Chapter 26 Lipids

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Chapter 26Lipids
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Lipids

• Lipids are naturally occurring substances grouped
  together on the basis of a common propertythey
  are more soluble in nonpolar solvents than in
  water.
• Some of the most important of themthe ones in
  this chapterare related in that they have acetic
  acid (acetate) as their biosynthetic origin.
• In many biosynthetic pathways a substance called
  acetyl coenzyme A serves as the source of acetate.

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26.1Acetyl Coenzyme A
4
Structure of Coenzyme A
R H Coenzyme A
5
Reactivity of Coenzyme A
Nucleophilic acyl substitution

HSCoA

• Acetyl coenzyme A is a source of an acetyl group
  toward biological nucleophiles it is an acetyl
  transfer agent.

6
Reactivity of Coenzyme A
can react via enol
E

• Acetyl coenzyme A reacts with biological
  electrophiles at its ? carbon atom.

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26.2Fats, Oils, and Fatty Acids
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Fats and Oils

• Fats and oils are naturally occurring mixture of
  triacylglycerols (also called triglycerides).
• Fats are solids oils are liquids.

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Fats and Oils

• Tristearin mp 72C

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Fats and Oils

• 2-Oleyl-1,3-distearylglycerol mp 43C

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Fats and Oils

• 2-Oleyl-1,3-distearylglycerolmp 43C

H2, Pt
Tristearinmp 72C
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Fatty Acids
H2O

• Acids obtained by the hydrolysis of fats and oils
  are called fatty acids.
• Fatty acids usually have an unbranched chain with
  an even number of carbon atoms.
• If double bonds are present, they are almost
  always cis.

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Table 26.1
Systematic name
Common name
Dodecanoic acid
Lauric acid
Tetradecanoic acid
Myristic acid
Hexadecanoic acid
Palmitic acid
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Table 26.1
Systematic name
Common name
Octadecanoic acid
Stearic acid
Icosanoic acid
Arachidic acid
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Table 26.1
Systematic name (Z)-9-Octadecenoic acid
Common name Oleic acid
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Table 26.1
Systematic name (9Z, 12Z)-9,12-Octadecadienoic
acid
Common name Linoleic acid
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Table 26.1
Systematic name (9Z, 12Z, 15Z)-9,12,15- Octadec
atrienoic acid
Common name Linolenic acid
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Table 26.1
Systematic name (5Z, 8Z, 11Z,
14Z)-5,8,11,14- Icosatetraenoic acid
Common name Arachidonic acid
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trans-Fatty Acids

• Are formed by isomerization that can occur when
  esters of cis-fatty acids are hydrogenated.

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H2, cat
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26.3Fatty Acid Biosynthesis
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Fatty Acid Biosynthesis

• Fatty acids are biosynthesized via acetyl
  coenzyme A.
• The group of enzymes involved in the overall
  process is called fatty acid synthetase.
• One of the key components of fatty acid
  synthetase is acyl carrier protein (ACPSH).

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Fatty Acid Biosynthesis

• An early step in fatty acid biosynthesis is the
  reaction of acyl carrier protein with acetyl
  coenzyme A.

HSACP
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Fatty Acid Biosynthesis

• A second molecule of acetyl coenzyme A reacts at
  its ? carbon atom with carbon dioxide (as HCO3)
  to give malonyl coenzyme A.

Acetylcoenzyme A
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Fatty Acid Biosynthesis

• Malonyl coenzyme A then reacts with acyl carrier
  protein.

Malonylcoenzyme A
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Fatty Acid Biosynthesis

• MalonylACP and acetylACP react by carbon-carbon
  bond formation, accompanied by decarboxylation.

SACP
CH3C
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Fatty Acid Biosynthesis

• In the next step, the ketone carbonyl is reduced
  to a secondary alcohol.

S-AcetoacetylACP
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Fatty Acid Biosynthesis

• The alcohol then dehydrates.

