LIPIDS

1
 LIPIDS

Lipids are water unsoluble

compounds, but they are soluble in
non-polar solvents ( petroleum
ether, benzene, acetone, etc).

2
 Lipids
• Lipids are the organic compounds
formed mainly from alcohol and fatty
acids combined together by ester
linkage.

O
H2O O
R CH2 OH HO C R R CH2 O C R
+
Fatty alcohol Fatty acid Esterase (lipase) ester (lipid)
 Lipids
The main types of lipids are:
• Fatty acids
• Glycerolipids
• Sphingolipids
• Polyisoprenic lipids
• Complex lipids
Most commonly occurring lipids are fatty
acids or ester of fatty acid
4
.

5
 Fatty acids
• They are organic carboxylic acids with
the long hydrocarbon chain (with even
or odd numbers).
General structure:
CH3 (CH 2)n COOH n = 0 : CH 3COOH n = 1 : propionic acid

n is almost always even

6
 Fatty acids
• Fatty acids can be classified either as:
– saturated or unsaturated
– according to the chain length:
• short chain FA: 2-4 carbon atoms
• medium chain FA: 6 –10 carbon
atoms
• long chain FA: 12 – 26 carbon
atoms
7
 Fatty acids

Essential fatty acids & those that can

not be biosynthesized in the body:
linoleic and linolenic are two
examples of essential fatty acids for
the human body.

8
 Fatty acids
–Nomenclature:
C18 = stearic acid (Stearate or n-
octadecanoic acid

9
 Common fatty acids
n = 4 butyric acid (butanoic acid)
n = 6 caproic acid (hexanoic acid)
n = 8 caprylic acid (octanoic acid)
n = 10 capric acid (decanoic acid)
n = 12: lauric acid (dodecanoic acid; C12:0)
n = 14: myristic acid (tetradecanoic acid; C14:0)

10
 Common fatty acids (cnt’d)
n = 16: palmitic acid (hexadecanoic acid; C16:0)
n = 18; stearic acid (octadecanoic acid; C18:0)
n = 20; arachidonic (eicosanoic acid; C20:0)
n= 22; behenic acid
n = 24; lignoceric acid
n = 26; cerotic acid

11
 Fatty acids
Prostaglandins and Leukotrienes =
Eicosanoids which are lipidic
compounds provided by
transformations of eicosanoic acids

12
 Leukotriene
• Leukotrienes are fatty molecules of
the immune system that contribute to
inflammation in asthma and
bronchitis. Leukotriene antagonists
are used to treat asthma and
bronchitis.
• Leukotrienes are naturally produced
by eicosanoid lipid mediators.

13
14
 Leukotriene
• Leukotrienes use both autocrine
signalling and paracrine signalling to
regulate the body's response.
• Leukotrienes are produced in the body
from arachidonc acid by the enzyme 5-
lipoxygenase. Their production usually
accompanies the production of
histamine.

15
 Leukotriene
• Leukotrienes produced within a cell
convey signals that either act on the
cell producing them (autocrine
signalling) or on neighboring cells
(paracrine signalling) to regulate the
immune response.

16
 Function
Leukotrienes act principally on a
subfamily of G protein coupled receptors.
They may also act upon peroxisome
proliferator-activated receptors.
Leukotrienes are involved in asthmatic
and allergic reactions and act to sustain
inflammatory reactions.

17
 Function

Several leukotriene receptor antagonists

such as montelukast and zafirlukast are
used to treat asthma. Recent research
points to a role of 5-lipoxygenase in
cardiovascular and neuropsychiatric
illnesses.
Leukotrienes are very important agents in
the inflammatory response.

18
 Function

Some such as LTB4 have a chemotactic

effect on migrating neutrophils, and as
such help to bring the necessary cells to
the tissue. Leukotrienes also have a
powerful effect in bronchoconstriction and
increase vascular permeability

19
 Prostaglandin
• A prostaglandin is any member of a
group of lipid compounds that are
derived enzymatically from fatty acids
and have important functions in the
animal body. Every prostaglandin
contains 20 carbon atoms, including a 5-
carbon ring.

20
 Prostaglandin
• They are mediators and have a
variety of strong physiological effects,
such as regulating the contraction
and relaxation of smooth muscle
tissue. Although they are technically
hormones, they are rarely classified
as such.

21
 Prostaglandin

• The prostaglandins, together with the

thromboxanes and prostacyclins,
form the prostanoid class of fatty acid
derivatives. The prostanoid is a
subclass of eicosanoids.

