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Shikimic Acid Pathway

Shikimic Acid Pathway. Shikimic Acid Illicium anisatum L. Illicinaceae {Shikimino-ki in Japanese} (1885) E. coli mutant strains pathway intermediate. Shikimic Acid Pathway. Important for aromatic compounds

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Shikimic Acid Pathway

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  1. Shikimic Acid Pathway Shikimic Acid Illiciumanisatum L. Illicinaceae {Shikimino-ki in Japanese} (1885) E. coli mutant strains pathway intermediate

  2. Shikimic Acid Pathway • Important for aromatic compounds • Precursor of aromatic amino acids (Phe, Tyr, Try) biosynthesis in bacteria, fungi & higher plants. ANIMALS! HUMAN! • Building block for other compounds: certain alkaloids, coumarins, phenyl propanes, vol. oils,.. • Starting point for tannins in all plants • Provide protection of plants against micro-organisms

  3. Biosynthesis of shikimic acid

  4. Scheme of the conversion of shikimic acid to cinnamic acid Shikimic acid → Chorismic acid → Prephenic acid → p-OH-phenylpyruvate ↓ ↓ ↓ Anthranilic acid Phenylpyruvate Tyrosine→alkaloids ↓ ↓ ↓ Tryptophan Phenylalanine p-coumaric acid ↙ ↓↓ ↘ ↙ Cinnamic acid ↘ p hytohormones (indol-3- ace tic acid Alkaloids alkaloids

  5. Possibilities of derivatives of cinnamic acid • 1-Substitution in aromatic ring • 2-State of the oxidation of the side chain • -CH=CH-COOH →Propenic acid, cinnamic acids • -CH=CH-CH2OH → Propenol, coniferylalcohols • CH2-CH=CH2 →Allyl, Eugenol (volatile oil) • -CH=CH-CH3 → Propenyl, Anethol (volatile oil) • -CH2-CH2-CH3 →n-propyl • 3- Shortening of the side chain Formation of phenol carboxylic acids and simple phenols

  6. Cinnamic acids Cinnamic acid p-coumaric acid Caffeic acid Ferulic acid Sinapic acid 5-OH-ferulic acid Tri-OH-cinnamic acid

  7. Formation of Phenylpropane Derivatives with Shorter Side Chain: Shortening of side chain by β-oxidation and subsequent decarboxylation (simple phenols) which might be linked to oxidation→hydroquinone→quinone

  8. Benzoic acids related to cinnamic acids Cinnamic acid ………………...Benzoic acid p-coumaric acid……………….p-OH-benzoic acid Caffeic acid………………........Protocatechuic acid Ferulic acid………………………Vanillic acid Sinapic acid……………………..Syringic acid Tri-OH-cinnamic acid……….Gallic acid

  9. Derivatives of dehydroshikimic acid

  10. Vanilla planifolia (Orchidaceae) • Vanillin produced from eugenol (in plants) or lignin is a degradation by-product of paper from wood (large scale preparation of vanillin) • Fermentation under blankets in the sun Eugenol Coniferylalcohol (lignin) Vanilloside (odourless ) is liberated during fermentation & oxidized to vanillin • Fine aroma and taste is due to other compounds better than pure vanillin

  11. Coumarins Name derived from Coumarouna (local Guyana name) for the seeds of Dipteryx odorata (Fabaceae) common name for Tonka bean Seeds as spirits spice (not used now, hepatotoxic & carcinogenic) Characteristic new mown hay smell Commonly used as sun UV protector Absorb short wave UV 230-315 nm & transmit long-wave UV 315 - 400 nm resulting in brown sun tan

  12. Characters of Coumarins • Free coumarins are organic solvents-soluble • Derivatives of α-chromone, differ in benzene ring substitutions (OH, OCH3, CH3) • Common in Apiaceae, Asteraceae, Fabaceae, Lamiaceae, Poaceae, Moraceae, Rutaceaea & Solanaceae • Characteristic UV (blue, yellow & purple) enhanced by ammonia • Umbelliferone R1=OH, R2=H • Aseculetin R1=R2= OH • Scopoletin R1=OCH2, R2= OH • Aseculus hippocastanum (horse-chestnut) (Hippocastanaceae) rich in aesculin (6β-D-glucosyloxyl-7-OH-coumarin ); used in sun tan preparations (both glycoside & aglycone) • Symptomatic Rx of cutaneous capillary fragility

  13. Biosynthesis of the coumarins

  14. Dicoumarol • Melilotus officinalis (Fabaceae) mould-infected sweet clover • Discovered by studying grazing cattle coagulation pattern (sweet clover disease) • Dicoumarol replaces vitamin K in prothrombin result in anti-coagulant effect • Prevention of thrombosis • Pharmaceutical industry: synthetic derivatives for p.o preparations • Extract: p.o & topically to Rx minor vascular disorders & acute attacks of piles

  15. Furanocoumarins (Photosensitizers) • Furan ring is derived from isopentyl pyrophosphate (mevalonic acid pathway) • 6,7 or 7,8 furanocoumarins • Furanocoumarins-rich plant families: Apiaceae, Fabaceae, Moraceae & Rutaceae • Roots, fruits or seeds

