SCH 511 Biosynthesis of Terpenoids - University of …. Solomon Derese 3 SCH 511 Terpenoids, also known as isoprenoids or terpenes, are naturally occurring organic compounds constructed

Dr. Solomon Derese 1

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Isoprenoids = Terpenes = Terpenoids

Compounds Derived from 5 Carbon Units

Biosynthesis of Terpenoids


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Learning Objectives

• Recognize the role of carbocations interpene biosynthesis

• Describe how carbocations are formedfrom pyrophosphate precursors

• Describe important reactions ofcarbocations in terpene biosynthesis

• Propose reasonable biosyntheticpathways to a variety of terpenes.


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Terpenoids, also known as isoprenoidsor terpenes, are naturally occurringorganic compounds constructed fromthe joining together of a five carbonprecursor.

Thus they have C5, C10, C15, C20, C25, C30,C40, Cn (n is more than 40) skeletal.


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They are subdivided, based on the number of C5units used to construct the terpenoids, into:

Hemiterpenes (C5), Monoterpenes (C10), Sesquiterpenes (C15), Diterpenes (C20), Sesterpenes (C25), Triterpenes (C30), Tetraterpenes (C40), and Polyterpenes (Cn , n > 40)


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The terpenes are a structurallydiverse and widely distributedfamily of natural productscontaining well over 30,000defined compounds identifiedfrom all kingdoms of life.


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The majority of terpenes have been isolatedfrom plants where they serve a broad rangeof roles in primary metabolism (includingseveral plant hormones and the mostabundant plant terpenoid, phytol, the sidechain of the photosynthetic pigmentchlorophyll) and in ecological interactions[as chemical defenses against herbivoresand pathogens, pollinator attractants,allelopathic agents].


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Chlorophyll


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O

H

Citronella

Monoterpenes [C10]

CO2H

Chrysanthemic acid

fragranceinsecticide

Sesquiterpenes [C15]

Humuleneaphid repellant

Farensene

Examples


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Diterpenes [C20]

Anti-fungal agent


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Anti-malarial drug from Artemisia annua

Artemisinin

12

Biosynthesis of TerpenesMethylerythritol Phosphate

(MEP)or

Diterpenes (C20)

Sesquiterpenes (C15)

Monoterpenes (C10)

Hemiterpenes (C5)


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The five-carbon building blocks of all terpenoids,isopentenyl diphosphate (IPP) and dimethylallyldiphosphate (DMAPP), are derived from twoindependent pathways localized in different cellularcompartments.The cytosol localized Mevalonate pathway providesC5 units for sesquiterpene and triterpenebiosynthesis.The methylerythritol phosphate (MEP ornonmevalonate) pathway, localized in the plastids,is thought to provide IPP and dimethylallyldiphosphate for hemiterpene, monoterpene, andditerpene and tetraterpene biosynthesis.


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CYTOSOL PLASTIDAcetyl CoA

Mevalonic Acid

Sesquiterpenesand

Triterpenes

G3P Pyruvate+

MethylErythritol Phosphate (MEP)

Hemiterpenes, monoterpenes, diterpenes,

and tetraterpene


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The Mevalonic Acid Pathway


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Biosynthesis of Mevalonic Acid

Three molecules of acetyl-coenzyme A are usedto form mevalonic acid. Two molecules combineinitially in a Claisen condensation to giveacetoacetyl-CoA, and a third is incorporated viaa stereospecific aldol addition giving thebranched-chain ester β-Hydroxy-β-MethylGlutaryl-CoA (HMG-CoA).

(3R)-Mevalonic Acid


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H2C SCoA

O

H

B Enz

H2C SCoA

O

H2C SCoA

O

O

S

O

CoA

Acetoacetyl CoA

Claisen

The mevalonate pathway doesnot use malonyl derivativesand it thus diverges from theacetate pathway at the veryfirst step.


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H3C SCoA

OEnz-SH

H3C SEnz

O :B-Enz

H2C SEnz

O

O

S

O

CoA

H-B-Enz

β-Hydroxy-β-MethylGlutaryl-CoA (HMG-CoA)

Stereospecific aldol reactionIn the second step, it should be noted that, onpurely chemical grounds, acetoacetyl-CoA isthe more acidic substrate, and might beexpected to act as the nucleophile rather thanthe third acetyl-CoA molecule. The enzymethus achieves what is a less favourablereaction.


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HMG-CoA Reductase

HMG-CoA

2 NADPH

(3R)-Mevalonic Acid

H2O The conversion ofHMGCoA into (3R)-MVA involves a two-step reduction of thethioester group to aprimary alcohol.


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The six-carbon compound MVA istransformed into the five-carbonphosphorylated isoprene units in aseries of reactions, beginning withphosphorylation of the primaryalcohol group. Decarboxylation /dehydration then give IPP.


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(3R)-Mevalonic Acid

H+

Isopentenyl pyrophosphateIPP

3,3-Dimethylallyl pyrophosphate

DMAPP


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IPP is isomerized to the other isoprene unit,DMAPP, by an isomerase enzyme whichstereospecifically removes the pro-R proton(HR) from C-2, and incorporates a protonfrom water on to C-4. Whilst theisomerization is reversible, the equilibriumlies heavily on the side of DMAPP.


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H+

Isopentenyl pyrophosphateIPP

3,3-Dimethylallyl pyrophosphate

DMAPP

Mevalonic acid/ MethylErythritol Phosphate (MEP)


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OPP

DMAPP

DMAPP possesses a good leaving group, thediphosphate, and can yield via an SN1 process anallylic carbocation which is stabilized by chargedelocalization.

This generates a reactive electrophile and thereforea good alkylating agent, DMAPP reacts as anelectrophile.


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In contrast, IPP with itsterminal double bond ismore likely to act as anucleophile, especiallytowards the electrophilicDMAPP.

IPP

DMAPPSN1

Electrophile(Electron deficient)

Nucleophile(Electron rich)


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These differing reactivities are the basisof terpenoid biosynthesis, andcarbocations feature strongly inmechanistic rationalizations of thepathways.

Therefore, terpenoids are synthesized byjoining IPP (a nucleophile) and DMAPP(an electrophile) in a head to tail manner.


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C C

C C

C.

C C

C

C C

.

Head

Tail

Head

Tail

OPP

OPP DMAPP

SN1

OPP

Head

Tail Head


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OPP

OPP

- OPP

OPP

Reaction of IPP and DMAPP

OPP

HH


SCH 511Joining Isoprene UnitsHead-to-Tail

Tail-to-Tail

Larger terpenoid units dimerize tail-to-tail.

Tail to Middle


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Limonene

Terpenes can be shown to be formed fromisoprene units.

Diagram showing howtwo isoprene unitscombine to form thelimonene skeleton.

SCH 511 Biosynthesis of Terpenoids - University of …. Solomon Derese 3 SCH 511 Terpenoids, also known as isoprenoids or terpenes, are naturally occurring organic compounds constructed

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