: morphine mimics (is an agonist) at endorphin receptors, hence its analgesic effects. At higher doses, it is a hypnotic, causing sleep. Morphine has a secondary effect on smooth muscle, causing it to relax: one unfortunate consequence of excessive opiate use (e.g. heroin addiction) is severe constipation.

Colchicine

From the corms of the autumn crocus (Colchium autumnale) comes colchicine. At low doses, it is an effective gout treatment, but at high concentrations, it is a very effective poison. Most bulbs and corms have chemical defences: several people are killed each year in onion/daffodil mix-ups. Colchicine has similar effects to paclitaxel, but for the opposite reason: it causes catastrophic depolymerisation of microtubules, therefore stops cell division just as the chromosomes are fully condensed. It is used in karyotyping of cells from amniocenteses.

Psilocybin and lysergamides

Lysergamides (ergoline alkaloids) were originally touted as agents for treating schizophrenia, and although the naturally occurring lysergamides found in morning glory (Ipomoea tricolor and Rivea corymbosa)) are quite weak compared to the tryptamine alkaloids found in magic mushrooms (Psilocybe semilanceata - psilocybin) or to LSD itself, they were used in divination (i.e. getting high with a religious gloss) by Aztec shamans. Mescaline is a protoalkaloid active principle of peyote (Lophophora williamsii), which is licensed for ritual use in the USA by members of the Native American Church. It has a somewhat different structure but similar psychedelic effects to lysergamides and tryptamines.

Fungi also produce secondary chemicals. Psilocybin is the indole alkaloid found in Psilocybe semilanceolata, and acts as an agonist at 'happy hormone' serotonin receptors in the brain. MDMA (Ecstasy) and fluoxetine (Prozac) act at the same receptors.

Nicotine and tetrapyrroles

The most widely used plant drug in the world? Nicotine is pyrrolidine/pyridine alkaloid from Nicotiana tabacum with stimulant properties. It acts on acetylcholine receptors and causes the release of adrenaline. It is also extremely toxic: children have been killed from eating the leaves of ornamental tobacco plants, and the evolutionary 'purpose' of nicotine is to act as an insecticide. Although acutely toxic, nicotine is not a carcinogen: the things responsible for the cancer associated with smoking are compounds such as benzo[a]pyrene from the tar and smoke.

Nicotine is an agonist at nicotinic acetylcholine receptors in part of the parasympathetic nervous system. Consequently, it causes skeletal muscle contraction. In contrast, curare is an antagonist, so it is used to paralyse people during operations.

Many prosthetic groups found in enzymes are formed from four pyrrole units joined together by methylene bridges: the 'tetrapyrrole' motif.

Haems (found in haemoglobin and cytochromes) and chlorophylls are typical tetrapyrroles. They contain a linked ring of four pyrrole units, which coordinate to a central metal ion: iron in haem; magnesium in chlorophylls.

Vitamin B₁₂ (cobalamin) is a corrin: this is much like a porphyrin, but note the 'missing' carbon atom in the ring.

Phytochromobilin (the chromophore in phytochrome) and the other bilin pigments, like urobilin (the yellow of urine) and bilirubin (the brown of faeces) have a tetrapyrrole motif, but lack the ring formation.

Vincristine and vinblastine

Originally thought to be of use in treating diabetes by the herbalists of the area in which Catharanthus grows (Madagascar), these two indole alkaloids from the Madagascan periwinkle (Catharanthus roseus) have been found to be extremely good anti-leukaemic agents, and have been partly responsible for the now very high survival rate for childhood leukaemia.

Strychnine and coniine

Strychnos nux-vomica and Conium maculatum are two of the assassin's plants of choice. Strychnine is a quinoline alkaloid derived from the nut of a tropical tree. Coniine, a piperidine alkaloid found in hemlock, causes paralysis and was the chemical Socrates was made to commit suicide with by the Athenians. It's also found in some carnivorous plants (such as Sarracenia flava), which use it to aid insect capture.

Terpenes

Whilst alkaloids are amino-acids and nucleobases gone bad, the toxic terpenes can be thought of as fats gone bad. Cholesterol and the membrane lipids of the Archaea are terpenes, but plants also use these derivatives of isoprene as anti-feedants and toxins. Although some terpenes are highly toxic, many of the less toxic ones are used as flavouring and colourings.

Terpenes are formed by the mevalonate pathway and are formed from repeating isoprene units (they are actually synthesised from a dimer of isoprene called geranyl pyrophosphate), and are named after the number of geranyl units they contain.