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Fatty Acid Biosynthesis
Reduction of the double bond yieldsACP bearing
an attached butanoyl group.

• Repeating the process gives a 6-carbon acyl
  group, then an 8-carbon one, then 10, etc.

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26.4Phospholipids
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Phospholipids

• Phospholipids are intermediates in the
  biosynthesis of triacylglycerols.
• The starting materials are L-glycerol 3-phosphate
  and the appropriate acyl coenzyme A molecules.

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• The diacylated species formed in this step is
  called a phosphatidic acid.

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• The phosphatidic acid then undergoes hydrolysis
  of its phosphate ester function.

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• Reaction with a third acyl coenzyme A molecule
  yields the triacylglycerol.

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Phosphatidylcholine

• Phosphatidic acids are intermediates in the
  formation of phosphatidylcholine.

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Phosphatidylcholine
polar "head group"
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Phosphatidylcholine
hydrophobic(lipophilic) "tails"
hydrophilic "head group"
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Cell Membranes
water

• Cell membranes are "lipid bilayers." Each layer
  has an assembly of phosphatidyl choline molecules
  as its main structural component.

water
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Cell Membranes
water

• The interior of the cell membrane is
  hydrocarbon-like. Polar materials cannot pass
  from one side to the other of the membrane.

water
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26.5Waxes
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Waxes

• Waxes are water-repelling solids that coat the
  leaves of plants, etc.
• Structurally, waxes are mixtures of esters. The
  esters are derived from fatty acids and
  long-chain alcohols.

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26.6Prostaglandins
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Prostaglandins

• Prostaglandins are involved in many biological
  processes.
• Are biosynthesized from linoleic acid (C18) via
  arachidonic acid (C20). (See Table 26.1)

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Examples PGE1 and PGF1?
PGE1
PGF1?
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Prostaglandin Biosynthesis

• PGE2 is biosynthesized from arachidonic acid
• The oxygens come from O2
• The enzyme involved (prostaglandin endoperoxide
  synthase) has cyclooxygenase (COX) acitivity

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Prostaglandin Biosynthesis
Arachidonic acid
O2fatty acid cyclooxygenase
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Prostaglandin Biosynthesis
reduction ofhydroperoxide
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Prostaglandin Biosynthesis
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Icosanoids
Icosanoids are compounds related to icosanoic
acid CH3(CH2)18CO2H.

• Icosanoids include prostaglandins thromboxanes
  prostacyclins leukotrienes

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Thromboxane A2 (TXA2)
Thromboxane A2 is biosynthesized from PGH2
TXA2 promotes platelet aggregation and blood
clotting
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Prostacyclin I2 (PGI2)
Like thromboxane A2, prostacyclin I2
isbiosynthesized from PGH2
PGI2 inhibits platelet aggregation and
relaxescoronary arteries
PGI2
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Leukotriene C4 (LTC4)
Leukotrienes arise from arachidonic acid viaa
different biosynthetic pathway. They are
thesubstances most responsible for
constrictingbronchial passages during asthma
attacks.
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Leukotriene C4 (LTC4)
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26.7Terpenes The Isoprene Rule
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Terpenes

• Terpenes are natural products that are
  structurally related to isoprene.

or
Isoprene(2-methyl-1,3-butadiene)
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Terpenes

• Myrcene (isolated from oil of bayberry) is a
  typical terpene.

or
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The Isoprene Unit

• An isoprene unit is the carbon skeleton of
  isoprene (ignoring the double bonds)

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The Isoprene Unit

• The isoprene units of myrcene are joined
  "head-to-tail."

head
tail
tail
head
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Table 26.2
Classification of Terpenes

• Class Number of carbon atoms
• Monoterpene 10
• Sesquiterpene 15
• Diterpene 20
• Sesterpene 25
• Triterpene 30
• Tetraterpene 40