22
 Function
There are currently ten known
prostaglandin receptors on various cell
types. Prostaglandins ligate a sub-
family of cell surface seven-
transmembrane receptors, G-protein-
coupled receptors. These receptors are
termed DP1-2, EP1-4, FP, IP1-2, and
TP, corresponding to the receptor that
ligates the corresponding prostaglandin
(e.g., DP1-2 receptors bind to PGD2). 23
 Function
The diversity of receptors means that
prostaglandins act on an array of cells and
have a wide variety of effects:
•cause constriction or dilation in vascular
smooth muscle cells
•cause aggregation or disaggregation of
platelets
•sensitize spinal neurons to pain
•decrease intraocular pressure
•regulate inflammatory mediation
24
 Function
• regulate calcium movement
• control hormone regulation
• control cell growth Prostaglandins are
potent but have a short half-life before
being inactivated and excreted.
Therefore, they send only paracrine
(locally active) or autocrine (acting on
the same cell from which it is
synthesized) signals.
25
26
 Functions
• It is an important mediator of
bronchoconstriction.
• It causes platelets to aggregate and blood
vessels to dilate. Thus it is important to the
process of hemostasis. At a concentration
of 10^-12 M, PAF causes life threatening
inflammation of the airways to induce
asthma like symptoms.
27
 Functions
• Toxins such as fragments of destroyed
bacteria induce the synthesis of PAF,
which causes a drop in blood pressure
and reduced volume of blood pumped
by the heart, which leads to shock and
maybe death.

28
 Less common fatty acids
H3C
R
• iso – isobutyric acid H C 3 HC 3
R

• odd carbon fatty acid – propionic acid CH 3

• hydroxy fatty acids – ricinoleic acid,

dihydroxystearic acid, cerebronic acid
• cyclic fatty acids – hydnocarpic,
chaulmoogric acid (CH ) -CO H
2 12 (CH ) -CO H
2 2 10 2

29
chaulmoogric acid hydnocarpic acid
H3C
COOH

CH3 CH3 CH3 CH3

PHYTANIC ACID

A plant derived fatty acid with 16 carbons and branches at C 3, C7, C11 and
C15. Present in dairy products and ruminant fats.
A peroxisome responsible for the metabolism of phytanic acid is defective
in some individuals. This leads to a disease called Refsum’s disease

Refsum’s disease is characterized by peripheral polyneuropathy, cerebellar

ataxia and retinitis pigmentosa

30
Less common fatty acids

H3C (CH 2)10 C C (CH 2)4 COOH

TARIRIC ACID

H2C CH (CH 2)4 C C C C (CH 2)7 COOH

ERYTHROGENIC ACID

These are alkyne fatty acids

31
 Unsaturated fatty acids
• Monoenoic acid (monounsaturated):

H3C Oleic acid:

HOOC
32
 Unsaturated fatty acids
• Dienoic acid: linoleic acid

CH3 (CH 2)4 CH=CH CH2 CH=CH (CH 2)7 COOH

cis
linoleic acid

33
 Unsaturated fatty acids
• Various conventions are in use for indicating the
number and position of the double bond(s)

18 9 1
H
H3C (CH 2)7 C CH( CH 2 )7COOH

10

18:1,9 or 9 18:1

 2 3 4 5 6 7 8 9 10 18
H3C CH 2CH2CH2CH2CH 2CH2CH2CH CH(CH2)7COOH

n 17 10 9 1
34
9, C18:1 or n-9, 18:1
 Unsaturated fatty acids
• Monoenoic acids (one double bond):
• 16:1, 9 : palmitoleic acid (9-hexadecenoic acid

• C18 : Δ9 : oleic acid (9-octadecenoic acid)

• 22:1, 13 : erucic acid (13-docosenoic acid)
• 24:1, 15 9: nervonic acid (15-tetracosenoic acid)

35
 Unsaturated fatty acids
• Trienoic acids (3 double bonds)
• 18:3; 9,12,15 : linolenic acid (9,12,15-
octadecatrienoic acid)
• Tetraenoic acids (4 double bonds)
• 20:4; 5,8,11,14 : arachidonic acid (5,8,11,14-
eicosatetraenoic acid)

36
 Unsaturated fatty acids
• Polyenoic acid (polyunsaturated):
arachidonic acid( C20, Δ5,8,11,14)

COOH

CH3

37
 Unsaturated fatty acids

• Pentaenoic acid (5 double bonds)

• 20:5; 5,8,11,14,17 : timnodonic acid or
EPA (5,8,11,14,17-eicosapentaenoic
acid)*
• Hexaenoic acid (6 double bonds)
• 22:6; 4,7,10,13,16,19 : cervonic acid or
DHA (4,7,10,13,16,19-docosahexaenoic
acid)*

Both FAs are found in cold water fish oils

38
 .

• Fats (graisses) are solids or semi solids

• Oils (huiles) are liquids

39
 Examples of oils
• Olive oil – from Oleo europa (olive tree)
• Corn oil – from Zea mays
• Peanut oil – from Arachis hypogaea
• Cottonseed oil – from Gossypium
• Sesame oil – from Sesamum indicum
• Linseed oil – from Linum usitatissimum
• Sunflower seed oil – from Helianthus annuus
• Rapeseed oil – from Brassica rapa
• Coconut oil – from Cocos nucifera

40
 Fatty acid reactions
• salt formation
NaOH
RCO2H RCO2-Na+ (a soap)

• ester formation
-H20
R'OH + RCO 2H RCO2R'

• lipid peroxidation
R' O2
R R R'
H H non-enzymatic
OOH
very reactive

41
 Neutral lipids
• Glycerides (fats and oils); glycerides
– Glycerol CH 2OH OH

H OH OH

CH 2OH OH

glycerol is a prochiral molecule

– Ester of glycerol - mono glycerides, diglycerides

and triglycerides

• Waxes (Cerides) – simple esters of long chain

alcohols with fatty acids
42
 GLYCERIDES

O O O

O
O R O R O R

OH OH R O

OH O R O R

O O

MONOGLYCERIDE DIGLYCERIDE TRIGLYCERIDE

Function: storage of energy in compact form and cushioning

43
 Stereospecific numbering
• carbon 2 of triglycerides is frequently
asymmetric since C-1 and C-3 may be
substituted with different acyl groups
• by convention we normally draw the
hydroxyl group at C-2 to the left.

