Secondary Metabolites Defined
Secondary metabolites, also known as secondary products or natural products, are organic compounds
that are not directly involved in the normal growth, development or reproduction of organisms, and are not
directly involved with “photosynthesis, respiration, solute transport, translocation, protein synthesis,
nutrient assimilation, or differentiation, or the formation of carbohydrates, proteins, and lipids...”
“Unlike primary metabolites, absence of secondary metabolites results not in immediate death, but in longterm
impairment of the organism's survivability/fecundity or aesthetics, or perhaps in no significant change at all.”
Secondary metabolites are often restricted to a single species or a narrow set of species
within a group, whereas primary metabolites are typically found throughout the plant kingdom.
In most cases, secondary metabolites have been found not to be simply metabolic waste products, but
instead to play important roles in plant defenses against pathogens or herbivores, and in other aspects of
plant ecology. These ecological roles include:
•
Protecting against animal herbivory (being eaten by herbivores including insects) and infection (by
microbes)
•
Aiding pollinators and seed-dispersing animals by serving as attractants in smell, color, or taste.
•
Aiding in plant-plant competition (including allelopathy) and in plant-microbe symbioses
These compounds can have a deleterious or beneficial effects in plants intended for human consumption.
The main groups are terpenes, phenolics, and nitrogen-containing compounds
Allelopathy Defined
Plants synthesizing
phenolics (including caffeic acid and ferulic acid) and other secondary
metabolites discussed in this chapter may impart these to the soil in the form of fallen leaves, decaying
litter, and root secretions. The inhibiting effects of these substances on germination or growth etc. of
neighboring plants is termed allelopathy, and can lead to better fitness through increased access to
light, water, and nutrients. The study of allelopathy in agriculture is important with respect to maximizing
crop yields. However, it is difficult to unravel the precise ecological function of most “secondary”
metabolites, though this designation often implies an ecological role . In the introduced
invasive weed Spotted knapweed (Centaurea maculosa), it is a polyphenolic tannin, catechin ,
that serves as its primary allelopathic root exudate.
Terpenes, Terpenoids and Isoprenoids
Terpenes (also called terpenoids or isoprenoids) are derived from one or more branched 5-carbon (C5)
isoprene units (actually either isopentane or isoprene units).
Classification and biosynthesis
Terpenes or terpenoids are classified by the number of isoprene units that are combined:
• 2 isoprene units (C10 terpenes) are termed monoterpenes
• 3 isoprene units (C15 terpenes) are termed sesquiterpenes
• 4 isoprene units (C20 terpenes) are termed diterpenes
• 6 isoprene units (C30 terpenes) are termed triterpenes
• 8 isoprene units (C40 terpenes) are termed tetraterpenes
• > 8 isoprene units (> C40 terpenes) are termed polyterpenoids
Terpenes are the major components of conifer resin, and of turpentine produced from resin. The name
“terpene” is derived from the word “turpentine” (which derived from terebinthine = pertaining to the
terebinth tree).
Terpenes or terpenoids are biosynthesized by either of two pathways leading to the
common C10 intermediary
Geranyl diphosphate(GPP):
• The Mevalonic acid pathway: starting with Acetyl-CoA (C2), leading to C5 Isopentenyl diphosphate
(IPP), then GPP.
• The Methylerythritol phosphate (MEP) pathway: starting with pyruvate (C3) and Glyceraldehyde 3-
phosphate (C3), leading to Methylerythritol phosphate (C5), then Dimethylallyl diphosphate
(DMAPP, C5), then GPP.
GPP can then be converted to
• Monoterpenes (C10 compounds such as geraniol, limonene, terpineol, alpha-pinene and betapinene),
or to
• Farnesyl diphosphate (FPP, C15), which can be converted to
- Sesquiterpenes (C15 compounds such as farnesol), or dimerized to
- Triterpenes (C30 compounds such as Squalene,92 which is the precursor of the sterols lanosterol
and cycloartenol, which are the precursors for all plant and animal steroids), or to
• Geranylgeranyl diphosphate (GGPP, C20), which can be converted to
- Diterpenes (C20 including cafestol, kahweol, cembrene, and taxadiene, and the derived C21
terpenophenolic compound Tetrahydrocannabinol from hemp Cannabis sativa), or dimerized to
-Tetraterpenes (C40 including lycopene, gamma-carotene, and alpha- and beta-carotenes), or to
- Polyterpenoids (> C40)
Terpene-derived compounds that are primary metabolites
Some terpenoids are considered to be primary metabolites as they participate in plant growth and
development, etc., and are discussed in other chapters. These include:
•
Gibberellins
•
Brassinosteroids (C28 brassinolide, derived from C30 triterpene squalene, )
•
Sterols (C27-C30, used to stabilize phospholipid membranes,)
•
Carotenoids (C40,) including xanthophylls and carotenes (used in PS etc., )
•
Tocopherols (including RRR-alpha-tocopherol AKA d-alpha-tocopherol AKA vitamin E,derived from
GGPP, )
•
Phytol side chain of Chlorophyll (C20, )
•
Abscisic acid (C15, )
•
Dolichols (polyterpenoid alcohols which serve as carriers and anchors for sugars in cell wall and
glycoprotein synthesis .