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Figure 26.6
Representative Monoterpenes
?-Phellandrene(eucalyptus)
Menthol(peppermint)
Citral(lemon grass)
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Figure 26.6
Representative Monoterpenes
?-Phellandrene(eucalyptus)
Menthol(peppermint)
Citral(lemon grass)
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Figure 26.6
Representative Monoterpenes
?-Phellandrene(eucalyptus)
Menthol(peppermint)
Citral(lemon grass)
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Figure 26.6
Representative Sesquiterpenes
H
?-Selinene(celery)
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Figure 26.6
Representative Sesquiterpenes
H
?-Selinene(celery)
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Figure 26.6
Representative Sesquiterpenes
?-Selinene(celery)
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Figure 26.6
Representative Diterpenes
Vitamin A
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Figure 26.6
Representative Diterpenes
Vitamin A
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Figure 26.6
Representative Diterpenes
Vitamin A
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Figure 26.6
Representative Triterpene
tail-to-tail linkage of isoprene units
Squalene(shark liver oil)
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26.8Isopentenyl PyrophosphateThe Biological
Isoprene Unit
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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).

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The Biological Isoprene Unit
3
Mevalonic acid
Isopentenyl pyrophosphate
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Isopentenyl Pyrophosphate
or
Isopentenyl pyrophosphate
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Isopentenyl and Dimethylallyl Pyrophosphate
Isopentenyl pyrophosphate is interconvertible
with2-methylallyl pyrophosphate.
Isopentenyl pyrophosphate
Dimethylallyl pyrophosphate

• Dimethylallyl pyrophosphate has a leaving group
  (pyrophosphate) at an allylic carbon it is
  reactive toward nucleophilic substitution at this
  position.

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26.9Carbon-Carbon Bond Formation in Terpene
Biosynthesis
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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.

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Carbon-Carbon Bond Formation
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After CC Bond Formation...

• The carbocation can lose a proton to give a
  double bond.

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After CC Bond Formation...
OPP

• This compound is called geranyl pyrophosphate.
  It can undergo hydrolysis of its pyrophosphate to
  give geraniol (rose oil).

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After CC Bond Formation...
OPP
H2O
Geraniol
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From 10 Carbons to 15
82
From 10 Carbons to 15
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From 10 Carbons to 15

• This compound is called farnesyl pyrophosphate.
• Hydrolysis of the pyrophosphate ester gives the
  alcohol farnesol (Figure 26.6).

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From 15 Carbons to 20

• Farnesyl pyrophosphate is extended by another
  isoprene unit by reaction with isopentenyl
  pyrophosphate.

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Cyclization

• Rings form by intramolecular carbon-carbon bond
  formation.

E double bond
Z double bond
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Limonene
OH
H2O
?-Terpineol
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Bicyclic Terpenes

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26.10The Pathway from Acetate to Isopentenyl
Pyrophosphate
89
Recall
3
Mevalonic acid
Isopentenyl pyrophosphate
90
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.

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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.

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Biosynthesis of Mevalonic Acid

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Biosynthesis of Mevalonic Acid

• Next, the acyl coenzyme A function is reduced.
• The product of this reduction is mevalonic acid.

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Mevalonicacid
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Conversion of Mevalonic Acid to Isopentenyl
Pyrophosphate

• The two hydroxyl groups of mevalonic acid undergo
  phosphorylation.

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Conversion of Mevalonic Acid to Isopentenyl
Pyrophosphate

• Phosphorylation is followed by a novel
  elimination involving loss of CO2 and PO43.

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Conversion of Mevalonic Acid to Isopentenyl
Pyrophosphate

• The product of this elimination is isopentenyl
  pyrophosphate.

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Biosynthetic pathway is based on experiments with
14C-labeled acetate
Mevalonic acid
Isopentenyl pyrophosphate
99
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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26.11Steroids Cholesterol
101
Structure of Cholesterol

• Fundamental framework of steroids is the
  tetracyclic unit shown.

