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POLYKETIDES, ACETOGENINS

POLYKETIDES, ACETOGENINS. C C. C-C. C-C. C-C. C-C. C-C. C-C. C-C. C-C. C C. C C. C-C. C-C. C-C. C-C. C-C. C-C. C-C. C-C. C-C. C-C. C-C. C-C. C-C. C-C. C-C. C-C. ACETYL COENZYME A. A TWO-CARBON BUILDING BLOCK. Acetyl CoA. Can be used like a

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POLYKETIDES, ACETOGENINS

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  1. POLYKETIDES, ACETOGENINS

  2. C C C-C C-C C-C C-C C-C C-C C-C C-C C C C C C-C C-C C-C C-C C-C C-C C-C C-C C-C C-C C-C C-C C-C C-C C-C C-C ACETYL COENZYME A A TWO-CARBON BUILDING BLOCK Acetyl CoA Can be used like a molecular “Lego” piece ….. well , sort of …..

  3. CLAISEN CONDENSATION LIKE THE ALDOL CONDENSATION BUT WITH ESTERS REVIEW REMEMBER CHEM 353 a b-ketoester CH3CH2OH Acidic a-hydrogens are removed in strong base to make an enolate anion which adds to the C=O of another molecule. - .. .. : : : .. -

  4. CONCATENATION OF “ACETATE UNITS” acetic acid acetyl CoA acetate unit

  5. ACETYL CoA UNITS ARE LINKED BY A CLAISEN-LIKE CONDENSATION Strong bases are not tolerated by biological systems. Nature does these condensations using malonyl CoA. WHY THIOESTERS ? Differences between an oxygen ester and a thioester: Thioesters are more prone to enolization. Thioesters are more reactive. :B ATP ADP Biotin malonyl CoA Biotin-COOH

  6. THE ENZYMES THAT ASSEMBLE ACETYL-CoA UNITS USE A DECARBOXYLATION OF MALONYL-CoA A “FREE” ENOLATE ION IS NEVER FORMED Enz-B: .. “CHAIN EXTENDER” malonyl CoA Enz-B: .. x2 - CO2 x1 acetyl CoA x3 “STARTER” x5 x4 a polyketide chain

  7. THERE ARE TWO CARBONYL GROUPS IN THE 2-UNIT POLYKETIDE CHAIN EITHER ONE CAN REACT .. 1 2 - CO2 LINEAR BRANCHED mevalonic acid POLYKETIDE CHAINS TERPENES STEROIDS ACETOGENINS

  8. THE ASSEMBLY ENZYMES acetyl - malonyl transferases acetylCoA starter H+ .. cys -S cys -SH :B .. - CO2 -SH -S :B malonylCoA .. extender - CO2 -SH etc. -S :B .. more malonylCoA’s -SH - CO2 .. -S -SH acyl carrier protein (ACP)

  9. H+ S -S-H -SH -S -SH -S H+ S -S -S -SH -SH -S BUILDING THE CHAIN ON A FLEXIBLE LINK ANOTHER MODEL OF THE ENZYME - CO2 transfer Malonyl-CoA Growing chain - CO2 etc

  10. POLYKETIDES ACCETOGENINS

  11. WE WILL LOOK AT POLYKETIDES FIRST 1 2 3 4 Polyketides are the precursors of the class of natural products called “acetogenins” internal aldol condensation H2O hydrolysis - CoASH enolization - H2O Orsellinic acid dehydration ( Lichen spp ) makes aromatic ring an “acetogenin” made from acetate units

  12. SOME OTHER SIMPLE ACETOGENINS internal Claisen 1) enolization 2) SAM Eugenone ( oil of cloves ) (found in Lichen )

  13. ANTHRAQUINONE LAXATIVES physicon emodin Penicillium spp Rhamnus spp Rumex spp Senna Casacra Rhubarb Aloes Frangula rhein aloe-emodin cascaroside

  14. GRISEOFULVIN Penicillium griseofulvin Anti-fungal, antibiotic for toenail and skin infections absorbed from stomach, concentrated in skin. SAM .. Aldol Cl+ Claisen reson. [O] . . . . FADH2 SAM griseofulvin

  15. MACROLIDES (LARGE RINGS) aldol 9 units aromatize NADPH lactonize .. NADPH, then dehydrate NADPH, then dehydrate, then FADH2 “macrolide” antibiotic acetylCoA + 8 malonylCoA The various reductions may be performed during the chain extension steps rather than afterward. zearalenone Gibberalla zeae

  16. DIFFERENT STARTERS AND EXTENDERS THE METHOD IS NOT RESTRICTED TO ACETATE UNITS ONLY

  17. MALONAMYL CoA STARTER malonamylCoA starter H+ .. cys -S cys -SH :B .. - CO2 -SH -S :B malonylCoA .. extender - CO2 -SH etc. -S :B .. more malonylCoA’s -SH - CO2 .. -S -SH acyl carrier protein (ACP)

  18. TETRACYCLINES actually starts from malonamyl CoA which can also form polyketides chlortetracycline malonamyl CoA aureomycin ….. since our main interest is alkaloids we will not study this series of compounds further, however, there are alkaloids that incorporate acetogenin pieces into a part of their structure.

  19. ERYTHROMYCIN A EXTENDER unchanged reduced dehydrated reduced methylmalonylCoA BUILT FROM 3-CARBON UNITS reduced 6x reduced reduced reduced propionylCoA STARTER lactonization oxidized oxidized D-desoamine oxidations add sugars L-cladinose erythromycin A

  20. QUINOLINE AND ACRIDINE ALKALOIDS 1x malonylCoA QUINOLINE TYPE ALKALOIDS STARTER 3x malonylCoA anthraniloyl-CoA from anthranilic acid, originating from another pathway (shikimic acid) ACRIDINE ALKALOIDS

  21. NARINGENIN - A FLAVONOID STARTER 3x malonyl-CoA 4-hydroxycinnamoyl-CoA aldol comes from the shikimic acid pathway A FLAVONOID Michael addition naringenin found in grapefruit flowers, fruit and rind as the 7-rhamnogylcoside

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