Terpenes that protect against herbivores
Some terpenes serve as toxins to deter herbivorous animals including insects:
Pyrethrin I and II are natural insecticidal monoterpene ester compounds deriving from Pyrethrum, the
extract of several Old World plants of the genus Chrysanthemum (e.g., C. coccineum and C. cinerariifolium).
Pyrethroids are synthetic analogs, and include permethrin. These have relatively low human toxicity.
Conifers such as pines, firs, and spruce accumulate monoterpenes (such as bicyclic α-pinene and β-
pinene) in resin stored in resin ducts or blisters in the needles, twigs, and trunk. These terpenes are
toxic to many but not all bark beetles. Resin ducts occur normally, or can be induced by the presence of
pathogens such as fungi, and in some conifers the mobilized resin contain “a mixture of monoterpenes,
sesquiterpenes, and diterpene resin acids”.
Cannabinoids: The psychoactive (hallucinogenic) cannabinoids include the C21 terpenophenolic compound
Tetrahydrocannabinol (THC), the most active cannabinoid found in the mj/ hemp plant
(Cannabis sativa). Others common cannabinoids in Cannabis include cannabidiol (CBD) and cannabinol
(CBN).Extremely low human toxicity.
Limonoids: according to the textbook are C30 triterpenes. [Other sources state that limonoids100 are
tetranortriterpenes, a term which I have not found defined. The limonoid Limonin has 26 carbons.]
These impart the bitter taste and characteristic scent of citrus (lemon, orange, etc.) fruit peel or rind. The
Neem tree (Azadirachta indica) is rich in the limonoid-related C35 tetranortriterpenoid azadirachtin.101
This compound is a powerful deterrent to insect feeding in low concentrations, and appears to have low
human toxicity.
Phytoecdysones: The triterpenoids known as phytoecdysones have the same basic structure as hormones (ecdysteroids such as ecdysone) that are used by insects in the molting of the cuticle, a process known as ecdysis. When insects ingest these chemicals (which are found for instance in thecommon fern Polypodium vulgare), they may prematurely molt or suffer other lethal effects. Nematodesm ay also be affected.
Triterpene-derived compounds directed against vertebrate herbivores include:
•
Cardenolides: These are glycosides found in foxglove (Digitalis lanata), milkweed, and oleander
(Nerium oleander).They are extremely cardiotoxic, but in low doses some are used therapeutically as
“cardiac glycosides” .
•
Saponins: These are found in plants such as Soapwort (Saponaria officinalis) and soapberry. The
saponin yamogenin is found in yams of the genus Dioscorea . Many yams require
detoxification processing before they can be eaten. (The tuber termed sweet potato in the U.S., Ipomoea
batatas, is not a Dioscorea yam.) Saponins are steroid or triterpene glycosides which, because of
detergent-like properties, can form complexes with sterols. They can therefore disrupt intestinal sterol
uptake and interfere with cell membrane function, and are utilized by plants at least in part as
antimicrobials (they disrupt fungal membranes by binding to sterols).
Terpenes that confer scents and flavors potentially useful to humans
In some plants, volatile monoterpenes and sesquiterpenes termed “essential oils” (when extracted) are present and confer a characteristic odor or aroma to the foliage. These aromatic compounds are often presented to potential predators in concentrated external form in “glandular hairs”.However, plants also use monoterpenes and other compounds to provide attractive scents for pollinators. The large number of aromatic plants from which essential oils for human use are derived include:
Plant Source Terpenes And Other Compounds Found In Essential Oil
Anise C10 trans-anethole (not a terpene)
Basil C10 eugenol and estragole (not terpenes), plus other aromatic compounds
Camphor laurel C10 camphor
Cinnamon C9 trans-cinnamaldehyde (not a terpene), plus other aromatic compounds
Citronella grass C10 citronellal, plus (+)-Citronellol, etc.