102
Structure of Cholesterol

• Cholesterol has the fundamental steroid skeleton
  modified as shown.

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Structure of Cholesterol
CH3
CH3
CH3
CH3
CH3
H
H
H
HO

• Some parts of the cholesterol molecule are
  isoprenoid. But other parts don't obey the
  isoprene rule. Also, cholesterol has 27 carbons,
  which is not a multiple of 5.

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Biosynthesis of Cholesterol

• Cholesterol is biosynthesized from the triterpene
  squalene. In the first step, squalene is
  converted to its 2,3-epoxide.

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Biosynthesis of Cholesterol

• To understand the second step, we need to look at
  squalene oxide in a different conformation, one
  that is in a geometry suitable for cyclization.

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Biosynthesis of Cholesterol

• Cyclization is triggered by epoxide ring opening.

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Biosynthesis of Cholesterol

• The five-membered ring expands to a six-membered
  one.

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Biosynthesis of Cholesterol
protosteryl cation

• Cyclization to form a tetracyclic carbocation.

109
Biosynthesis of Cholesterol

• Deprotonation and multiple migrations.

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Biosynthesis of Cholesterol

• The product of this rearrangement is a triterpene
  called lanosterol. A number of enzyme-catalyzed
  steps follow that convert lanosterol to
  cholesterol.

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Cholesterol

• Cholesterol is the biosynthetic precursor to a
  large number of important steroids
• Bile acids Vitamin D Corticosteroids Sex
  hormones

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26.12Vitamin D
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Cholesterol

• Cholesterol is the precursor to vitamin D.
• Enzymes dehydrogenate cholesterol to introduce a
  second double bond in conjugation with the
  existing one. The product of this reaction is
  called 7-dehydrocholesterol.

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7-Dehydrocholesterol
CH3
CH3
CH3
CH3
CH3
H
H
HO

• Sunlight converts 7-dehydrocholesterol on the
  skin's surface to vitamin D3.

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Vitamin D3
CH3

• Insufficient sunlight can lead to a deficiency of
  vitamin D3, interfering with Ca2 transport and
  bone development. Rickets can result.

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26.13Bile Acids
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Cholesterol

• Oxidation in the liver degrades the cholesterol
  side chain and introduces OH groups at various
  positions on the steroid skeleton. Cholic acid
  (next slide) is the most abundant of the bile
  acids.

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Cholic Acid

• Salts of cholic acid amides (bile salts), such as
  sodium taurocholate (next slide), act as
  emulsifying agents to aid digestion.

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Sodium Taurocholate
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26.14Corticosteroids
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Cholesterol

• Enzymatic degradation of the side chain and
  oxidation of various positions on the steroid
  skeleton convert cholesterol to corticosteroids.

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Cortisol
O
OH
CH3
HO
OH
CH3
H
H
H
O

• Cortisol is the most abundant of the
  corticosteroids. Enzyme-catalyzed oxidation of
  cortisol gives cortisone.

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Cortisone
O
OH
CH3
O
OH
CH3
H
H
H
O

• Corticosteroids are involved in maintaining
  electrolyte levels, in the metabolism of
  carbohydrates, and in mediating the allergic
  response.

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26.15Sex Hormones
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Testosterone

• Testosterone is the main male sex hormone.

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Estradiol
OH
H3C
H
H
H
HO

• Estradiol is a female sex hormone involved in
  regulating the menstrual cycle and in
  reproduction.

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Progesterone

• Supresses ovulation during pregnancy.

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26.16Carotenoids
129
Carotenoids

• Carotenoids are naturally occurring pigments.
• Structurally, carotenoids are tetraterpenes.
  They have 40 carbons. Two C20 units are linked
  in a tail-to-tail fashion.
• Examples are lycopene and ?-carotene.

130
Carotenoids
Lycopene (tomatoes)
?-Carotene (carrots)
131
End of Chapter 26