Secondary Metabolites

Secondary metabolites are organic compounds that are not directly involved in the normal growth, development, or reproduction of organisms. Unlike primary metabolites, absence of secondary metabolites does not result in immediate death, but rather in long-term impairment of the organism's survivability, fecundity, or aesthetics, or perhaps in no significant change at all. Secondary metabolites are often restricted to a narrow set of species within a phylogenetic group. Secondary metabolites often play an important role in plant defence against herbivory and other interspecies defences.

Categories

Most of the secondary metabolites of interest to humankind fit into categories which classify secondary metabolites based on their biosynthetic origin. Since secondary metabolites are often created by modified primary metabolite syntheses, or borrow substrates of primary metabolite origin, these categories should not be interpreted as saying that all molecules in the category are secondary metabolites (for example the steroid category), but rather that there are secondary metabolites in these categories.

Microscale molecules

Alkaloids usually a small, heavily derivatised amino acid:

• • Hyoscyamine, present in Datura stramonium

  • Atropine, present in Atropa belladonna, Deadly nightshade

  • Cocaine, present in Erythroxylon coca the Coca plant

  • Codeine and Morphine, present in Papaver somniferum, the opium poppy

  • Tetrodotoxin, a microbial product in Fugu and some salamanders

  • Vincristine & Vinblastine, mitotic inhibitors found in the Rosy Periwinkle

Terpenoids come from semiterpene oligomerization:

• • Azadirachtin - Neem tree.

  • Artemisinin, present in Artemisia annua Chinese wormwood

  • tetrahydrocannabinol, present in cannabis sativa

Steroids (Terpenes with a particular ring structure)

Saponins - plant steroids, often glycosylated

Glycosides (heavily modified sugar molecules):

• • Nojirimycin

  • Glucosinolates

Phenols:

• • Resveratrol

Phenazines:

• • Pyocyanin

  • Phenazine-1-carboxylic acid (and derivatives)

Larger-scale molecules 

Polyketides:

• • • • Erythromycin

      • Discodermolide

Fatty acid synthase products :

• • • • FR-900848

      • U-106305

      • phloroglucinols

Nonribosomal peptides:

• • • • Vancomycin

      • Thiostrepton

      • Ramoplanin

      • Teicoplanin

      • Gramicidin

      • Bacitracin

Hybrids of the above three:

• • • • Epothilone

• • • Polyphenols

Non-'small molecules' - DNA, RNA, ribosome, or polysaccharide classical biopolymers

Ribosomal peptides:

• • • • Microcin-J25

Toxic By-products

Cochicine

Colchicine is a toxic natural product and secondary metabolite, originally extracted from plants of the genus Colchicum. It was used originally to treat rheumatic complaints, especially gout, and still finds use for these purposes today despite dosing issues concerning its toxicity. It was also prescribed for its cathartic and emetic effects. Colchicines’ present medicinal use is in the treatment of gout and familial Mediterranean fever; it can also be used as initial treatment for pericarditis and preventing recurrences of the condition. It is also being investigated for its use as an anticancer drug. In neurons, axoplasmic transport is disrupted by colchicine.

Alkaloids 

Alkaloids are a group of naturally occurring chemical compounds which mostly contain basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids. Beside carbon, hydrogen and nitrogen, molecules of alkaloids may contain sulphur and rarely chlorine, bromine or phosphorus.

Alkaloids are produced by a large variety of organisms, including bacteria, fungi, plants, and animals and are part of the group of natural products. Many alkaloids can be purified from crude extracts by acid-base extraction. Many alkaloids are toxic to other organisms. They often have pharmacological effects and are used as medications, as recreational drugs, or in entheogenic rituals. Examples are the local anesthetic and stimulant cocaine, the stimulant caffeine, nicotine, the analgesic morphine, or the antimalarial drug, quinine. Although alkaloids act on a diversity of metabolic systems in humans and other animals, they almost uniformly invoke a bitter taste.

The boundary between alkaloids and other nitrogen-containing natural compounds is not clear-cut. Compounds like amino acid peptides, proteins, nucleotides, nucleic acid, amines and antibiotics are usually not called alkaloids. Natural compounds containing nitrogen in the exocyclic position are usually attributed to amines rather than alkaloids. Some authors, however, consider alkaloids a special case of amines.

Biological precursors of most alkaloids are amino acids, such as ornithine, lysine, phenylalanine, tyrosine, tryptophan, histidine, aspartic acid and anthranilic acid; all these amino acids, except anthranilic acid, are proteinogenic that is they are contained in proteins. Nicotinic acid can be synthesized from tryptophan or aspartic acid. Ways of alkaloid biosynthesis are too numerous and can not be easily classified. However, there is a few typical reactions involved in the biosynthesis of various classes of alkaloids, including synthesis of Schiff bases and Mannich reaction.

Synthesis of Schiff Bases

Schiff bases can be obtained by reacting amines with ketones or aldehydes. These reactions are a common method of producing C=N bonds.

 In the biosynthesis of alkaloids, such reactions may take place within a molecule, such as in the synthesis of piperidine:

Mannich reaction

In integral component of the Mannich reaction, in addition to an amine and a carbonyl compound, is a carbanion, which plays the role of the nucleophile in the nucleophilic addition to the ion formed by the reaction of the amine and the carbonyl.