44
 Acetyl number

• some fatty acids have hydroxyl groups

OH OH

H3C (CH 2)21 CH COOH H3C (CH 2)5 CH CH2 CH CH (CH 2)7 COOH
cerebronic acid ricinoleic acid

The acetyl number gives the proportion of these hydroxyl-containing fatty

acids in a given sample of fat or oil
acetic anhydride
fatty acid fatty acid fatty acid

OH O C CH3 OH

O +
acetylated fatty acid H3C COOH

titrate with standardized 45

KOH
 WAXES
• simple esters of fatty acids (usually saturated with
long chain monohydric alcohols)

H3C (CH 2)14 C O CH 2 (CH 2)28-CH 3

fatty acid
long chain alcohol

Beeswax – also includes some free alcohol and fatty acids

Spermaceti – contains cetyl palmitate (from whale oil) –useful for
Pharmaceuticals (creams/ointments; tableting and granulation)
Carnauba wax – from a palm tree from brazil – a hard wax used on
46
cars and boats
 Waxes

H3C (CH 2)14 CH2-OH cetyl alcohol

H3C (CH 2)24 CH2-OH hexacosanol

H3C (CH 2)28 CH2-OH triacontanol (myricyl alcohol)

Examples of long chain monohydric alcohols found in waxes

47
 Phospholipids
• the major components of cell membranes
– phosphoglycerides
O

O O R
fatty acids (hydrophobic tail)
glycerol O R'
O-
O O X
P

O
phosphate
Phospholipids are generally composed of FAs, a nitrogenous base, phosphoric
acid and either glycerol, inositol or sphingosine 48
 O

O O R
fatty acids (hydrophobic tail)
glycerol O R'
O-
O O X
P

O
phosphate
X = H (phosphatidic acid) - precursor to other phospholipids

X = CH2-CH2-N+(CH3)3 phosphatidyl choline

X = CH2-CH(COO-)NH3+ phosphatidyl serine

X = CH2-CH2-NH3+ phosphatidyl ethanolamine 49

 Phosphatidyl inositol

Commonly utilized in cellular signaling

50
 Sphingolipids

Based on sphingosine instead of glycerol OH

OH

sphingosine NH2

R long chain hydrocarbon

HO

NH2 attach fatty acid here

OH attach polar head group here

51
 Sphingomyelin (a ceramide)
HO R
O

NH R' usually palmitic acid

O-
O O
P N(CH3)+

O
phosphatidyl choline (also can be ethanolamine)

It is a ubiquitous component of animal cell membranes, where it is by far the most

abundant sphingolipid. It can comprise as much as 50% of the lipids in certain tissues,
though it is usually lower in concentration than phosphatidylcholine
52
 Ether glycerophospholipids
• Possess an ether linkage instead of an
acyl group at the C-1 position of glycerol
– PAF ( platelet activating factor)
– Important in blood cloting
– A potent mediator in inflammation, allergic response and
in shock (also responsible for asthma-like symptom
– The ether linkage is stable in either acid or base
– Plasmalogens: cis a,b-unsaturated ethers

– The alpha/beta unsaturated ether can be hydrolyzed more easily

53
 glycolipids

HO R
O

NH R'

O SUGAR polar head is a sugar

beta linkage

There are different types of glycolipids: cerebrosides, gangliosides,

54
lactosylceramides
 GLYCOLIPIDS
• Cerebrosides
• One sugar molecule
–Galactocerebroside – in
neuronal membranes
–Glucocerebrosides –
elsewhere in the body
• Sulfatides or
sulfogalactocerebrosides
• A sulfuric acid ester of
galactocerebroside
55
 GLYCOLIPIDS
• Globosides: ceramide
oligosaccharides
• Lactosylceramide
–2 sugars ( eg. lactose)
• Gangliosides
• Have a more complex
oligosaccharide attached
• Biological functions: cell-cell
recognition; receptors for
hormones
56
 Cerebrosides

•Cerebrosides is the common name

for a group of glycosphingolipids called
monoglycosylceramides which are
important components in animal
muscle and nerve cell membranes.
•They consist of a ceramide with a
single sugar residue at the 1-hydroxyl
moiety.

