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I. Terpenes
Many naturally occurring compounds, including fragrances, have carbon skeletonsthat contain n 5 carbons, where n= integer. These compounds, terpenes, arecomprised of a common structural unit known as an isoprene.
H2C
CH
H2C
CH2
CH2
Realize however, that the actual compound isoprene is not present in the terpene; it
only forms the characteristic structure of the carbon skeleton. This is because oncethe isoprene units are linked together, they can undergo a variety of chemicaltransformations, including reduction, hydration, cyclization, etc.
What is important is the way the units are linked together. There are isoprene rulesthat specify the proper and necessary linkages.
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1. Isoprene Rules
Although terpenes consist of C5 units, they are for historical reasons named andclassified according to the number of C10 units.
# Carbons Classification # Isoprenes Must have
10 Monoterpene 2 1 head-to-tail linkage
15 Sesquiterpene 3 2 head-to-tail linkages
20 Diterpene 4 3 head-to-tail linkages
30 Triterpene Derived from two sesquiterpenes (2 C15)
40 Tetraterpene Derived from two diterpenes (2 C20)
How are the two sesquiterpenes and diterpenes joined in the C30 and C40compounds, respectively?
Important: other linkages may be present, but the above rules must be obeyed inorder for a compound to be classified as a terpene.
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2. Examples of Terpenes
Monoterpenes (C10 = 2 isoprenes) must have one HT linkage (shown in blue).
Other linkages maybe be present (shown in red).
Myrcene(bayberry)
Limonene(lemon/orange)
Menthol(peppermint)
OH
CHO
Citronella(lemon grass)
Cyclizations, oxidations, etc. can be done, but the isoprene rules are obeyed.
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Sesquiterpenes have three isoprene units and two H
T linkages
Bisabolene
(termite pheromone)
Turmeron
(tumeric)
O
Caryophyllene
(misc essential oils)
Diterpenes have four isoprene units and three HT linkages
COOH
OH
Steviol (from thesweet-tastingStevia shrub)
COOH
OH
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Triterpenes are two sesquiterpenes linked T
T (with 4 total H
T)
HO
OH
Dammarenediol (ginseng)
Tetraterpenes are two diterpenes linked TT (with 6 total HT)
Lycopene (red colour of tomatoes)
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3. Biosynthesis of Terpenes
The precursors for terpene biosynthesis are C5 units: dimethylallyl pryrophosphateand isopentenyl pyrophosphate. While the reaction occurs somewhere between SN1and SN2, it is helpful to analyze it as though it proceeded entirely by SN1.
OPP
OPP
IPP-OPP
(nucleophile)
Both are resonance-stabilized, but we need toadd a Nu to the primary in order to link the tail
DMA-OPP(electrophile)
E
E
unstable
Ionization forms unstable CC, but the addition of E+ formsa much more stable tertiary, so IPP-OPP acts as a Nu instead
OPP
DMA-OPP easily loses OPP to make a stable carbocation; hence, DMA-OPP willbehave as an electrophile. IPP-OPP, on the other hand, will not ionize, because it
does not give a stable carbocation. Thus, IPP-OPP acts as a nucleophile.
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The reaction between the DMA-OPP and IPP-OPP is better shown as follows:
OPP
OPP
+
OPP
OPP T
H
H
OPP
new doublebond is trans
Geranyl-OPP(C10 with one H-T link)
The C10 Geranyl-OPP (GPP) can be used to make monoterpenes, or, because thepink portion resembles DMA-OPP, it can act as an electrophile and be elongated.
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If geranyl pyrophosphate is diverted to the biosynthesis of monoterpenes, variousreactions can occur. These are just some of the many possibilities:
OPP
Geranyl-OPP
OPP
resonanceand rotation
H
=
myrcene
HH2O
geraniol
OH
=
limonene
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If the elongation route is taken, then a maximum of C20 is achieved. The C15 and C20products can be used to make sesqui- and diterpenes.
OPP
Geranyl-OPP
OPP
Farnesyl-OPP(C15 with two H-T)
OPP
Geranylgeranyl-OPP
(C20 with three H-T)
OPP
OPP
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If elongation stops at C20, where do the C30 and C40 terpenes come from? They arise
from the reductive dimerization of two C15 or C20 units. The reaction uses NADPH,but its mechanism still remains a mystery.
O P
O
O
O P
O
O
O
OP
O
O
OP
O
O
O
NADPH
Farnesyl pyrophosphate
Squalene
Squalene is subsequently used for the biosynthesis of other triterpenes andsteroids.
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4. Origin of DMA-OPP and IPP-OPP
The branched C5 compounds used for terpenes are made fromacetoacetyl thioester, an intermediate in fatty-acid biosynthesis.
o Recall that this -keto thiolester is formed from the Claisencondensation between malonyl thioester and acetyl thioester.
A critical reaction that initiates the biosynthesis of the C5 compounds is an aldolreaction between acetoacetyl thioester and acetyl thioester.
o In the aldol, acetyl thioester is used, and not malonyl thioester, because the
equilibrium constant for an aldol condensation is much more favourable(unlike the Claisen condensation).
o This reaction forms a branchedC6 compound, a -hydroxy dithioester, wherethe beginnings of an isoprene skeleton are recognizable.
CH3 C CH2 C SR
O O
CH3 C SR
O+
CH3 C CH2 C SR
OH O
CH2
C
O
SR
H H
N
B T
SR
O O
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If we compare the aldol condensation product to IPP-OPP, we can predict thereactions that need to occur.