Cloves C10 eugenol (not a terpene) plus other aromatic compounds
Eucalyptus C10 eucalyptol AKA 1,8 cineole
Fennel C10 trans-anethole (not a terpene)
Ginger C15 zingiberene and other terpenoids
Lemon C10 d-limonene, the main odor constituent of citrus, plant family Rutaceae
Lemongrass C10 geranial [AKA citral A] and neral [AKA citral B]
[many] C10 linalool (widespread in floral scents and fruits including
guava, peach,
plum, pineapple, and passionfruit)
Peppermint C10 menthol, along with C10 menthone and menthyl esters
Rose C10 geraniol plus C10 l-citronellol (AKA (–
-Citronellol), etc.
Sage C10 cineole, borneol, and thujone (all terpenes), etc.
Tarragon C10 estragole (not a terpene)
Phenolics
Phenol consists of a benzene aromatic ring with an attached hydroxyl (-OH) group. Phenolic compounds are a heterogeneous group that have one or more such C6 aromatic rings bound to hydroxyls. These vary substantially in size and water solubility.
Biosynthesis
Shikimic Acid pathway: Most plant phenolics are synthesized in the Shikimic Acid pathway, starting with the C4 Erythrose-4-phosphate (from the Oxidative Pentose Phosphate Pathway) or C3 phosphoenolpyruvic acid (PEP, from glycolysis) and leading to C7 Shikimic acid. From Shikimic acid, pathways continue :
• through Gallic acid to hydrolyzable tannins
• through Chorismic acid (which can also lead to Tryptophan), Prephenic acid, and Arogenic acid to the aromatic AAs Phenylalanine or Tyrosine, and to trans-Cinnamic acid and Simple phenolics.
• from Simple phenolics (including C6-C3 Phenylpropanoids such as trans-Cinnamic acid and pcoumaric acid, and C6-C1 compounds such as benzoic acid) to lignin, flavonoids, condensed
tannins, and other phenolics.
Malonic pathway: The malonic pathway, found in fungi and bacteria, is an alternative pathway for synthesizing phenolic compounds, but is of lesser importance in higher plants. (The shikimic acid pathway is not found in animals, and they therefore cannot synthesize the aromatic amino acids.)
The removal of ammonia from phenylalanine to yield trans-Cinnamic Acid plus NH3 by the cleaving of the C-N bond is catalyzed by phenylalanine ammonia-lyase (PAL). This enzyme is located at a branch point between primary metabolism (such as protein synthesis) and secondary metabolism (synthesis of phenolics and alkaloids, etc.) A plant subjected to stresses such as fungal infection increases its expression of PAL and therefore synthesizes relatively more phenolic secondary metabolites .
Simple phenolics
Phenylalanine leads to simple phenolics such as
• Phenylpropanoids (C6-C3 ) such as trans-Cinnamic acid and derivatives such as caffeic acid and ferulic acid
• Coumarins are C6-C3 Phenylpropanoid lactones or cyclic esters such as coumarin (benzopyrone) and umbelliferone. Coumarin is a “toxin found in many plants, notably in high concentration in the tonka bean, woodruff, mullein, and bison grass. It has a sweet scent, readily recognised as the scent of newlymown hay... The name comes from a French word, coumarou, for the tonka bean.” Warfarin (Coumadin™
is a C19 synthetic derivative of coumarin, and was named for the Wisconsin Alumni
Shikimic acid: named after the Japanese flower shikimi (Illicium anisatum)
It inhibits the vitamin K–dependent synthesis of biologically active forms of
certain clotting factors.
•
Psoralen is a plant furanocoumarin (a coumarin with an added furan ring) that is phototoxic to cells of insects and animals when activated by exposure to UV-A (320-400 nm) light .
Psoralen (named after Psoralea corylifolia) is used in P-UVA treatment of psoriasis, etc. Psoralen and the closely related furanocoumarin Angelicin along with their methoxy derivatives occur in a number of plants belonging to the Umbelliferae (Apiaceae) family—caraway, carrot, celery, coriander, cumin,dill, fennel, giant hogweed, parsley, cow parsley, parsnip, cow parsnip, etc.—as well as Rutaceae such as lime, Bergamot orange, lemon, etc. along with plants of other genera. These compounds can cause a non-immunological photosensitization such as “string-trimmer” (“weed-eater”
dermatitis.
Insects that ingest psoralens may be sensitized and have to adapt by avoiding UVA light.
• Benzoic acid derivatives: These are C6-C1 compounds formed from phenylpropanoids, and include vanillin and salicylic acid. (Benzoic acid was named after gum benzoin, also called styrax resin.)