57
 Cerebrosides
•Cerebrosides is the common name
for a group of glycosphingolipids called
monoglycosylceramides which are
important components in animal
muscle and nerve cell membranes.
•They consist of a ceramide with a
single sugar residue at the 1-hydroxyl
moiety. The sugar residue can be
either glucose or galactose; the two
major types are therefore called
glucocerebrosides and
galactocerebrosides.
Galactocerebrosides are typically 58
 Structure and Function

• The fundamental structure of a cerebroside is

ceramide. Monoglycosyl and
oligoglycosylceramides having a mono or
polysaccharide bonded glycosidically to the
terminal OH group of ceramide is defined as a
cerebroside. Sphingosine is the main long-chain
base present in ceramide.

59
 Structure and Function
• Galactosylceramide is the principal
glycosphingolipid in brain tissue.
Galactosylceramides are present in all nervous
tissues, and can compose up to 2% dry weight
of grey matter and 12% of white matter. They
are major constituents of oligodendrocytes.
Glucosylceramide is found at low levels in
animal cells such as the spleen, erythrocytes,
and nervous tissues, especially neurons.
Glucosylceramide is a major constituent of skin
lipids, where it is essential for lamellar body
formation in the stratum corneum and to
maintain the water permeability barrier of the
skin.

60
• Glucosylceramide is the only glycosphingolipid common
to plants, fungi and animals. It is usually considered to
be the principal glycosphingolipid in plants. It is a major
component of the outer layer of the plasma membrane.
Galactosylceramides have not been found in plants.
• Monogalactosylceramide is the largest single component
of the myelin sheath of nerves.The sugar moiety is linked
glycosidically to the C-1 hydroxyl group of ceramide,
such as in lactosylceramide.

61
 Sulfatides
• Sulfatides are a class of sulfated
galactosylceramides synthesized primarily in the
oligodendrocytes in the central nervous system.
Sulfatides are a type of sulfolipid.

62
 Gangliosides
• complex glycosphingolipids that consist of
a ceramide backbone with 3 or more
sugars esterified,one of these being a
sialic acid such as N-acetylneuraminic
acid
• common gangliosides: GM1, GM2, GM3,
GD1a, GD1b, GT1a, GT1b, Gq1b

63
 Ganglioside nomenclature
• letter G refers to the name ganglioside
• the subscripts M, D, T and Q indicate
mono-, di-, tri, and quatra(tetra)-sialic-
containing gangliosides
• the numerical subscripts 1, 2, and 3
designate the carbohydrate sequence
attached to ceramide

64
 Ganglioside nomenclature
• Numerical subscripts:
• 1. Gal-GalNAc-Gal-Glc-ceramide
• 2. GalNAc-Gal-Glc-ceramide
• 3. Gal-Glc-ceramide

65
 N-Acetyl-D-galactosamine D-galactose D-glucose

CH 2OH CH 2OH CH 2OH CH 2OH

OH OH H
O O O O O
OH O OH
H H

H O H
H H H H
O
H OH H NH H OH H OH
H H
C O HO C C CH 2
D-Galactose
CH 3 H NH
C
O H O C O
H3C C NH O COO- C
R
CHOH H

CHOH
CH 2OH H
H

OH H

N-acetylneuraminidate (sialic acid)

A ganglioside (GM1)

66
 Cardiolipids
O O

O H2C O C R1 R4 C O CH2 O

R2 C O C H O H O H C O C R3

H2C O P O CH2 C CH2 O P O CH2

OH OH OH
glycerol
glycerol
glycerol

A polyglycerol phospholipid; makes up 15% of total lipid-phosphorus

content of the myocardium – associated with the cell membrane

Cardiolipids are antigenic and as such are used in serologic test for
syphilis (Wasserman test) 67
 Sulfolipids
• also called sulfatides or cerebroside
sulfates
• contained in brain lipids
• sulfate esters of cerebrosides
• present in low levels in liver, lung, kidney,
spleen, skeletal muscle and heart
• function is not established

68
 Blood groups
• determined by various glycolipids on RBCs
• A antigens
Ac
AcN Gal N Glu-sphi ngosine

L-Fucose

• B antigens
Gal Gal NAc-Glu-sphingosine

• H antigens
L-Fucose

Gal NAc--Glu-sphi ngosine

(found on type O blood cells)
L-Fucose

not recognized by anti-A or anti-B antibodies 69

 Cholesterol and cholesterol
esters
H3C
CH3

CH3 H
hydrophobic
O
H H

OH drawn this way R O

usually palmitate

hydrophillic

70
STEROID NUMBERING
SYSTEM
18
12 17
11
19 C 13 D 16
1
2 9 14 15
10 8
A B
3 5 7
4 6
71
STEREOCHEMISTRY OF
STEROIDS
CH3
CH3 CH3 H
CH3 H
H

H H
H
H
CH3 H CH3

H H

CH3 H CH3

H OH

HO H
O

72
 Cholesterol sources,
biosynthesis and degradation
• diet: only found in animal fat
• biosynthesis: primarily synthesized in the
liver from acetyl-coA;
• degradation: only occurs in the liver

73
 Cholesterol and cholesterol
esters

H
H

O
H H
H H
HO
R O

usually palmitate

The hydroxyl at C-3 is hydrophilic; the rest of the

molecule is hydrophobic; also 8 centers of asymmetry 74
 Cholesterol and cholesterol
esters

