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Ergot alkaloids

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Ergot alkaloids

  2. 2. ALKALOIDS  Alkaloids are a group of naturally occuring chemical compounds that mostly contain basic nitrogen atoms.  Alkaloids are produced by a large variety of organisms including bacteria, fungi, plants, and animals.  They can be purified from crude extracts of these organisms by acid-base extraction 2
  3. 3. Chemistry Colour less Crystalline Non – volatile solids are soluble in organic solvent Insoluble in water 3
  4. 4. Ergot alkaloids  Ergot alkaloids are nitrogen-containing natural products belonging to indole alkaloids.  The best known producers are fungi of the phylum Ascomycota, e.g., Claviceps, Epichloë, Penicillium and Aspergillus species. 4
  5. 5. Occurrence:  Ergot alkaloids were first developed from the sclerotium of the parasitic ascomycete Claviceps purpurae, which developes on rye and other grasses.  The term ERGOT is used to refer both to the fungus developing in the rye plant and to the alkaloids which are produced by the fungus.  Presently there are 40 known ergot alkaloids produced by various Claviceps strains. 5
  6. 6. Pharmacological properties:  Stimulation of the sympathetic nervous system.  Ergovanine is used to hasten labor and prevent postpartum bleeding.  Ergotamine is a compound produced by Claviceps purpurea and is a powerful vasoconstrictor, which means it constricts the blood vessels and thus the blood flow.  A mixture of dihydrocompounds from ergocristine , ergocriptine , and ergocornine is used for treatment of disturbances of preipheral and central circulation system 6
  7. 7. Claviceps purpurae 7
  8. 8. Developemental Cycle of claviceps 8
  9. 9. 9
  10. 10. Producersof alkaloids Organism Plant host Alkaloid content Alkaloids produced Claviceps purpurae Rye wheat 0.1-0.5 Ergocornine Ergocryptine Ergosine C. fusiforims Pennisetum typhoids 0.3 Chanoclavine Elymoclavine Ergometrine C.gigantae Zea mais 0.03 Pyroclavine Festuclavine C.paspali Paspalum spp 0.003 D-Lysergic acid α-Hydroxyethyl lysergamide 10
  11. 11. structure  Ergot alkaloids are classified among the indole alkaloids and are derived from the tetracyclic ergoline ring system.  Ergot alkaloids are classified into two classes 1) Clavine alkaloids or Clavines : Have ergoline as a basic structure but contain no peptide bonds. EX: Festuclavine , Dihydroelymoclavine , etc., 2) Lysergic acid alkaloids or Ergo alkaloids :In these component D-lysergic acid is linked with tricyclic peptide. EX: Ergometrine , Ergocorine , etc., 11
  12. 12. Contd., 12
  13. 13. biosynthesis  Alkaloids synthesis occurs upon the endoplasmic reticulum in claviceps when it is grown in submerged culture. FORMATION OF ERGOMETRINE FROM MEVALONATE Mevalonate Isopentenyl pyrophosphate Dimethylallyl pyrophsphate 13
  14. 14. Tryptophan Dimethylallyl tryptophan a Chanoclavine Agroclavine Elymoclavine 14
  15. 15. 8,2 Lysergic acid Lysergic acid Lysegylalanine Α-Hydroxyethyllysergamide Ergometrine 15
  16. 16. Formation of the ergoline scaffold-biosynthetic pathway 16
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  20. 20. Production of ergot alkaloids There are a number of methods of obtaining ergot alkaloids:  Chemical synthesis  Culture of Claviceps strains on the respective host  Microbial fermentation  Surface culture  With immobilized cells Culture on the host plant or in submerged culture are the process most used commercially. 20
  21. 21. Chemical synthesis  Total chemical synthesis of ergot alkaloids is possible, but currently this is not cost-effective.  Lysergic acid which is produced fermentatively can be chemically transformed into the desired alkaloids.  Ergoline derivatives used medically using this method, with the exception of peptide bonds. 21
  22. 22. Surface culture: A process has been described for the large- scale production of ergot alkaloids using surface cultures of C.purpurae grown under sterile conditions. The advantage of this process is that a higher prportion of the more desirable ergotamine and ergotoxine alkaloids are formed. 22
  23. 23. Semicontinuous transformation with immobilized mycelium 23  A process has been developed for semicontinuous alkaloid production using immobilized mycelium of Claviceps purpurae and C.fusiformis.  C.purpurae which forms Ergometrine and and mixture of chanoclavin , agroclavin and elymoclavin , the best results has been obtained by immobilization in 4% calcium alginate gel.
  24. 24. Contd., 24  Concentration of algine increases to 8% - yield of alkaloid increased by 35%, but the main product is agroclavin due to reduced Oxygen diffusion.  To prevent contaminaton problem during the long incubation period with the immobilized mycelium, an antibiotic chloromphenicol was added.
  25. 25. Production by fermentation  Three species of Claviceps are currently used in the production of alkaloids by fermentation. C.paspali C.fusiformis C.purpurae  Submerged culture produced about 20mg alkaloid/l  Strain development and culture medium optimization resulted in a commercial process which had alkaloid titres of 5g/l 25
  26. 26. Stages of fermentation process: Homogenized mycelium of a 5-10day agar slant culture conidium suspension Growth in shake flask Preculture 48 hour Production culture 26
  27. 27. Regulationn of alkaloid production in cultures:  To produce alkaloids the medium must contain an organic acid of the TCAcycle or a related compound as well as carbohydrate.  Mannitol and succinate : production of lysergic acid.  Sucrose and citrate : production of Ergotamine and Ergocristine.  Ergot alkaloid production exhibits a typical phosphate regulation. 27
  28. 28. Contd.,  In the trophophase (3-4 days), after free phosphate used up, growth ceases and the culture enters the idiophase.  Tryptophan induces alkaloid synthesis and serves as a precursor.  In submerged culture, synthesis of the alkaloid is increased considerably when aspargine is used as a Nitrogen source instead of ammonium salts. 28
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