• Monoterpenes (1 geranyl unit).
  • Limonene (the smell of lemons), menthol (of mint), pinene (of pine): the essential oils (and characteristic smell) of most pines is due to volatile monoterpenes.
  • Pyrethroids: insecticidal compounds from Chrysanthemum, much used in pest control.
• Seqsuiterpenes (1 and a half units, i.e. 3 isoprene units).
  • Abscisin: the plant dormancy hormone.
  • Gossypol (a dimeric sesquiterpene): a steroid mimic, which interferes with the growth of insect larvae on cotton, and also interferes with human sperm synthesis.
  • Lactones: cyclic esters, also insecticidal.
• Diterpenes (2).
  • Gibberellin: a plant growth hormone.
  • Abscisic acid: another plant growth hormone.
  • Phorbol: a toxic compound found in spurges (Euphorbia) contributing to their extreme toxicity to livestock.
• Triterpenes (3, and most of them are steroids).
  • Ponasterone acts as a phytoecdysone, and prevents insect pests from moulting properly. All steroid hormones (like testosterone and oestrogen) and cholesterol are also triterpenes.
  • Limonoids: the bitter principal in citrus fruits.
  • Saponins: soapy compounds found in many plants, including soapwort and horse chestnut, which had been used as detergents before the advent of soap.
  • Cardenolides: including digitoxigenin, used in heart medications. This compound is a glycoside: a steroid bound to a sugar molecule.
• Tetraterpenes (4).
  • Carotenoids: precursors to vitamin A, and often the cause of yellow, red or orange pigmentation in plants. Tetraterpenes usually contain many double bonds and are brightly coloured. Carotenoids used as photosynthetic accessory pigments.

    
    β-Carotene

  • Chlorophyll also contains a tetraterpene 'tail' connected to the active porphyrin group, so as to anchor it in the thylakoid membrane.
• Polyterpenes (n).
  • Rubber: a poly-cis-terpene, with high elasticity.

    
    Rubber

  • Gutta percha: a poly-trans-terpene, with much lower elasticity.

Tetrahydrocannabinol

THC is a cannabinoid terpenophenolic found in the resin of hemp (Cannabis sativa). It has analgesic and euphoric properties, and synthetic analogues with more of the former and fewer of the latter are licensed in some countries for the treatment of chronic pain. Cannabinoids act at anandamine receptors: some of these are involved in pain attenuation, and others in the hypothalamus in modulation of appetite, hence the well known 'munchies' effect. The seeds are also a useful source of vegetable oil, and the bast fibres in the stem are used to produce textiles.

Phenolics

Phenolics are chemicals formed by the shikimate and malonate pathways, and contain one or more benzene rings. The archetypal phenolic compounds are the aromatic amino acids tryptophan, tyrosine and phenylalanine. Animals use the phenolic melanin as a sun screen. However, plants use phenolics in many other ways. Simple phenolics include antifeedants, such as tannins, and phytoalexins are a mixed bag of phenolics secreted into dying cells as a scorched earth policy, to prevent further growth of fungal pathogens. Flavonoids and anthocyanins are the colourings of fruits and flowers (often purple, red or blue) and UV-protectants. The blue colours of most fruits and flowers are produced by anthocyanin flavonoids, such as delphinidin from Delphinium:

Shikonin

Although shikonin (a red pigment from Lithospermum erythrorhizon) has alleged disinfectant/antibiotic properties, and is used in Chinese herbal medicine as such, it is mostly used as a red dye. Plant cell cultures can be made to produce huge amounts of the dye, making it one of the few successful applications of plant cell culture in the production of pharmaceuticals.

Ephedrine

Used as a decongestant, ephedrine is derived from a group of plants with half the features of conifers and half the features of flowering plants, the gnetophytes, in particular Ephedra sinica. Ephedrine is also banned as a performance enhancing drug, hence the screams of 'it was my cold remedy, guv' every time an athlete gets done for doping. Ephedrine is an amphetamine alkaloid, and a favourite starting point for the production of crystal meth.

Curare

Originally curare was used as an arrow poison in Amazonia (from the tree Chondodendron tomentosum), then used as a paralytic during surgery, to prevent fidgeting under the surgeon's knife. It is now largely replaced by synthetic analogues. It acts at the same receptors as nicotine but has an antagonistic rather than agonistic effect.

Tannins and lignin

Not all phenolics are so lethally toxic. Many, such as tannins, cinnamates, vanillin, and coumarins cause indigestion rather than death: they inhibit digestive enzymes, prevented the would-be herbivore from digesting its lunch. Lignin is a polymer of phenolic alcohols, contributing to wood's durability and strength. Lignin is massively crosslinked, which accounts for much of the compressive strength of plant cell walls.

Miscellaneous

Glucosinolates

Sulfur finds its way into anti-feedants too. Damage to the leaves of mustard and its relatives (cabbages) mixes vacuolar glucosinolates (sulfur and cyanide containing glycosides) and cytosolic thioglucosidase enzymes. This generates a toxic cocktail of cyanides (R-C≡N), thiocyanates (R-S-C≡N) and isothiocyanates (R-N=C=S). These are responsible for the unpleasant smell of boiled cabbage.

Ricin

Ricinus communis is the castor oil plant, and source of ricin, a cytotoxic protein that was made famous by the assassination of a Bulgarian dissident (Georgi Markov) with a ricin tipped umbrella in London in 1978.

Test yourself

1. Describe the importance of pyrroles.
2. Why are terpenes important in plants and animals?
3. What chemicals do plants have at their disposal to attack potential herbivores?

Answers

Bibliography

• Taiz, L. and Zeiger, E. (2006). Plant Physiology. 4th edition. Sinauer Associates Incorporated, Sunderland, Massachusetts. 315-344. "Secondary metabolites and plant defense".