A1914 1.1

Jack G Woolley, De Montfort University, Leicester, UK Alkaloids are basic (alkali-like), nitrogen-containing organic constituents found in some plants. They give positive responses with Dragendorff, Mayer, Hager and Wagner Alkaloids are organic bases. Many alkaloids are poiso- nous, others are addictive (e.g. cocaine), and some are used clinically (e.g. morphine [XXXI]). More than 10 000alkaloids are nowknow exceptions, for example pacletaxel from yew(a Gymnos- XXVII], isolated from opium by Derosne in trine [XXXIII] from Equisetum (both Pteridophytes), and may be extracted from the cell with acidified water or even fungi, e.g. ergometrine (Claviceps). These structures alcohol, or alternatively they are soluble in organic are shown in Figure 1. The distribution of alkaloids in the solvents (e.g. chloroform) when the plant is rendered alkaline. Alkaloids are normally classified according to theheterocyclic ring system they possess, but some authorsprefer a classification based on their biosynthetic origins from amino acids, e.g. phenylalanine [XVII], tyrosine[XVIII] or tryptophan [XIX] (Scheme 2).
Many authors consider alkaloids to be exclusively plantproducts, but similar compounds are found elsewhere. Ofparticular interest are the extremely toxic skin secretions from ‘poison dart’ frogs of South America (e.g. batracho-toxin from Dendrobates and Phyllobates). Simply wiping Alkaloids are common in the Angiosperms (Mono- and the dart across the back of the frog is said to be sufficient to Dicotyledons), but rare in lower plants, although there are produce a poison dart. Epipedobates tricolor (Ecuadoran General structure and basicity of alkaloids.
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net Alkaloids are produced by secondary metabolism ofprimary metabolites, usually amino acids. These pathways are long, intricate, stereochemically precise and energy consuming, and are assumed to be of evolutionary benefit.
Normally these routes are explored using isotopically labelled precursors that are introduced into the plant, asshown in Schemes 3 and 4.
[XXXIII]
In many instances enzymes mediating single steps in the pathways have been isolated and characterized and in a growing number of cases the gene encoding the enzyme hasbeen isolated and cloned. Good examples are the PMT(putrescine methyltransferase) and H6H (hyoscyamine 6-hydroxylase) genes involved in the biosynthesis of hyoscine[XLI] (scopolamine) in Atropa and Hyoscyamus. The H6H tree frog) is of much interest since epibatidine [XXXIV] is c.
enzyme is unusual in that it catalyses two steps, as 200 times more potent than morphine [XXXI] as an analgesic. Even the humble ladybird secretes the alkaloidcoccinelline [XXXV] for defence (Figure 2).
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net Table 1 Distribution of alkaloids in the plant kingdom
Psilocybine [XXII]
Yohimbine [XXI]
Reserpine [XX]
Serpentine [XXIV]
Vinblastine [XXV]
Berberine [XXIX]
Mescaline [XXX]
Calystegines [XLII]
Palustrine [XXXIII]
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net Table 1 – continued
Lycopodine [XXXII]
Morphine [XXXI]
Narcotine [XXVII]
Papaverine [XXVI]
Emetine [XXVII]
Hyoscine [XLI]
Hyoscyamine [XXXIX]
Hyoscyamus (hb)Duboisia (hb) aPart of plant used: (l), leaves; (s), seeds; (hb), herbs; (bk), bark; (rh), rhizome; (tb), tuber (green); (fr), fruits; (lt), latex; (r), roots; (c), corm; (fb), fruiting body; (b), bulb; (m), mushroom.
bBiological activity relates to the plant and not necessarily the alkaloids that are listed as representative examples of the families.
from the male during copulation, the eggs subsequentlybeing laid on a suitable (protective) plant. On hatching the Moths of the Arctiidae and Ctenuchidae are well known to larvae sequester pyrrolizidines from eating the leaves of the sequester pyrrolizidine alkaloids, but many insects of the host. There is often a specific relationship between insect Coleoptera, Homoptera, Lepidoptera and Orthoptera do and host. The cinnabar moth (Tyria jacobaea) feeds on the same as a means of protection against predators.
ragwort (Senecio jacobaea) and accumulates senecionine Aphids ingest pyrrolizidines from the sap of plants and [XLVI] and other bases. The death’s-head hawk moth ladybirds feeding on the aphids are thereby able to (Acherontia atropus) sequesters calystegines [XLII] from accumulate these alkaloids. Eggs acquire the bases, usually potato plant leaves. Some insects of the Arctiidae feeding ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net on Boraginaceous plants convert sequestered pyrrolizidine alkaloids, e.g. [XLIII] into the male courtship pheromone The poisonous and therapeutic effects of plants havebeen known since time immemorial, but the active An alkaloid from a frog [XXXIV] and from an insect [XXXV].
constituents have been studied for only about 200 years.
