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9.0 Alkaloids. RA Macahig FM Dayrit. Introduction. - PowerPoint PPT Presentation

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  • 9.0 AlkaloidsRA MacahigFM Dayrit

  • 9.0 Alkaloids (Dayrit)* Among all the groups of natural products, alkaloids have the most colorful history, having achieved the most fame and notoriety as drugs. Where alkaloids occur, they tend to dominate the biological activity. Despite their relatively limited distribution, the alkaloids probably have the most significant impact in human history particularly in medicine, social issues, economics and politics. In 1819, Carl Friedrich Meissner, a pioneering German pharmacist, coined the term alkaloid which referred to any natural product with the characteristic presence of the basic nitrogen atom, excluding peptides. (Amides, however, are generally included.)Introduction

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)* Because many alkaloids can be purified from crude extracts by acid-base extraction and recrystallization, these were the first natural products to be purified, characterized and commercialized. IntroductionThe powerful and immediate effects of alkaloids are thought to be due to the presence of the cationizable N-atom which gives it lipid- and water-soluble characteristics, and enables it to cross membrane barriers more readily.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)* The alkaloids have a relatively limited distribution in nature compared with the other natural product groups. Alkaloids were originally thought to be uniquely plant products until the 1950s when several alkaloids were isolated from bacteria, fungi and algae, insects, and amphibians. IntroductionA number of fungi produce toxic alkaloids, notably Claviceps purpurea. Many of the earliest pure compounds to be used as drugs developed were alkaloids: Cocaine: anaesthetic, from South American Erythroxylum coca Quinine: antimalarial, from the bark of the Cinchona tree Morphine: anaesthetic, from opium (Papaver somniferum) Emetine: for amoebiasis, from ipecac, the powdered roots (Cephaelis species) Strychnine: poison, from the seeds of Strychnos nux-vomica

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Introduction In the plant kingdom, the angiosperms produce alkaloids: Apocynaceae, Papaveraceae, Rubiaceae, Ranunculaceae, Solanaceae, and Berberidaceae. Among the monocots, only the Amaryllidaeae and Liliaceae produce alkaloids.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Introduction Some animals, notably some soft corals and frogs produce highly bioactive alkaloids. In some cases, however, the alkaloids were found to have been ingested in the diet by the organism and then modified for use. Well-known examples are the pyrrolizidine alkaloids in caterpillars and moths. Alkaloids are much less common in mammals.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)* There are four major groups of nitrogen-containing organic compounds in biological systems: the amino acids (peptides and proteins), the nucleoside bases (DNA and RNA), the porphyrins; and the alkaloids. The first 3 groups are primary metabolites; the alkaloids are secondary metabolites.Introduction Alkaloids are defined simply as nitrogen-containing natural products. In terms of chemical structure, alkaloids can be classified into the following: 2, 3, and 4 alkyl amines; and heterocyclic amines (e.g., pyrrolidine, pyridine, indole, quinoline, and isoquinoline).

    9.0 Alkaloids (Dayrit)

  • Ajmaline, antiarrythmic that functions by inhibition of glucose uptake by heart tissue mitochondria Atropine (hyoscyamine), anticholinergic, antidote to nerve gas poisoning Caffeine, widely used central nervous system stimulant Camptothecin, potent anticancer agent Cocaine, topical anesthetic, potent central nervous system stimulant, and adrenergic blocking agent, drug of abuse(Kutchan, The Plant Cell, 7, 1059-1070, July 1995)

  • * Codeine, relatively nonaddictive analgesic and antitussive; Coniine, first alkaloid to be synthesized, extremely toxic, causes paralysis of motor nerve endings, used in homeopathy Emetine, orally active emetic, amoebicide; morphine, powerful narcotic analgesic, addictive drug of abuse; Nicotine, highly toxic, causes respiratory paralysis, horticultural insecticide Pilocarpine, peripheral stimulant of the parasympathetic system, used to treat glaucoma Quinine, traditional antimalarial, important in treating Plasmodium falcipafum strains that are resistant to other antimalarials

  • * Sanguinarine, antibacterial showing antiplaque activity, used in toothpastes and oral rinses Scopolamine, powerful narcotic, used as a sedative for motion sickness Strychnine, violent tetanic poison, rat poison, used in homeopathy; Taxol, antitumor agent (+)-Tubocurarine, nondepolarizing muscle relaxant producing paralysis, adjuvant to anesthesia Vinblastine, antineoplastic that is used to treat Hodgkins disease and other lymphomas.

  • 9.0 Alkaloids (Dayrit)*Survey of some well-known alkaloids.