-Lignin
Lignin is a complex hydrophobic “phenolic” which is considered by the textbook to be a secondary metabolite. It is highly branched polymer of phenylpropanoid groups, with uncertain overall structure. It forms from 3 phenylpropanoid alcohols: conifereryl, coumaryl, and sinapyl alcohols, and contains manyn 3-dimensional linking C–C and C–O–C bonds. Its important roles are many , including providing structural strength and mechanical rigidity to stems and trunks and preventing collapse under negative pressure of xylem tracheary elements. These properties allow upward growth and improved competitive fitness, and made possible tall plant colonization on dry land. In addition, lignin improves the
survivability of plants by making them tougher and more indigestible to herbivores, as well as more resistant to wounding and infection.It also contributes to wound healing.
Flavonoids
Flavonoids (AKA “bioflavonoids”
are another major class of phenolics, derived from a combination of the shikimic acid and malonic acid pathways. These are C6-C3-C6 compounds combining two aromatic C6 rings connected by a C3 bridge which may be cyclized into a benzopyrone ring. They often have glycoside
substituents. In human use, they are noted for antioxidant properties and various potential health applications are under investigation. Their derivatives include:
•
Anthocyanins: These are colored flavonoids that confer pigmentation that are used in flowers and fruits (along with carotenoids) to attract animals visually to promote pollination and fruit or seed dispersal through fruit ingestion. They may serve as accessory pigments to protect leaves from photoinhibition from excess light
and UV radiation (thats why crpos developed in greenhouses are nutrient def.). They are responsible for most of the
red, pink, purple, and blue colors seen in plants (whereas carotenoids including xanthophylls often confer orange, yellow, or red coloration.) They occur in all tissues of higher plants, including leaves, stems, roots, flowers, and fruits. They include anthocyanin (which is a glycoside, having an attached sugar or glycone), and the sugar-free (aglycone) anthocyanidins. The latter come with various substituents, confering colors such as orange red (pelargonidin), purplish red (cyanidin), bluish purple (delphinidin), rosy red (peonidin), and purple (petunidin). The intense blue of Commelina communis (dayflower) arises from a complex of multiple anthocyanins and other compounds. Anthocyanins are located in the vacuole, are strong antioxidants, and are found in high concentration in blueberry, blackberry, marionberry, black raspberry, raspberry, blackcurrant,
chokeberry, cherry, eggplant, red grape, etc.
•
Flavones and Flavonols: These typically absorb wavelengths in the UV part of the spectrum producing a pattern in flowers which is not visible to humans but is visible to insects such as bees.
Such patterns form “nectar guides” for insect pollinators .
Flavones and flavonols in the
epidermis of leaves also serve as “sunscreens” to protect the leaves from excess UV-B (280-320 nm).
Flavones and Flavonols (or isoflavones) are also secreted by legumes to help form the symbiosis with nitrogen-fixing rhizobia. Natural flavones include Apigenin, Luteolin, and Tangeritin; natural flavonols include Quercetin and Myricetin.
•
Isoflavones (Isoflavonoids): These have the phenyl group shifted to the middle of the bridging carbons. They are found mostly in Fabaceae (Leguminosae, legumes such as beans and soybeans)and are strong anti-oxidants. Some are phytoestrogens or are anti-estrogenic (e.g., they have been shown to cause reproductive failure in sheep and quails). Some serve as phytoalexins (antimicrobial compounds). Rotenoids are used as insecticides and fish poisons. Soybean isoflavonoids may have anti-cancer benefits but have also been linked to immune abnormalities.Soybean isoflavones include genistein and daidzein.
Tannins
Tannins: Like lignins, tanninsare plant phenolic compounds which serve a defensive role by reducing plant edibility. These are astringent (mouth puckering) bitter polyphenols that bind or precipitate proteins nonspecifically (including the digestive enzymes of herbivores), by means of either hydrogen bonding or covalent bonding of protein –NH2 groups . They may also reduce the bioavailability of metal ions in herbivores by chelating them. Ingested tannins can decrease the digestibility of proteins, thereby reducing the nutritive value to herbivores of plants and plant parts, deterring herbivore feeding. (Some animals such as rodents and rabbits secrete salivary proline-rich proteins that improve tannin ntolerance.) Tannins are mainly located in the vacuoles or surface wax of the plants. They are also found in the nonliving heartwood of conifers, where they may help to inhibit microbial activity. They are used in
tanning to bind collagen in animal hides, thereby increasing the resistance to microbes and heat, etc.
Tannins are found in many human foods and beverages: black tea, red wine (perhaps contributing tonbreputed cardiac health benefits), beer hops, unripe fruits, various ripe fruits including pomegranates, persimmons, cranberries, strawberries, blackberries, blueberries, apple, grapes, smoked foods, etc.