H H

HO

Functions: -serves as a component of membranes of cells (increases or

moderates membrane fluidity
-precursor to steroid hormones
-storage and transport – cholesterol esters 75
 Functions of cholesterol
• serves as a component of membranes of
cells (increases or moderates membrane
fluidity)
• precursor to steroid hormones and bile
acids
• storage and transport –cholesterol esters

76
 Prostaglandins and other
eicosanoids (prostanoids)
• local hormones, unstable, key mediators
of inflammation
• derivatives of prostanoic acid

9 8 COOH

20
11 12
15

prostanoic acid
77
 O

O O R

O
O-
O O H20
P X phospholipase A 2 (enzyme that hydrolyzes
at the sn-2 position - inhibited
O
indirectly by corticosteroids)

COOH

CH 3

COX is inhibibited by prostaglandin synthase

aspirin and other NSAIDs (also known as cyclooxygenase)

very unstable O COOH

bond
O

78
OH
PGH 2
 O COOH

OH
PGH 2

O
HO
COOH
COOH

HO
OH
HO
OH
PGE 2 PGF 2a
key mediator of inflammation

79
O O O HO
R1 R1 R1 R1

R2 R2 R2 R2
PGA PGB PGC O
PGD

O HO
R1 R1
R1 R1
O
O
R2 R2 O
R2
HO HO
R2
PGE PGFa PGG and PGH
HO
PGI

O OH
R1
R1 R1 R1
O
R2
R2 O R2 HO O R2
O
O
PGJ PGK TXA TXB

80
SUBSTITUTION PATTERN OF PROSTANOIDS
 Prostacyclins, thromboxanes
and leukotrienes
• PGH2 in platelets is converted to thromboxane
A2 (TXA2) a vasoconstrictor which also promotes
platelet aggregation
• PGH2 in vascular endothelial cells is converted
to PGI2, a vasodilator which inhibits platelet
aggregation
• Aspirin’s irreversible inhibition of platelet COX
leads to its anticoagulant effect

81
 Functions of eicosanoids
• Prostaglandins – particularly PGE1 – block
gastric production and thus are gastric
protection agents
• Misoprostol (Cytotec) is a stable PGE1 analog
that is used to prevent ulceration by long term
NSAID treatment
• PGE1 also has vasodilator effects
– Alprostadil (PGE1) – used to treat infants with
congenital heart defects
– Also used in impotance (Muse)

82
 Functions of eicosanoids
• PGF2a – causes constriction of the uterus
– Carboprost; “Hebamate” (15-Me-PGF2a) –
induces abortions
• PGE2 is applied locally to help induce
labor at term

83
 Leukotrienes
Leukotrienes are derived from arachidonic acid via the enzyme
5-lipoxygenase which converts arachidonic acid to 5-HPETE
(5-hydroperoxyeicosatetranoic acid) and subsequently by
dehydration to LTA4

OH
OH
COOH
COOH
H S
H S C5H11
C5H11
Cys Gly
Cys
gGlu
gGlu
LEUKOTRIENE F 4 (LTF 4) LEUKOTRIENE C 4 (LTC 4)

peptidoleukotrienes
84
 Leukotrienes
Leukotrienes are synthesized in neutrophils, monocytes, macrophages,
mast cells and keratinocytes. Also in lung, spleen, brain and heart.
A mixture of LTC4, LTD4 and LTE4 was previously known as the
slow-reacting substance of anaphylaxis

OH
OH
COOH
COOH
H S
H S C5H11
C5H11
Cys Gly
Cys

LEUKOTRIENE E 4 (LTE 4) LEUKOTRIENE D 4 (LTD 4)

peptidoleukotrienes
85
 Leukotrienes

Non-peptidoleuktrienes: LTA4 is formed by dehydration of

5-HPETE, and LTB4 by hydrolysis of the epoxide of LTA4

O
COOH

C5H11
HO
LEUKOTRIENE A 4 (LTA 4) COOH
C5H11 OH

LEKOTRIENE B 4 (LTB 4)

86
 Biological activities of leukotrienes

1. LTB4 - potent chemoattractent

- mediator of hyperalgesia
- growth factor for keratinocytes
2. LTC4 - constricts lung smooth muscle
- promotes capillary leakage
1000 X histamine
3. LTD4 - constricts smooth muscle; lung
- airway hyperactivity
- vasoconstriction
4. LTE4 - 1000 x less potent than LTD4
(except in asthmatics)
87
Leukotriene receptor
antagonists

Zafirlukast
(Accolate)

Montelukast
(Singulair)

88
 Lipid-linked proteins
• Lipid-linked proteins (different from
lipoproteins)
– lipoproteins that have lipids covalently
attached to them
– these proteins are peripheral membrane
proteins

89
 Lipid-linked proteins
• 3 types are most common:
– Prenylated proteins
• Farnesylated proteins (C15 isoprene unit)
• Geranylgeranylated proteins (C20 isoprene unit)
– Fatty acylated proteins
• Myristoylated proteins (C14)
• Palmitoylated proteins (C16)