CH3 C CH2 C SR
OH O
CH2 CO
SR
H H
N
B T
CH3 C CH2
CH2 CH2 OPP
IPP-OPP
o The extra C attached to one of the heads needs to be lost.
o The tail needs to be reduced to an alcohol, and then phosphorylated.
o The OH on the neck needs to be removed.
o A double bond between the neck and a head needs to be formed.
The intermediate relating the aldol condensation product and IPP-OPP is acompound called mevalonic acid.
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First, one of the thioesters is hydrolyzed by an enzyme to a carboxylic acid. Thestarting material is achiral, but the product is chiral. However, the enzyme ensuresthat only one stereoisomer is formed.
A couple of enzyme-catalyzed reductions then take us to mevalonic acid.
CH3 C CH2 C SR
OH O
CH2 C
O
SR
CH3 C CH2 COO
OH
CH2 C
O
SR
CH3 C CH2 COO
OH
CH2 CHO
CH3 C CH2 COO
OH
CH2 CH2OH
Mevalonic acid
H2O
NADH
NADH
*
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The primary alcohol of mevalonic acid is then phosphorylated twice, to give a
pyrophosphate. The alcohol on the neck is also phosphorylated.
Why phosphorylate the neck OH? Instead of a -keto group, a -phosphate leavinggroup accepts the electrons generated during the decarboxylation reaction.
CH3 C CH2 COO
OH
CH2 CH2OH
3 ATP 3 ADPCH3 C CH2 C
O
CH2 CH2 OPP
O
O
PO
OH
O
CH3 C CH2
CH2 CH2 OPP
OPP
Isopentenylpyrophosphate
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The biosynthesized IPP-OPP can then be converted to DMA-OPP by an
isomerization reaction.
OPP
Isopentenylpyrophosphate
H
OPP
H
OPP
Dimethylallylpyrophosphate
As we have seen, in the biosynthesis of terpenes,
IPP-OPP
DMA-OPP
And the reaction joins them together in a head-to-tail manner.
Try and see if you can determine how many ATP and NADH are required tosynthesize IPP-OPP or DMA-OPP using acetyl CoA as the starting material.
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J. Steroids These compounds are plant and animal lipids that consist of a characteristic
tetracyclic fused-ring system: three 6-membered rings and one five-membered ring.
H
CH3
H
HCH3
HA
C D
B
1
3
5
6
9810
11 13
14
15
17
Usually, the rings are fused in a transmanner. The H and CH3 groups are also transto each other, and they are also in the axial positions.
Such an arrangement results in a planar, rigid structure, and this flatness isimportant as cell-membrane components flat molecules take up less space.
Steroids are synthesized from terpenes (and not fatty acids), and they usually alsohave axial methyl groups at C-10 and C13.
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1. Biosynthesis of Lanosterol: an Intermediate to Cholesterol
Cholesterol is biosynthesized from the triterpene (C30) squalene. If we redrawsqualene, we can notice where the cyclization reactions need to occur so that newcarbon-carbon bonds are formed.
Squalene
The green dashes are to-be-madebonds that will form the rings.
The necessary C-C bonds are formed by the reaction of a carbocation with analkene, similar to the acid-catalyzed self-polymerization reaction observed in thesynthesis of alkylbenzene sulfonate detergents.
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First, squalene is enzymatically oxidized to an epoxide. Because of its strainednature, epoxides open very easily in the presence of an acid (review the acid-catalyzed opening of epoxides). The Nu is the electron-rich alkene.
O O
H
H
HOHOHO
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HO HO
HH
=
HO
H
H
H H
HO
H
H
A rearragement caused by a series of 1,2-hydride and1,2-alkyl shifts occurs. These involve the movement of H
atoms and CH3 groups, along with their bonding electrons.
Lanosterol
These reactions lead to lanosterol, an intermediate in cholesterol biosynthesis.
Note that there are 7 chiral centres in lanosterol, and none in squalene. Althoughthere are 27 = 128 possible stereoisomers, only one is formed. This is because theenzymes that perform these cyclization and rearrangement reactions place the
starting materials in the proper orientation.
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HO
Chair ChairBoat
HO
H
H
H
H
HO
H
H
H
HO
H
H
Lanosterol
This is the "side view" of thesame reaction, and it shows
the ring conformations
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K. Fat-Soluble Vitamins Vitamins are divided into two broad classes, those that are water-soluble and those
that are fat-soluble, which are considered to be lipids (A, D, E, K).
1. Vitamin A (Retinol)
Vitamin A is formed only in animals, but it arises from the metabolism of a
provitamin found in plants: -carotene.
carotene
CH2OH
Retinol (stored in liver as ester)
cleave at T-T
Because vitamin A is fat-soluble, it can also be accumulated in the body just likeother fat-soluble compounds. These include PCBs, dioxins, DDT, and methyl-Hg.
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The best understood role of vitamin A is its participation in the visual cycle (rod
cells). Retinol is oxidized to retinal (vitamin A aldehyde) in the body, which forms animine with an NH2 group in the protein opsin. This retinal-opsin complex isresponsible for the vision process.
enzyme
Light absorption causesdouble-bond isomerizationand release of 11-trans-retinal from the enzyme
imine formation
+HH
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2. Vitamin E
Vitamin E is a terpenoid (acompound derived from aterpene).
It possesses a sterically
hindered phenolic OH group that is responsible for the antioxidant action of vitaminE. It loses H atoms(proton + electron) to give a resonance-stabilized free radical.
The H quenches other free radicals that may damage biomolecules. The vitamin Eradical is stable and hindered, so it does not cause damage.
Synthetic antioxidants such as butylated hydroxy toluene(BHT)are used as food preservatives.
OH
O
HO terpenoid (isoprenoid)
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