Some alkaloids are derived from the labelled (*) amino acid tryptophan.
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net The biosynthetic origins of some alkaloids. The precursor tyrosine is labelled with isotopic carbon (*) and during biosynthesis the alkaloidal metabolites are specifically labelled at the sites shown (*).
After the discovery of the first alkaloid, narcotine, other alkaloids were rapidly discovered: morphine (opium),strychnine (Strychnos nux-vomica seeds), emetine (ipeca- Establishing the site of synthesis is difficult since the site of cuanha root), quinine (Cinchona bark) and coniine storage is not necessarily the site of synthesis. Grafting experiments (within the same plant family) where the scion Alkaloids are used medicinally in their own right of a non-alkaloid-producing plant (e.g. Cyphomandra) w as e.g. hyoscyamine [XXXIX] and vinblastine [XXV] and bound to the stock of an alkaloid-producing plant (e.g.
they have often provided lead compounds for the devel- Datura) showed that the scion contained tropane alka- opment of synthetic drugs. For example, cocaine was the loids. The reciprocal graft gave a Datura scion devoid of first local anaesthetic, quinine the first antimalarial and alkaloids. Root cultures of Solanaceous plants (Datura, tubocurarine the first neuromuscular blocking agent.
Atropa, Hyoscyamus, Duboisia, Nicotiana, etc.) all produce Recent discoveries include pacletaxel from the Pacific alkaloids in the absence of the aerial parts. In contrast, the Yewand epibatidine [XXXIV]. Alkaloids frequently have shoot is the site of synthesis in Ephedra (ephedrine), powerful physiological effects; some of these are listed in hemlock (coniine) and lupin (lupanine). At the subcellular level, alkaloids frequently accumulate as salts within thevacuole, which has a slightly acid pH. It is now possible toshow where individual genes are activated within tissues.
The H6H gene is not switched on unless its adjacent 5’ ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net [XXXVII]
[XXXVIII]
Biosynthesis of hyoscine (scopolamine); this involves the enzymes putrescine methyltransferase (PMT) and hyoscyamine 6-hydroxylase construct was transferred to Atropa and Hyoscyamus.
Sections of the plant were then incubated with a substratethat becomes blue by the action of the GUS enzyme. The GUS was expressed solely in the pericycle region of the rootand therefore the H6H gene is as well.
Many useful plants growin inaccessible parts of the world or where access is limited by political uncertainties. Some are in short supply and do not lend themselves to farming, or are perhaps slow growing (e.g. the Pacific Yew, Taxus brevifolia, the source of pacletaxel). Sometimes the desired alkaloid is present only in trace quantities (e.g. vinblastine[XXV] from Catharanthus roseus). For these and other reasons, there has been an enormous effort to growmedicinal plants in flasks (or fermenters) where alkaloid Some alkaloids sequestered and metabolized by insects.
production may be optimized, carried out without seasonalvariations and when required. Plants are differentiated intoroots, shoots, etc. and within the tissues into xylem, promoter region of the DNA is activated. Replacing the phloem, etc. Under the influence of plant hormones (IAA, H6H gene with a ‘reporter’ gene (GUS, a b-glucuronidase- indoleacetic acid, or the synthetic weedkiller 2,4-D), plants encoding gene) behind the promoter ensures that the new dedifferentiate into identical single-cell clumps (callus).
gene is expressed when the promoter is activated. The new Callus can be broken down into a suspension culture when ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net Table 2 Some biological actions of alkaloids
Papaverine [XXVI]
Ergotamine, ergometrine, yohimbine [XXI]
Emetine [XXVII], conessine
Morphine [XXXI], codeine
Camptothecine, demecolcine (desacetylmethylcolchicine), ellipticine, indicine N-oxide, maytansine, pacletaxel,
vincristine, vinblastine [XXV]
Hyoscine, (scopolamine) [XLI], hyoscyamine [XXXIX]
Cevadine, veratrine, reserpine [XX], serpentine [XXIV],
Arecoline, hyoscyamine [XXXIX], muscarine, pilocarpine
Reserpine [XX], serpentine [XXIV]
Caffeine,a cathine, cocaine, ephedrine, lobeline, strychnine Codeine, narcotine [XXVII]
Emetine [XXVII] (emetic)
Bufotenine, harmine, mescaline, psilocybine [XXII]
Harmine, yohimbine [XXI]
Calystegines (as [XLII])
a Caffeine is sometimes regarded as an alkaloid, even though it fails to give the normal alkaloid precipitation tests. It is related to the nucleic acids.