90
 Lipid-linked proteins
• glycosylphosphatidylinositol-linked
proteins (GPI-linked proteins)
– occur in all eukaryotes, but are particularly
abundant in parasitic protozoa
– located only on the exterior surface of the
plasma membrane

91
Fatty acylated proteins

92
Prenylated proteins

93
GPI-linked proteins

94
 LIPOPROTEINS
• spherical particles with a hydrophobic core
(TG and esterified cholesterol)
• apolipoproteins on the surface
• large: apoB (b-48 and B-100) atherogenic
• smaller: apoA-I, apoC-II, apoE
• classified on the basis of density and
electrophoretic mobility (VLDL; LDL;
IDL;HDL; Lp(a)

95
 Major lipoprotein classes
• chylomicrons
– density <<1.006
– diameter 80 - 500 nm
– dietary triglycerides
– apoB-48, apoA-I, apoA-II, apoA-IV, apoC-II/C-
III, apoE
– remains at origin in electrophoretic field

96
 Major lipoprotein classes
• VLDL
– density >1.006
– diameter 30 - 80nm
– endogenous triglycerides
– apoB-100, apoE, apoC-II/C-III
– prebeta in electrophoresis

97
 Major lipoprotein classes
• IDL (intermediate density lipoproteins)
– density: 1.006 - 1.019
– diameter: 25 - 35nm
– cholesteryl esters and triglycerides
– apoB-100, apoE, apoC-II/C-III
– slow pre-beta

98
 Major lipoprotein classes
• HDL (high density lipoproteins)
– density: 1.063-1.210
– diameter: 5-12nm
– cholesteryl esters and phospholipids
– apoA-I, apoA-II, apoC-II/C-III
– alpha (electrophoresis)

99
 Major lipoprotein classes
• LDL (low density lipoproteins)
– density: 1.019 - 1.063
– diameter: 18-25nm
– cholesteryl esters
– apoB-100
– beta (electrophoresis)
– < 130 LDL cholesterol is desirable, 130-159 is
borderline high and >160 is high

100
 Terpenes
• simple lipids, but lack fatty acid component
• formed by the combination of 2 or more
molecules of 2-methyl-1,3-butadiene (isoprene)
• monoterpene (C-10) – made up of 2 isoprene
units
• sesquiterpene (C-15) – made up of 3 isoprene
units
• diterpene (C-20) – made up of 4 isoprene units

101
 Monoterpenes

CHO
OH

limonene citronellal menthol camphene

Monoterpenes are readily recognized by their characterisitic flavors

and odors ( limonene in lemons, citronellal in roses and geraniums,
pinene in turpentine and menthol from peppermint
102
 Sesquiterpenes

HO

bisabolene eudesmol

103
 Diterpenes
OH

CH 2OH O

HO
H
C CH 3 COOH

O
phytol gibberelic acid

CH 3 CH 3 H
H3C CH 3

CH 3 All-trans-retinal

104
 Triterpenes

HO
H
squalene lanosterol

Triterpenes are C-30 compounds are addition products of 2 sesquiterpenes;

Both squalene and lanosterol are precursors of cholesterol and other steroids

105
 Other terpenes
• tetraterpenes (C-40) are not as common as
mono, di, and triterpenes
– include the carotenoids such as beta-carotene
(precursor of vitamin A) and lycopene found in
tomatoes
– usually colorful compounds due to highly
conjugated system
• polyisoprenoids or polyprenols consist of
numerous isoprene adducts (8 – 22)
– examples include dolichol phosphate, undecaprenyl
alcohol (bactoprenol) and the side chains of
vitamins K, vitamin E and coenzyme Q
106
 Metabolism of Lipids.
• The main pathways in which the lipids
can be involved are:
• Beta oxydation
• Ketogenesis
• Krebs cycle
• Conversion of lipids into proteins and
carbohydrates
107
 β-oxidation

β-oxidation is the process by which

fatty acids, in the form of Acyl-CoA
molecules, are broken down in
mitochondria and/or in peroxisomes to
generate Acetyl-CoA, the entry
molecule for the Krebs cycle.

108
 The inputs of β-oxidation

• The molecules that start this cycle (the inputs)

are the saturated fatty acid and coenzyme A
products (fatty acyl-CoA). The fatty acids
involved can be even numbered carbon chains
with no double bonds. (The ones with double
bonds are unsaturated and will be discussed
later.) Some other inputs that are added after
the cycle has started are FAD, water, ATP, and
NAD+.

109
 The outputs of β-oxidation
• The products of this pathway (the outputs)
include FADH2, NADH, acetyl-CoA, and of
course, the final products. The final fatty
acid products are acetyl-CoA for the even
numbered fatty acids (without double
bonds), and for those with an odd number
of carbons, it is 3-carbon propionyl-CoA
instead.

110
The beta oxidation of fatty acids involve three stages:

1. Activation of fatty acids in the cytosol

2. Transport of fatty acids into mitochondria
3. Beta oxidation proper in the mitochondrial matrix

Activation of fatty acids

Free fatty acids can penetrate the plasma membrane due
to their poor water solubility and high fat solubility. Once in
the cytosol, a fatty acid reacts with ATP to give a fatty acyl
adenylate, plus inorganic pyrophosphate. This reactive acyl
adenylate then reacts with free coenzyme A to give a fatty
acyl-CoA ester plus AMP.
111
 .
• .