    9.0 Alkaloids (Dayrit)

    (

    Coniine from hemlock (Conium maculatum) was used by the ancient Greeks for state executions. Its most famous victim was Socrates.

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    Lysergic acid is an opiate produced by Claviceps purpurea, a parasitic fungus that grows on some grain crops. The unhygienic practices of medieval Europe caused outbreaks of convulsion which was called St. Anthonys Fire.

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    Nicotine is the principal alkaloid in Nicotiana tabacum. It is addictive and has been recently classified as a drug.

  • 9.0 Alkaloids (Dayrit)*

    9.0 Alkaloids (Dayrit)

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    Strychnine was first purified in 1818 by Pelletier and Magendie from the seeds of Strychnos nux-vomica, a plant native to India. It is a deadly poison and was used for many centuries as a rodenticide and vermicide. It is so chemically and biologically stable that it has been found in bodies exhumed after several years (this makes it a bad choice for a poison!) Strychnine was first synthesized in 1954.

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    Quinine was first purified by Pelletier and Caventou in 1820. It is the major alkaloid from the bark of the Cinchona tree. Christened the Jesuit bark, the bark was traditionally used by Peruvian indians for fever due to malaria. Quinine was the principal antimalarial drug up to WW II, after which it was supplanted by chloroquin.

  • 9.0 Alkaloids (Dayrit)* Merck, one of the worlds largest pharmaceutical companies, made its initial fortune from cocaine, morphine, and codeine.

    9.0 Alkaloids (Dayrit)

    (

    Cocaine is the chief alkaloid of the South American coca bush. It has anaesthetic properties but is very addictive.

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    Morphine was first isolated by Sertrner in 1806 from Papaver somniferum. It is still valued up to this day for its pain-killing properties, although it is highly addictive. It was first synthesized in 1952. Codeine is the methyl derivative.

  • 9.0 Alkaloids (Dayrit)*

    9.0 Alkaloids (Dayrit)

    (

    Mescaline is a well-known hallucinogenic compound extracted from the Indian peyote cactus, Laphophora williamsii.

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    Caffeine is perhaps one of the most widely consumed alkaloids in the world. It is a member of a group of xanthine alkaloids which is present in coffee. The other famous xanthines, theobromine and theophylline, are found in tea and cocoa, respectively.

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    Vinblastine is the anticancer drug from Catharanthus roseus (locally known as chichirica). Because it occurs in very minute amounts in the plant, this plant has been the subject of intense biotechnology research to try to produce it in vitro using cell culture techniques.

  • 9.0 Alkaloids (Dayrit)* Many alkaloids are toxic in the cytoplasm, even in the plants that produce them. Their accumulation, therefore, requires a well-regulated and compartmentalized system. The most common storage organ is the vacuole. Introduction In some plants, alkaloids are synthesized in one part of the plant and then are transported to another part for storage. In tobacco, for example, alkaloids (e.g., nicotine) are synthesized in the roots and are then transported via the xylem to the leaves where they are accumulated.

    9.0 Alkaloids (Dayrit)

    (

    Coniine from hemlock (Conium maculatum) was used by the ancient Greeks for state executions. Its most famous victim was Socrates.

  • 9.0 Alkaloids (Dayrit)*Among the natural products groups, the biochemistry of alkaloids is the most complex. Introduction Many alkaloids are mixed metabolites. Enzymes involved in alkaloid biosynthesis are associated with diverse subcellular compartments including the cytosol, vacuole, tonoplast membrane, endoplasmic reticulum, chloroplast stroma, thylakoid membranes, and perhaps unique biosynthetic or transport vesicles. Localization studies have shown that sequential alkaloid biosynthetic enzymes can also occur in distinct cell types, suggesting the intercellular transport of pathway intermediates. (PJ Facchini, Ann. Rev. of Plant Physiol. and Plant Mol. Bio., Vol. 52: 29-66)

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Despite the wide variety and complex structures observed among the alkaloids, most of the compounds from this group are formed from only a handful of starting materials. The nitrogen and the initial carbon skeleton are derived from the following: A. aliphatic amino acids: lysine, glutamic acid, and ornithine; B. aromatic amino acids: phenylalanine, tyrosine, and tryptophan; and C. others: secologanin: terpene-derived C10 unit. Overview

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*The major reactions in alkaloid biosynthesis are common biosynthetic mechanisms: Oxidation: epoxidation, aromatic hydroxylation, etc. Oxidation: dehydrogenation (-2[H]); in the case of the alkaloids, this includes the conversion of amine imine. Reduction: hydrogenation (+2[H]); in the case of the alkaloids, this includes the conversion of imine amine. Phenolic dimerization by radical coupling. Decarboxylation, in particular in the conversion of amino acid to amine. Overview

