Alkaloids - Introduction and importance to humans = small organic molecules (secondary metabolites) of plants which contain nitrogen (typically in a ring) - alkaloids are pharmaceutically significant - traditional and modern uses (25%/75% of drugs are plant derived, mostly alkaloids) - many have neurological effects - presumed due to the presence of nitrogen (mimic neutrotransmitters) - potent toxins and defenses - many highly toxic compounds, and with strong biological effects - interesting chemical ecology and co-evolution with insects Many human physiological effects Quinine (Cinchona officinalis) - antibiotics (anti-malarial) Morphine (Papaver somniferum - painkiller (analgesic) Taxol - (Taxus brevifolia) - anticancer drug Vinblastine (Catharanthus roseus) - anticancer drug Coniine (Conium maculatum) - toxin Nicotine (Nicotiana tabacum) - insecticide, stimulant Atropine(Atropa belladonna) - dilate pupils Cocaine (Erythroxylon coca) - Caffeine (Coffea arabica) - stimulant Tubocurarine (Chondodenron tomentosum) - muscle relaxant during surgery Examples of mechanism of action: - block neuroreceptors (morphine, codeine) - block reuptake of neuroreceptor (cocaine-dopamine) - disrupt cytoskeleton - tubulin (taxol) - mimic neurotransmitter action (nicotine-acetylcholine) - block signaling (cAMP phosphodiesterase - caffeine) Features and Characteristics - N makes them basic in solution -> called alkaloids for this reason - structurally diverse: 12,000+ structures - 20% of all plant species have alkaloids - concentrated in specific plant taxa (families, genera, species), but these are scattered around the plant kingdom (independent evolution of alkaloids many times) - biosynthetically diverse (arise from different amino acids) - strong biological effects (see ecological examples) Alkaloid Families and General Rules for Biosynthesis - families classified by ring structure (see Fig 16.1] - derived from key amino acids [exception: purine alkaloids, from xanthine] 2 Key amino acid for alkaloid synthesis: tyrosine --> morphine, codeine (poppy alkaloids) tryptophan --> quinine (quinoline alkaloids) vinblastine (indole alkaloids) glutamate (via ornithine) --> cocaine (tropane alkaloids) -- > nicotine (tobacco alkaloids) -- > senecionine (pyrrollizidine alkaloids) aspartate -> nicotine (other portion) xanthine (from purine nucleotide synthesis) --> caffeine, theobromine (purine alkaloids) In addition: - protoalkaloids have N, but not in ring (taxol) - pseudoalkaloids (N added late) (solanidine) - non-protein amino acids can be toxic, but are not alkaloids General features of alkaloid biosynthesis: - many biosynthetic steps are required -> complex structures - any one plant typically accumulates a mix of related alkaloids - usually begins with decarboxylation of amino acid (eg) tyr -> tyramine, trp -> tryptamine - central intermediate can give rise to different final products: (strictosidine for diverse quinoline alkaloids, reticuline for isoquinoline and poppy alkaloids) 3 Alkaloids often have organ-specific synthesis / storage: (bark, roots, flowers) - also: cell-specific synthesis / storage: (latex ducts and laticifers (poppy alkaloids), epidermis (Vinca alkaloids), idioblasts) Example 1 - Localization of enzymes for poppy alkaloids in root and leaf idioblasts (berberine bridge enzyme BBE) phloem parenchyma (OMTs and AT), capsule and stem laticifers (COR - codeinone reductase, final morphinan products) Example 2 - Case study of dimeric monoterpene indole terpenoid alkaloids (MIAs) from Vinca - sequestered within cells and special structures - biosynthesis of components in different cell types (phloem parenchyma (DXP pathway), epidermis (TDC, STR) , idioblasts (DAT). - distribution of end products: catharanthine in epidermis and vindoline in laticifer (see Roepke et al. PNAS 107 p.15291 (2010): - potential of dimeric subunit linkages during plant damage and defense reactions ? 4 5 .