112
Lipid Metabolism

113
The fatty acyl-CoA is then reacted with carnitine to form
acylcarnitine, which is transported across the inner
mitochondrial membrane by a translocase enzyme in the
membrane.

Four recurring steps:

1. Dehydrogenation by FAD: The first step is the

oxidation of the fatty acid by Acyl-CoA-
Dehydrogenase. The enzyme catalyzes the
formation of a double bond between the C-2 and C-
3.
114
2. Hydration: The next step is the hydration of the bond
between C-2 and C-3.

3. Oxidation by NAD+: The third step is the oxidation

of L-β-hydroxyacyl CoA by NAD+. This converts the
hydroxyl group into a keto group.

4. Thiolysis: The final step is the cleavage of β-

ketoacyl CoA by the thiol group of another molecule of
CoA. The thiol is inserted between C-2 and C-3.
Role of Krebs cycle

115
Beta Oxidation

116
1. Dehydrogenation by FAD:

117
Beta Oxidation

118
2. Hydratation:

119
Beta Oxidation

120
3. Oxidation by NAD+:

121
Beta Oxidation

122
4. Thiolysis:

123
 β-oxidation: summary of 4 reactions

124
 b-oxidation of even-number saturated F.A

These saturated fatty acids are catabolized by the beta

oxidation pathway according to the above mentioned
reactions of b-oxidation.

Example:
b- oxidation of stearic acid which is C18.

After activation, stearic acid becomes stearyl-CoA

which will enter reactions of b-oxidation as follows:

125
2. Dehydrogenation of acyl CoA by
Acyl CoA dehydrogenase with
liberation of FADH2 and formation
of a double bond between alpha
and β carbon.(Trans-2-Enoyl-coA)

3. Hydration of double bond by enoyl-

CoA hydratase and formation of β
–hydroxyacyl-coA.

4. Dehydrogenation by β -hydroxy-
acyl CoA dehydrogenase with
liberation of NADH2 and formation
of β ketoacyl-coA.

5. Cleavage of 2 carbon fragments by

a thiolase then generate acetyl
CoA and acyl CoA

126
Complete oxidation of
Octadecanoic acid

Acyl-CoA synthase
ATP+ AMP+
H-SCoA PPi 2Pi

127
CALCULATION OF ATP
 If N=Number of carbons (e.g: C18 in our case)
 Number of Acetyl-CoA = N/2 x 12 ATP
 Rounds of b-oxidation =(N/2)-1 x 5 ATP:
Number of FADH2 = (N/2)-1 x 2 ATP
Number of NADH2 = (N/2)-1 x 3 ATP
For N= C18 , N/2 = 9 (N/2)-1 = 8
Total number of energy (ATP) produced = 148 ATPs
Total number of ATP gained by a cell = 148 ATPs-1 ATPs
expended in activation of stearic acid into stearyl-CoA

128
 β-oxidation of odd-numbered F.A
• Chains with an odd-number of carbons are
oxidized in the same manner as even-
numbered chains, but the final products are
propionyl-CoA and acetyl-CoA.
• Propionyl CoA is converted into succinyl-CoA
(which is an intermediate in the Kreb’s cycle) in
a reaction that involves vitamin B12.
• Succinyl CoA can then enter the Kreb’s cycle.

129
β-oxidation of odd-numbered F.A

• Because it cannot be completely

metabolized in the citric acid cycle, the
products of its partial reaction must be
removed in a process called cataplerosis.
This allows regeneration of the citric acid
cycle intermediates, possibly an important
process in certain metabolic diseases.

130
 β-Oxidation of Odd-Number Fatty Acids:
Requirement of 3 extra Reactions
• Cattle and other ruminant
animals form large amounts of
the three carbon propionate
(CH3-CH2-COO-).
1 1. carboxylation of propionyl-CoA
to D-methylmalonyl-CoA by
propionyl-CoA carboxylase
2. convert D-methymalonyl-CoA
2 to L-methylmalonyl-CoA by
TCA methylmalonyl-CoA epimerase
3. L-methylmalonyl-CoA to
succinyl-CoA by
methylmalonyl-CoA epimerase
• succinyl-CoA enter K.C
3
131
 Example:
calculation ATP produced by 4,7,11 trimethyl-
hexadecanoic acid:
At the position of methyl groups the molecules
of propionyl-CoA will be formed (instead of
acetyl-CoA):
 Number of acetyl-coA: 5 x 12 ATP=60 ATP
 Rounds of b-oxidation : 7 x 5 ATP=35 ATP
 Succinyl-coA (propionyl-CoA): 3 x 6 ATP =18 ATP
 Total ATP produced=113 ATP
 Balance =113-4=99 ATP (Minus 4=1 ATP for
activation and 3 ATP for conversion of propionyl-CoA132
 b-oxidation of unsaturated F.A

Unsaturated fatty acids are catabolized by the b-oxidation

pathway, but they require two additional enzymes to handle
the cis-double bonds.