  16. Furanocoumarin Natural Derivatives • Psoralea corylifolia (Fabaceae) fruits • Ammi majus (Apiaceae) fruits الخلّة الشيطاني • Ammi visnaga !!! • Cause dermatitis after consumption or direct contact of skin with such plants followed by exposure to sun (only 6,7-furanocoumarins; 7,8-furanocoumarin derivatives are inactive) Medicinal value: • Photo chemotherapy: Rx of vitiligo as part of PUVA for repigmentation of skin • UVA= 320nm + p.o+ topical psoralen or derivatives Psoriasis: abnormal epidermal production of scaly skin

  17. Example of Medicinally-valuable Furanocoumarins • Commonly known as Psoralens • Psoralen R1=R2= H • Bergapten R1= OCH3, R2=H [5-MOP] • *Xanthotoxin R1= H , R2= OCH3 * Xanthotoxin= Methoxsalen = 8-MOP nat. or semisynthetic derivative of psoralen p.o medication • Imperatorin R1=H , R2 = CH2-CH=C(CH3)2 • Trioxalon = TMP 4,5,8-trimethylpsoralen (synthetic) topical or bath sol. Then exposure to UVA @ 320-380 nm

  18. MOP of PUVA & Toxicity • Interfere with DNA by forming bridges between its base pairs (pyrimidine part) • Double bonds of furanocoumarin are activated by UV radiation • Inhibits replication & transcription of DNA & synthesis of RNA & cell division • Rx of psoriasis is based on the basis of DNA synthesis, inhibitory effect by furanocoumarins

  19. Photosensitization Mechanism: Binding of activated 3,4- double bond in furanocoumarin with 5,6-double bond of pyrimidine base pair in DNABinding of 4’,5’-double bond of psoralen molc. with a second molecule of pyrimidine base of another base pair

  20. Lignin & Lignans • Lignin is plant polymer acting as strengthening material for plant cell wall & matrix for cellulose micro-fibrils • Represent a large no. of aromatic material based on C6C3 building unit • Lignins formed by oxidative coupling of hyroxycinnamyl alcohol monomers by peroxidase enzymes [p-coumaryl-, coniferyl- and sinapyl-alcohol] • Lignans are dimeric phenylpropanes (C-18) coupled at the central carbon of the side chain [via their ß-carbon of the side chain]

  21. Formation of the lignans Dimers of cinnamic acid linked via their ß-carbons and further modifications; i.e. Podophyllotoxin ↓ ↓

  22. Podophyllotoxin: 2 C6C3[Coniferylalcohol]via several intermediates • Dried root & rhizhome of Podophyllum peltatum [May apple, mandrake] (Berberidaceae) USA & Canada • Structure elucidated in 1930’s; planar structure with 4 chiral centers • C2H5OH extract = Podophyllin (20% podophyllotoxin, 10% β-peltatin, 5% α-peltatin) • Traditionally as cathartic, purgative, antiviral, warts remedy • Trans lactone ring is essential for anti-tumor action; aromatization of ring C↓activity. Too toxic to be used clinically! • [OH-] converts into inactive isomer (e.g.epi-podophyllatoxin) • Classified as microtubule inhibitor [inhibits polymerization of tubulin and stop cell division at the beginning of metaphase]

  23. Etoposide and teniposide • As semisynthetic anticancer agents developed from 4’-demethylepipodophyllotoxin • They act as Topo II inhibitors (prevention of DNA synthesis and replication) • Etoposide : small cell lung cancer, breast cancer, leukemia & Hodgkin’s disease,… Teniposide : brain and bladder cancer,… • Glycosides < active than genins < side effects

  24. Podophyllotoxin & Peltatins • Lignans formed by oxidative coupling of 2 cinnamic acid residues (dimeric phenylpropane derivatives) known as LIGNANS

  25. Tannins & Gallic acid • Gallic acid is the building block of many tannins Properties of Tannins: • H2O solubility !! (colloidal aq. Solution in A` PH) • Binds proteins to form indigestible complex (leather tanning) • Amorphous • Astringent taste (unripe fruits, in all organs or organ-specific) • Fe+2 salts binding producing dark blue or greenish black sol. Complexes (ink) • Ppt with metals e.g. Cu, Pb (acetate salts to separate tannins from extracts); ppt gelatin and alkaloids; • Large MW (1000-5000) • Pseudotannins (MW~500)

  26. Hydrolysable tannins • Possibilities of condensation of the gallic acid

  27. Hydrolysable H+ or enzymes Rx produce simple molecules A)Ellagitannins B) Gallotannins Condensed H+ or Enzymes Rx produce complex insoluble compounds Complex polymers Biosynthesis from acetate or shikimate pathway Building units are catechins + flavonoids estrefied with gallic acid Classification of Tannins

  28. Medicinal Value of Tannins Limited Application: Based on ability to bind proteins to form indigestible complex • Diarrhea • Bleeding gums • Skin injuries preparations

  29. Hamamelis • Dried leaves of Hamamelis virginiana L. (Hamamelidaceae) • North America & Canada • Gallotanins Uses: • Infussions & extracts in haemorrhoids (topical pharmaceuticals) • Topically skin inflammation • Face lotions as astringent

  30. Galls • Vegetable growths as a result of insect infections of the leaves & twigs of Quercus infetoria (Fagaceae) • 70-80% tannins from Turkey, Syria, Greece & Iran Uses: • Rx of catarrh & infection • Stop bleeding locally • Alkaloid poisoning remedy (insoluble comlex) • Ink preparation • Textiles dyeing esp. leather

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