the culture fluid is agitated and this kind of homogeneous generates hairy (fluffy) roots (even from leaf tissue). By culture is ideal for large-scale production. Unfortunately, inserting desirable genes into their plasmids, Agrobacteria despite much effort, cultures cannot yet be persuaded to are used to transfer newgenes to plants. Some plants that produce anything like the quantity of alkaloid found in the have been grown in culture are listed in Table 3.
Hairy root cultures are much used in research into the biosynthesis of alkaloids. They are produced by exposingsterilized plant parts to strains of the soil microorganism Agrobacterium rhizogenes, which is able to transfer part ofits own DNA (T-DNA) from a plasmid (a circular loop of Alkaloids of the pyrrolizidine [XIII] and indolizidine double-stranded DNA) to the plant’s nuclear genome. The [XLVII] types cause serious toxicity (and death) in T-DNA carries genes encoding the biosynthesis of plant livestock, mainly horses, cattle and sheep that graze on hormones and for the production of opines, unusual plants containing them (Table 4). Pyrrolizidines, especially nutritional amino acids required by the microorganism. As those bases with a C1–C2 double bond, e.g. heliotridine a consequence the invaded tissue, when rid of Agrobacteria [XLIII], cause chronic liver damage and malignant using antibiotics, continues to produce opines and it tumours, but monocrotaline [XLV] damages the lungs as ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net Table 3 Alkaloids from plants that have been grown in tissue culture conditions
Serpentine [XXIV]
Emetine [XXVII]
Hyoscine [XLI] and
Hyoscyamine [XXXIX]
(meteloides)Datura stramonium Morphine [XXXI] and codeine
Reserpine [XX]
a r, root; hr, hairy root; c, callus; sc, suspension cultures. Relative quantities of alkaloids, +; t, trace. (A very approximate series of estimations.) well. Ironically the pyrrolizidine alkaloid indicine N-oxide histologically visible neurological damage to neurons in is used in the treatment of cancer. Indolizidines, swainso- the brain and ultimately death. (Figure 4).
nine [XLVIII] and castanospermine [XLIX], are powerful Less well known are the more-recently described glycosidase inhibitors that cause ‘locoism’, leading to calystegines (nortropanes), e.g. calystegine B2 [XLII], ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net Table 4 Toxic plants
Senecionine [XLVI]
Swainsonine [XLVIII]
Castanospermine [XLIX]
Monocrotaline [XLV]
Monocrotaline [XLV]
Swainsonine [XLVIII]
Swainsonine [XLVIII]
Calystegines [XLII]
Calystegines (as [XLII])
Swainsonine [XLVIII]
Swainsonine [XLVIII]
a (B), Boraginaceae; (C), Compositae; (L), Leguminosae; (C), Convolvulaceae, (S) Solanaceae.
b (P), Pyrrolizidine.
c (c), cows; (h), horses; (p), pigs; (s), sheep.
[XLVIII]
Some alkaloids that cause poisoning of livestock.
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net which are, like the indolizidines, sugar-mimic glycosidase Cordell GA (1981) Introduction to Alkaloids. NewYork: Wiley.
inhibitors. Since these are widely distributed in the Cordell GA (1998) The Alkaloids, vol. 52, NewYork: Academic Press. [a Solanaceae and occur in potato, aubergine, etc., some continuing series of expert reviews].
concern has been expressed as to their possible toxicity to Evans WC (1996) Pharmacognosy. London: WB Saunders.
Manske RFH and Holmes HL (1950) The Alkaloids, vol. 1. NewYork: Pelletier SW (1983) Alkaloids: Chemical and Biological Perspectives, vol.
Pelletier SW (1998) Alkaloids: Chemical and Biological Perspectives, vol.
Bull LB, Culvenor CCJ and Dick AT (1968) The Pyrrolizidine Alkaloids.
12, Oxford: Pergamon Press [a continuing series of expert reviews].
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net

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