The Mannich reaction can proceed both intermolecularly and intramolecularly:

Dimer alkaloids

In addition to the described above monomeric alkaloids, there are also dimeric, and even trimeric and tetrameric alkaloids formed upon condensation of two, three and four monomeric alkaloids. Dimeric alkaloids are usually formed from monomers of the same type through the following mechanisms:

• • Mannich reaction, resulting in, e.g. voacamine

  • Michael reaction (villalstonine).

  • Condensation of aldehydes with amines (toxiferine).

  • Oxidative addition of phenols (dauricine and tubocurarine).

  • Lactonisation (carpaine).

Secondary byproducts in more detail

Phytotoxin 

Phytoxin refers to a substance produced by a plant that is toxic or a substance that is toxic to the plant. Many substances produced by plants are secondary metabolites and are the by-products of primary physiological processes. Some examples of phytotoxins are alkaloids, terpenes, phenolics, herbicides and substances produced by bacteria.

Alkaloids

Alkaloids are derived from amino acids, and contain nitrogen. They are medically important by interfering with components of the nervous system affecting membrane transport, protein synthesis, and enzyme activities. They generally have a bitter taste. Alkaloids usually end in “ine” (caffeine, nicotine, cocaine, morphine, and ephedrine).

Terpenes

Terpenes are made of water insoluble lipids, and synthesised from acetyl CoA or basic intermediates of glycolysis. They often end in -ol (menthol) and make the majority of plant essential oils.

• • Monoterpenes are found in gymnosperms and collect in the resin ducts and maybe released after an insect begins to feed to attract the insect's natural enemies.

  • Sesquiterpenes are bitter tasting to humans and are found on glandular hairs or subdermal pigments.

  • Diterpenes are contained in resin and block and deter insect feeding. Taxol, an important anticancer drug is found in this group.

  • Triterpenes mimic the insect molting hormone ecdysone, disrupting molting and development and is often lethal. They are usually found in citrus fruit, and produce a bitter substance called limonoid that deters insect feeding.

  • Glycosides are made of one or more sugars combined with a non-sugar like aglycone, which usually determines the level of toxicity. Cyanogenic glycosides are found in many plant seeds like cherries, apples, and plums. Cyanogenic glycosides produce cyanide and are extremely poisonous. Cardenolides have a bitter taste and influence NA+/K+ activated ATPases in human heart, they may slow or strengthen the heart rate. Saponins have lipid and water soluble components with detergent properties. Saponins form complexes with sterols and interfere with their uptake.

Phenolics

Phenolics are made of a hydroxyl group bonded to an aromatic hydrocarbon. Furanocoumarin is a phenolic and is non-toxic until activated by light. Furanocoumarin blocks the transcription and repair of DNA. Tannins are another group of phenolics and they are important in tanning leather. Lignins, also a group of phenolics, is the most common compound on earth and helps conduct water in plant stems and fill spaces in the cell.

Glucosinolates are anions that occur only in the cells of a limited number of dicotyledonous families. Glucosinolates are very common in the order Capparales (best-known family: Brassicaceae) where they occur in every species hitherto examined. Among the best-known representatives are the active ingredients of horse-radish, radish and mustard. The elimination of aliphatic Glucosinolates in rape achieved by cultivation resulted in so-called double zero varieties (00-varieties). The cultivation of simple zero varieties is based on the elimination of erucid acid, a long-chained unsaturated fatty acid.

The first record mentioning the use of rubber goes back to the 11th century. Since this time, the Indians of Middle America use rubber balls in their ball games. From a chemical point of view rubber is a carbohydrate consisting of high molecular weight chains of 1, 4 - polyisoprene residues in cis-configuration (caoutchouc). The main source is Hevea brasiliensis. Gutta-percha consists of 1,4 - polyisoprene residues in trans-configuration. Its molecular weight is far below that of rubber. The main source is Palaquium gutta. A similar substance, balata, is obtained from Mimosops balata.

Chicle

Chicle (obtained from Achras sapota), finally, is a polymer containing both cis- and trans-bonds (in the ratio 1:2). It is the basic substance of bubble gum. Altogether, more than 1800 plant polyisoprenes have been identified. Their cellular concentrations are usually small, and their molecular weights are relatively low.

Polyisoprenes 

Polyisoprenes occur in certain plant cells as small latex particles. They can be seen in the electron microscope as clearly defined, cytoplasmatic inclusions specific for the respective species.

Plant amines are derivatives of ammonia. Their collective structures are:

• • primary amines: NH2R

  • secondary amines: NHRR'

  • tertiary amines: NRR'R''

  • quaternary amines: N+RR'R''R'''(OH-)

A wide range of plant amines can be found in the most different plant cells. They are usually generated by the decarboxylation of amino acids or by transamination of aldehydes. The distinction between plant amines and alkaloids is sometimes a little arbitrary. Some, like mescaline, are counted among the alkaloids although in a chemical sense they are amines.

Aliphatic amines are often produced during anthesis, i.e. the opening of a flower or the formation of the fruiting body of certain fungi (like the stinkhorn, for example). They are insect-attractants. A good example of insect attractants is the aliphatic-aromatic amines in Araceae (lords-and-ladies, arum and others).

Among the di- and polyamines are putrescine (NH2(CH2)4NH2), as well as spermidine (NH2(CH2)3NH(CH2)4NH2) and spermine (NH2(CH2)3NH(CH2)4NH(CH2)3NH2). They occur in nearly all eucaryotic cells and interact with the DNA double helix. Among the tryptamines are the phytohormone indole-3-acetic acids (IAA) as well as serotonin.

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