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Reactions which are particular to alkaloid biosynthesis.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Reactions which are particular to alkaloid biosynthesis.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Aliphatic alkaloids The aliphatic alkaloids can be classified into three main types, depending on its biogenesis: the amino acid ornithine the amino acid lysine the polyketide pathway with the nitrogen atom being introduced in a late step.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Aliphatic alkaloids from ornithineGlutamic is transformed into ornithine by addition of another CH2 unit. Therefore, in a way, glutamic acid is the original precursor and ornithine is the immediate precursor. Decarboxylation and loss of one nitrogen leads to formation of the pyrrolidine ring. There are three main types: pyrrolidine (monocyclic), tropane (bicyclic) and pyrrolizidine (fused).

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Ornithine comes from glutamic acid.

    9.0 Alkaloids (Dayrit)

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  • 9.0 Alkaloids (Dayrit)*Pyrrolidine alkaloids from ornithine. Labeling studies show that although pyrrolidine itself is symmetric, the biosynthesis is regiospecific. This suggests that once ornithine is held by the enzyme, biosynthesis proceeds without release of any of the intermediates.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Tropane alkaloids from ornithine. Consistent with what has been observed, labeling shows that the biosynthesis is regiospecific.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Pyrrolizidine alkaloids from ornithine. Pyrrolizidine alkaloids are common in the butterflies Senecio and Crotolaria species.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Pyrrolizidine alkaloids are converted into aphrodisiac substances which the male butterflies store in its wing hair pencils. These compounds also protect the plants against feeding by mammals because these compounds are converted in the liver into toxic and carcinogenic compounds.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Polyhydroxylated cycloalkyl alkaloids found in the leaves, flowers and seeds of Ipomoea carnea (Convolvulaceae) cause natural intoxication of livestock by inhibiting key digestive enzymes. Alkaloids 1 and 2 are powerful inhibitors of lysosomal a-mannosidase; 3, 4, and 6 showed potent inhibitory activity toward rat lysosomal b-glucosidase; and alkaloid 5 was a moderate inhibitor of a- and b-mannosidases. (Haraguchi, et al., J. Agric. Food Chem. 2003, 51, 4995-5000.)

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Aliphatic alkaloids from lysineLysine is modified following an analogous pathway to ornithine. There are many similarities between the ornithine-derived and lysine-derived alkaloids. The alkaloids produced are the 6-membered piperidine, homotropane and quinolizidine structures.

    9.0 Alkaloids (Dayrit)

  • Alkaloids from lysine. 1-Piperidine and pellieterine are key intermediates to this group of alkaloids.

  • 9.0 Alkaloids (Dayrit)*Quinolizidine alkaloids have the characteristic fused 6,6-bicyclic group and are derived from lysine. Lupinine is a dimeric metabolite while sparteine is trimeric.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Aliphatic alkaloids from polyketidesSome aliphatic alkaloids are derived from the polyketide pathway. The biogenesis of these alkaloids can be determined by studies using labeled acetyl CoA.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Polyketide-derived piperidine alkaloids. Some alkaloids having the piperidine-type structure are not derived from lysine.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Alkaloids from phenylalanine and tyrosineThe aromatic alkaloids derived from phenylalanine and tyrosine form a diverse and often structurally complex group of metabolites. By tradition, these alkaloids are identified according to plant family, of which the best known are: Papaveraceae, Morphinan, Erythria, Berberidaceae, Amaryllidaceae. Structurally and biosynthetically, there are six main groupings: 1. Phenylethylamines 2. Phenylethylamine + alkyl aldehyde or ketone 3. Phenylethylamine + benzaldehyde (C6-C1)4. Phenylethylamine + C6-C25. Phenylethylamine + C6-C36. Phenylethylamine + secologanin

