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Dr. Solomon Derese 1
SCH 511
Isoprenoids = Terpenes = Terpenoids
Compounds Derived from 5 Carbon Units
Biosynthesis of Terpenoids
Dr. Solomon Derese 2
SCH 511
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.
Dr. Solomon Derese 3
SCH 511
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.
Dr. Solomon Derese 4
SCH 511
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)
Dr. Solomon Derese 5
SCH 511
The terpenes are a structurallydiverse and widely distributedfamily of natural productscontaining well over 30,000defined compounds identifiedfrom all kingdoms of life.
Dr. Solomon Derese 6
SCH 511
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].
Dr. Solomon Derese 8
SCH 511
O
H
Citronella
Monoterpenes [C10]
CO2H
Chrysanthemic acid
fragranceinsecticide
Sesquiterpenes [C15]
Humuleneaphid repellant
Farensene
Examples
12
Biosynthesis of TerpenesMethylerythritol Phosphate
(MEP)or
Diterpenes (C20)
Sesquiterpenes (C15)
Monoterpenes (C10)
Hemiterpenes (C5)
Dr. Solomon Derese 13
SCH 511
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.
Dr. Solomon Derese 14
SCH 511
CYTOSOL PLASTIDAcetyl CoA
Mevalonic Acid
Sesquiterpenesand
Triterpenes
G3P Pyruvate+
MethylErythritol Phosphate (MEP)
Hemiterpenes, monoterpenes, diterpenes,
and tetraterpene
Dr. Solomon Derese 16
SCH 511
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
Dr. Solomon Derese 17
SCH 511
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.
Dr. Solomon Derese 18
SCH 511
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.
Dr. Solomon Derese 19
SCH 511
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.
Dr. Solomon Derese 20
SCH 511
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.
Dr. Solomon Derese 21
SCH 511
(3R)-Mevalonic Acid
H+
Isopentenyl pyrophosphateIPP
3,3-Dimethylallyl pyrophosphate
DMAPP
Dr. Solomon Derese 22
SCH 511
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.
Dr. Solomon Derese 23
SCH 511
H+
Isopentenyl pyrophosphateIPP
3,3-Dimethylallyl pyrophosphate
DMAPP
Mevalonic acid/ MethylErythritol Phosphate (MEP)
Dr. Solomon Derese 24
SCH 511
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.
Dr. Solomon Derese 25
SCH 511
In contrast, IPP with itsterminal double bond ismore likely to act as anucleophile, especiallytowards the electrophilicDMAPP.
IPP
DMAPPSN1
Electrophile(Electron deficient)
Nucleophile(Electron rich)
Dr. Solomon Derese 26
SCH 511
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.
Dr. Solomon Derese 27
SCH 511
C C
C C
C.
C C
C
C C
.
Head
Tail
Head
Tail
OPP
OPP DMAPP
SN1
OPP
Head
Tail Head
Dr. Solomon Derese 29
SCH 511Joining Isoprene UnitsHead-to-Tail
Tail-to-Tail
Larger terpenoid units dimerize tail-to-tail.
Tail to Middle