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Biosynthesis of Terpenes

Biosynthesis of Terpenes. Chem-465. Isopentenyl Pyrophosphate:. The Biological Isoprene Unit. References. Dellas, N., Thomas, S. T., Manning, G., and Noel, J. P. (2013) Discovery of a metabolic alternative to the classical mevalonate pathway. eLife 2, e00672

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Biosynthesis of Terpenes

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  1. Biosynthesis of Terpenes Chem-465

  2. Isopentenyl Pyrophosphate: The Biological Isoprene Unit

  3. References • Dellas, N., Thomas, S. T., Manning, G., and Noel, J. P. (2013) Discovery of a metabolic alternative to the classical mevalonate pathway. eLife 2, e00672 • 2.   Vinokur JM, Korman TP, Cao Z, Bowie JU (2014) Evidence of a novel mevalonate pathway in archaea. Biochemistry 53:4161–4168.

  4. Azami Y, Hattori A, Nishimura H, Kawaide H, YoshimuraT, Hemmi H (2014) (R)-mevalonate-3-phosphate is an intermediate of the mevalonate pathway in Thermoplasmaacidophilum. J BiolChem 289:15957–15967. • 4.  Goldstein, J. L., and Brown, S. B. (1990) Regulation of the mevalonate pathway. Nature 343, 425−430

  5. Biosynthesis of terpenes may be studied in two parts: • (A) Synthesis of Activated 5-C units: • (B) Condensation of activated 5-C units IPP and DPP to form terpenes: • DPP=Dimethyallyl pyrophosphate • IPP=Isopentenyl pyrophosphate 

  6. IPP=Isopentenyl pyrophosphate

  7. DPP=Dimethyallyl pyrophosphate An allyl group is a substituent with the structural formula H2C=CH−CH2R, where R is the rest of the molecule

  8. The Biological Isoprene Unit • The isoprene units in terpenes do not come from isoprene. • They come from isopentenyl pyrophosphate. • Isopentenyl pyrophosphate (5 carbons) comes from acetate (2 carbons) via Mevalonate (6 carbons).

  9. O CH3 O CH3COH HOCCH2CCH2CH2OH OH CH3 O O H2C CCH2CH2OPOPOH The Biological Isoprene Unit 3 Mevalonic acid Isopentenyl pyrophosphate

  10. CH3 O O H2C CCH2CH2OPOPOH OPP Isopentenyl Pyrophosphate or Isopentenyl pyrophosphate

  11. OPP OPP Isopentenyl and Dimethylallyl Pyrophosphate Isopentenyl pyrophosphate is interconvertible with2-methylallyl pyrophosphate. • Dimethylallyl pyrophosphate has a leaving group (pyrophosphate) at an allylic carbon; it is reactive toward nucleophilic substitution at this position. Isopentenyl pyrophosphate Dimethylallyl pyrophosphate

  12. Carbon-Carbon Bond Formation in Terpene Biosynthesis

  13. OPP + OPP Carbon-Carbon Bond Formation • The key process involves the double bond of isopentenyl pyrophosphate acting as a nucleophile toward the allylic carbon of dimethylallyl pyrophosphate.

  14. OPP + OPP – OPP + OPP Carbon-Carbon Bond Formation

  15. + OPP After C—C Bond Formation... • The carbocation can lose a proton to give a double bond.

  16. + – H + OPP After C—C Bond Formation... • The carbocation can lose a proton to give a double bond. OPP

  17. After C—C Bond Formation... • This compound is called geranyl pyrophosphate. It can undergo hydrolysis of its pyrophosphate to give geraniol (rose oil). OPP

  18. OH After C—C Bond Formation... OPP H2O Geraniol

  19. OPP + OPP Geranyl pyrophosphate + OPP From 10 Carbons to 15

  20. OPP + – H + OPP From 10 Carbons to 15

  21. OPP From 10 Carbons to 15 • This compound is called farnesyl pyrophosphate. • Hydrolysis of the pyrophosphate ester gives the Alcohol farnesol

  22. OPP OPP From 15 Carbons to 20 • Farnesyl pyrophosphate is extended by another isoprene unit by reaction with isopentenyl pyrophosphate.

  23. + OPP OPP Cyclization • Rings form by intramolecular carbon-carbon bond formation. E double bond Z double bond

  24. + – H + Limonene OH H2O a-Terpineol

  25. + Bicyclic Terpenes + + + a-Pinene b-Pinene

  26. The Pathway from Acetate to Isopentenyl Pyrophosphate

  27. Thiolases, also known as acetyl-coenzyme A • Acetyltransferases (ACAT), are enzymes which convert two units of acetyl-CoA toacetoacetylCoA in the mevalonate pathway.

  28. O CH3 O CH3COH HOCCH2CCH2CH2OH OH CH3 O O H2C CCH2CH2OPOPOH Recall 3 Mevalonic acid Isopentenyl pyrophosphate

  29. Structure of acetyl co enzyme A

  30. S-Aceto Acetyl coenzyme a

  31. O O CH3CCH2CSCoA Biosynthesis of Mevalonic Acid • In a sequence analogous to the early steps of fatty acid biosynthesis, acetyl coenzyme A is converted to S-acetoacetyl coenzyme A. S-Acetoacetylcoenzyme A

  32. O O O CH3CCH2CSCoA CH3CSCoA Biosynthesis of Mevalonic Acid • In the next step, S-acetoacetyl coenzyme A reacts with acetyl coenzyme A. • Nucleophilic addition of acetyl coenzyme A (probably via its enol) to the ketone carbonyl of S-acetoacetyl coenzyme A occurs. +

  33. O O O CH3CCH2CSCoA CH3CSCoA HO O CH3CCH2CSCoA CH2COH O Biosynthesis of Mevalonic Acid +

  34. HO O CH3CCH2CSCoA CH2COH O Biosynthesis of Mevalonic Acid • Next, the acyl coenzyme A function is reduced. • The product of this reduction is mevalonic acid.

  35. HO CH3CCH2CH2OH CH2COH O HO O CH3CCH2CSCoA CH2COH O Mevalonicacid

  36. 2– HO OPO3 CH3CCH2CH2OH CH3CCH2CH2OPP CH2COH CH2COH O O Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate • The two hydroxyl groups of mevalonic acid undergo phosphorylation.

  37. 3– OPO3 2– OPO3 CH3CCH2CH2OPP – •• CH2 O C •• •• O C O O Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate • Phosphorylation is followed by a novel elimination involving loss of CO2 and PO43–. CH3CCH2CH2OPP CH2

  38. CH3CCH2CH2OPP CH2 Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate • The product of this elimination is isopentenyl pyrophosphate.

  39. O CH3 O CH3COH HOCCH2CCH2CH2OH OH CH3 O O H2C CCH2CH2OPOPOH Biosynthetic pathway is based on experiments with 14C-labeled acetate Mevalonic acid Isopentenyl pyrophosphate

  40. CH3 O O O CH3COH H2C CCH2CH2OPOPOH • • O • • • • H Biosynthetic pathway is based on experiments with 14C-labeled acetate • Citronellal biosynthesized using 14C-labeled acetate as the carbon source had the labeled carbons in the positions indicated.

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