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Alkaloids from phenylalanine/tyrosine. Structurally, there are six main types.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Alkaloids from phenylalanine/tyrosine. Structurally, there are six main types.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Alkaloids from phenylalanine/ tyrosine: Simple phenylethylamines. Biosynthesis of this group involves simply loss of the carboxylic acid carbon. Some important members of this group are the hallucinogenic compound mescaline and the drug epinephrine.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Alkaloids from phenylalanine/ tyrosine: Condensation of phenylethylamine with alkyl aldehydes or ketones. This group of alkaloids is formed via a Pictet-Springler or Bischler-Napieralski condensation. The alkaloids shown here are found in the hallucinogenic peyote cactus plant.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Alkaloids from phenylalanine / tyrosine + Ar-C1. Phenylethylamine couples with Ar-C1 (benzaldehyde) via a Pictet-Springler condensation. This is followed by oxidation of the phenol.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Alkaloids from phenylalanine / tyrosine + Ar-C1. The two oxidized rings can couple via different folding conformations leading to para-para, para-ortho or ortho-para coupling.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Alkaloids from phenylalanine / tyrosine + Ar-C1. (overview) Coupling of the radical intermediates in different folding conformations leads to para-para, para-ortho and ortho-para couplings. This is a theme that is repeated for other alkaloids with similar structural characteristics. The alkaloid families that comprise this group include the Amaryllidaceae and Mesembrine species.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Alkaloids from phenylalanine / tyrosine + Ar-C2. Condensation of phenylethylamine with an Ar-C2 group, such as phenylpyruvic acid, yields the benzyltetrahydro isoquinoline structure. These alkaloids are characteristic of the Papaveraceae. Reticuline is a key intermediate of this group.

    9.0 Alkaloids (Dayrit)

  • Alkaloids from phenylalanine / tyrosine + Ar-C2. The Aprophine alkaloids are produced by oxidation of reticuline. Various isomeric radical intermediates are formed.

  • *Alkaloids from phenylalanine / tyrosine + Ar-C2. Four regiochemical couplings are observed: ortho-ortho, ortho-para, para-ortho, and para-para.

  • Alkaloids from phenylalanine / tyrosine + Ar-C2. The Aprophine alkaloids are produced by radical coupling of the benzylisoquinoline system of reticuline.

  • 9.0 Alkaloids (Dayrit)*Schematic presentation of the biosynthesis of codeine, laudanine, and (S)-scoulerine from (S)-norcoclaurine in the opium poppy. The cellular localizations of the enzymes indicated have been determined experimentally. (Jorgensen et al., Curr Opinion in Plant Biol 2005, 8:280291)

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Alkaloids from phenylalanine/tyrosine + Ar-C2. The morphine alkaloids are produced from thebaine. Note that the level of methylation decreases towards the end of the biosynthetic sequence from thebaine codeine morphine.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Alkaloids from phenylalanine / tyrosine + Ar-C2. Coupling using the N-methyl group.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Alkaloids from phenylalanine / tyrosine + Ar-C3. This group is homologous to the benzyltetrahydro-isoquinolines (dopamine + C2). The biosynthetic steps are assumed to be similar.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Alkaloids from phenylalanine / tyrosine + secologanin. Secologanin is an iridoid belonging to the monoterpene group. Condensation of phenylethylamine with secologanin leads to a group of mixed metabolites.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Alkaloids from phenylalanine / tyrosine + secologanin.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Alkaloids from tryptophan: the indole alkaloids The indole alkaloids are derived from tryptophan and are found in both plants and microorganisms. They comprise the single largest group of alkaloids, accounting for almost one-fourth of all alkaloids isolated. Many of the members of this group are biologically active and some possess very important medicinal properties. Among the best known sources are: Catharanthus, Curare, Rauwolfia, and Vinca plant species and the ergot fungi. The indole alkaloids can be classified as follows: 1. Simple indole alkylamines2. Simple -carbolines3. Tryptophan + C5 4. Tryptamine + secologanin

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Indole alkaloids. Structural groups..

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Indole alkaloids. Structural groups..

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Simple indole alkaloids. Decarboxylation of tryptophan yields serotonin, a neurotransmitter; methylation yields bufotenin, a hallucinogenic compound isolated from toadstools.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Simple indole alkaloids. Bishler-Napieralski condensation of tryptamine with simple alkyl groups yields the b-carbolines. The harmanes are CNS stimulants.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Ergot alkaloids. Condensation with C5 DMAPP. This group of metabolites is produced by the fungus Claviceps purpurea and includes the hallucinogen lysergic acid.

    9.0 Alkaloids (Dayrit)

  • Indole alkaloids: tryptophan + secologanin. More than 1,100 compounds from this group of mixed metabolites have been identified. They occur predominantly in Loganiaciae, Apocynaceae, and Rubiaceae. This figure gives the major skeletal types.

  • Indole alkaloids: tryptophan + secologanin. The Vincosan alkaloids yield straight-forward incorporation of secologanin. Loss of glucose enables more extensive structural changes to occur. The glycoside is hypothesized to act as a protecting group. Many alkaloids are formed from strictosidine.