Dietary tannins may have beneficial anti-oxidant properties. There are two categories :
• Condensed tannins: These consists of polymers of flavonoid units (such as epicatechin or catechin), and can be hydrolyzed to anthocyanidins (thus they are also termed proanthocyanidins). They are
common constituents of woody plants, reducing their edibility.
• Hydrolyzable tannins: These are smaller, and may be hydrolyzed to a sugar plus phenolic acids: gallic acid (in gallotannins), or ellagic acid (in ellagitannins).
Nitrogen-Containing Secondary Metabolites
This is a large and heterogeneous grouping of secondary metabolites (thus excluding primary metabolites such as amino acids, proteins, nucleotides, various amides and amines, etc.). The term includes plant alkaloids, cyanogenic glycosides, glucosinolates, and non-proteinogenic amino acids. Although they are synthesized from common amino acids (and polyamines), many are toxic to animals.
Alkaloids
There are more than 15,000 natural plant alkaloids and they are found in 20% of vascular plant species.
The N is usually found in a heterocyclic ring, but exceptions include Capsaicinoids115 (from genusCapsicum) and natural Phenethylamines such as mescaline (from several Cactaceae including the peyote cactus Lophophora williamsii), levodopa and dopamine (from Mucuna pruriens), and ephedrine(from various Ephedra species). Most alkaloids are water soluble and “alkaline”, and therefore at physiological pH typically are positively charged due to protonation of the N by H+. They serve primarily as plant defenses, and are no longer regarded as simply nitrogenous wastes or nitrogen storage compounds.
They poison and kill many unadapted domestic livestock each year, particularly lupines (Lupinus),larkspur (Delphinium), and groundsel (Senecio). Plant alkaloids poisonous to humans include some classic poisons:
•
aconitine (from Aconitum, known as aconite, monkshood, or wolfsbane)
•
atropine (from Atropa belladonna and other Solanaceae)
•
coniine (from poison hemlock Conium maculatum and Yellow pitcher plant Sarracenia flava)
•
muscarine (from various mushrooms including Inocybe and Clitocybe)
•
solanine and chaconine (from the nightshade Solanaceae family such as light-exposed green-tinged[and often bitter tasting] potato tubers and sprouts, but also eggplants, tomatoes, and peppers).
•
strychnine and brucine (extremely bitter alkaloids obtained from the seeds of the tree Strychnos nuxvomica)
Although most alkaloids are toxic to humans in sufficient doses, many natural plant alkaloids are useful tohumans in controlled doses, and many are psychoactive .
•
atropine (from Atropa belladonna and other Solanaceae)
•
caffeine (from coffee, tea, cacao, yerba mate, guarana)
•
capsaicin and dihydrocapsaicin (the most abundant and hottest capsaicinoids from peppers of genus Capsicum )
•
cocaine (from the coca plant, Erythroxylum coca)
•
codeine (from the opium poppy, Papaver somniferum)
•
emetine (from ipecac, the dried rhizome and roots of the Ipecacuanha plant Psychotria ipecacuanha)
•
ergotamine (from the ergot fungus, Claviceps purpurea, and related fungi)
•
hyoscyamine (from Hyoscamus niger and mandrake Mandragora officinarum and other Solanaceae)
•
levodopa (L-DOPA) and dopamine (from Mucuna pruriens)118
•
mescaline (from several Cactaceae including the peyote cactus Lophophora williamsii)119
•
morphine (from the opium poppy, Papaver somniferum)
•
nicotine (from tobacco and coca, and in lower quantities in tomato, potato, eggplant, and greenpepper.
•
nicotinic acid (niacin, from leafy vegetables, broccoli, tomatoes, asparagus, avocados, etc.)
•
papaverine (from the opium poppy, Papaver somniferum)
•
pilocarpine (from Rutaceae of genus Pilocarpus)
•
piperine and chavicine (these produce the pungency of black pepper)121
•
psilocybin (hallucinogen derived from mushrooms of genus Psilocybe)
•
quinine and quinidine (from trees of genus Cinchona)
•
reserpine (from the root of Rauwolfia serpentina)
•
scopolamine (from family Solanaceae such as henbane or jimson weed Datura species)
•
theobromine (from the cacao tree, Theobroma cacao)
•
theophylline (from tea and the cacao tree, Theobroma cacao)
•
vincristine and vinblastine (from Madagascar periwinkle Catharanthus roseus, formerly Vinca rosea)
Many alkaloids employed as human drugs are synthetic or semi-synthetic:
•
amphetamine (from ephedrine)
•
heroin (from the opium poppy, Papaver somniferum)
• lysergic acid diethylamide LSD (hallucinogen derived from lysergic acid derived from ergot of genus Claviceps)