  • 9.0 Alkaloids (Dayrit)*Indole alkaloids: tryptophan + secologanin. Loss of glucose initiates the chemical transformation. Reserpine is a tranquilizer and sedative isolated from the roots of Rauwolfia serpentina.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Indole alkaloids: tryptophan + secologanin. Strychnine (from the seeds of Strychnos nux-vomica) was used in medicine as a CNS stimulant. At higher doses, it was used as poison for humans and rodents.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Indole alkaloids: tryptophan + secologanin. The cinchona alkaloids (from the bark of Cinchona spp.) involve extensive rearrangement.Quinine was used as an antimalarial drug.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Alkaloids from other pathways Other groups of alkaloids arise from various pathways. A number of them are metabolites from other biogenetic groups, but are classified as alkaloids simply because they have an amine functionality. This mixed group of alkaloids includes: the quinoline alkaloids (from anthranilic acid, shikimates) terpene alkaloids nicotine alkaloids xanthine alkaloids.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Quinoline alkaloids. Except for the cinchona alkaloids, the quinoline alkaloids are mixed metabolites being derived from anthranilic acid, which belongs to the shikimate group, and polyketides.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*The terpene alkaloids. The sequence of addition of nitrogen into the terpene is suggested to be: R-CH2-OH R-CHO R-CH2-NH2 (where R is a terpene metabolite).

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*The terpene alkaloids. Steroidal alkaloids are formed from completed steroids. Solasidine and tomatidine occur in potatoes and tomatoes, respectively.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Nicotine alkaloidsTobacco (Nicotiana tabacum) is another plant from which a large commercial sector has formed. It is a practice that originated from the American Indians. Nicotiana comes from the name of Jean Nicot, a French diplomat who probably introduced the habit to Europe; tabacum comes from the Indian name for the pipe that was used to smoke it. Nicotine, the chief constituent of N. tabacum, is formed from nicotinic acid.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Nicotinic acid. In plants, nicotinic acid is biosynthesized from tryptophan.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Nicotinic acid. In bacteria, nicotinic acid is biosynthesized from glyceraldehyde + aspartic acid.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Nicotinic acid. Mimosine, which resembles phenylalanine, is a toxin found in grass which is used as animal feed.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Nicotinic acid. Biosynthesis of nicotine. Nicotine is a ganglionic cholinergic-receptor agonist. Chronic ingestion of nicotine often results in psychological addiction and physical dependence.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Xanthine alkaloids are important components of a number of culturally, historically and commercially important plants, in particular coffee, cola (kolanut), tea and cacao (chocolate). The active constituents are methyl xanthines, the best known of which are: caffeine, which occurs in coffee (Coffea arabica); theophylline, which is found in tea (Camellia sinensis); and theobromine, which is found in cacao (Theobroma cacao). Note that theophylline and theobromine are isomers.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*The methylxanthines (caffeine, theophylline and theobromine) are CNS stimulants and smooth muscle relaxants. Research into their physiological mechanisms are continuing research topics. The biogenetic origin of xanthine is complex and arises from various primary metabolites. Carbons 2 and 8 come from an active 1-carbon fragment (e.g, formate, methyl methionine, etc.); carbon 6 comes form CO2; and carbon atoms 4 and 5 and nitrogen 7 come from glycine. The nitrogen atom at 1 comes from aspartic acid, while those at 3 and 9 come from the amide nitrogen of glutamine.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Summary Structurally, the alkaloids are a very diverse group; the only unifying characteristic is the presence of an amine. The origin of the carbons in alkaloids include the aliphatic amino acids (ornithine and lysine), aromatic amino acids (phenylalanine, tyrosine and tryptophan, which arises from shikimic acid via phenylpropanoids), anthranilic acid (from shikimic acid), polyketides, and terpenes.

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*SummaryThe alkaloids are divided into characteristic structures, which are also usually associated with specific plants or organisms. Among the best known groups of alkaloids are: Tropane alkaloids (e.g., Atropa) Pyrrolizidine alkaloids Phenylethylamines: (e.g., Ephedra) Phenylalanine + C6-C2: (e.g., Aprophine, Papaver and Erythrina) Tryptophan + DMAPP: (e.g., ergot alkaloids) Tryptophan + secologanin: (Vinca, Catharanthus, Strychnos, Cinchona) Steroidal alkaloids Nicotinic acid: (Nicotiana) Xanthine alkaloids: (Coffea, Camelia, Theobroma)

    9.0 Alkaloids (Dayrit)

  • 9.0 Alkaloids (Dayrit)*Overview of alkaloid biosynthesis. The biogenetic location of the xanthines is diverse and not included here.

    9.0 Alkaloids (Dayrit)

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    *****************************************************************************