These fatty acids (with one cis-double bond) go through the

beta oxidation cycle as many times as they can before
coming to the double bond. The Enoyl-CoA Isomerase
makes the cis-double bond into a trans-double bond and
moves it over one carbon.
This product can then continue through the beta oxidation
pathway

133
b-oxidation of unsaturated F.A

• β-oxidation of unsaturated fatty acids poses a

problem since the location of a cis bond can
prevent the formation of a trans-δ2 bond. These
situations are handled by an additional two
enzymes.
• Whatever the conformation of the hydrocarbon
chain, β-oxidation occurs normally until the acyl
CoA (because of the presence of a double bond)
is not an appropriate substrate for acyl CoA
dehydrogenase, or enoyl CoA hydratase:

134
b-oxidation of unsaturated F.A

• If the acyl CoA contains a cis-Δ3 bond, then cis-

δ3-Enoyl CoA isomerase will convert the bond to
a trans-Δ2 bond, which is a regular substrate.
• If the acyl CoA contains a cis-Δ4 double bond,
then its dehydrogenation yields a 2,4-dienoyl
intermediate, which is not a substrate for enoyl
CoA hydratase. However, the enzyme 2,4
Dienoyl CoA reductase reduces the intermediate,
using NADPH, into trans-Δ3-enoyl CoA. As in the
above case, this compound is converted into a
suitable intermediate by cis-Δ3-Enoyl CoA
isomerase.
135
 b-oxidation of Unsaturated Fatty Acids

For polyunsaturated fatty acids (with more than one

cis-double bond) it goes through the same thing, but
it only goes through one more round of beta
oxidation because then you get to a fatty acid with a
trans and a cis double bond.

For this we use 2,4-dienoyl-CoA reductase to

produce a trans-3-enoyl product which is converted
by an enoyl-CoA isomerase to a trans-2-enoyl-CoA
which then goes normally through the pathway.

136
 b-oxidation of unsaturated F.A
Example: Linoleic acid= C18, Δ9,12
 If the acyl CoA contains a cis-Δ3 bond, then cis-
Δ3-Enoyl CoA isomerase will convert the bond to
a trans-Δ2 bond, which is a regular substrate
 If the acyl CoA contains a cis-Δ4 double bond,
then its dehydrogenation yields a 2,4-dienoyl
intermediate, which is not a substrate for enoyl
CoA hydratase. However, the enzyme 2,4
Dienoyl CoA reductase reduces the intermediate,
using NADPH, into trans-Δ3-enoyl CoA. As in the
above case, this compound is converted into a
suitable intermediate by 3,2-Enoyl CoA
isomerase
137
Carnitine serves as a transporter of Acyl
group because after having reacted with an
Acyl CoA, the formed compound (Carnitine-
Acyl) is transportable across the inner
membrane of mitochondrion by a carrier
protein called « Translocase».

After having been carried accross, the

reaction between Carnitine-Acyl and CoA-
SH yield the Acyl CoA ready to undergo
β-oxidation.

138
139
140
141
142
143
144
 Energy production (ATP)
For each time a molecule of Acetyl CoA is
produced, one molecule of FADH2 and a
molecule of NADH,H+ must have been
released respectively during
dehydrogenation and oxidation phase of β
oxydation.

In case of a Cis 3 enoyl CoA, no molecule

of FADH2 because the synthesis trans 2
enoyl CoA should consist of isomerisation of
3 enoyl CoA into 2 enoyl CoA : no
dehydrogenation phase will take place.
145
In case of 4 enoyl CoA, the dehydrogenation
would harvest a 2,4 dienoyl CoA which will
have to be hydrogenated (reduced) by
NADH,H+ into a trans 3 enoyl CoA

General formulas
NC= Number of carbons
NAC= Number of produced acetyl CoA
NFADH2= Number of produced FADH2
NNADH,H+ = Number of produced NADH,H+

146
In case the F.A is unsaturated:
n3= Number of 3 bonds during β oxidation
n4= Number of 4 bonds during β oxidation

147
Acetyl CoA can generate 12 ATP (T.C.A Cycle,
1 NADH,H+ can generate 3 ATAP (electrons
transport chain)
While FADH2 can generate 2 ATP ( electrons
transport chain)
148
The total generated ATP can be illustrated as
below:
 Number of acetyl-coA: 9 x 12 ATP= 108 ATP
 Rounds of b-oxidation : 7 x 5 ATP=35 ATP
 Total ATP produced=143 ATP
 Balance =143-1=142 ATP (Minus 1 ATP used for
activation of linoleic acid into linoleyl-CoA)

149
 β-oxidation of fatty acids

To summarize:
 odd numbered double bonds are handled
by the isomerase.
 even numbered bonds by the reductase
(which creates an odd numbered double
bond) and the isomerase.

150
 KETOGENESIS

Process by which ketone bodies are

produced as a result of fatty acid
break down.

151
 Synthesis of the Ketones
 When the level of glycogen in the liver is high
the production of β-hydroxybutyrate increases.
When carbohydrate utilization is low or deficient,
the level of oxaloacetate will also be low,
resulting in a reduced flux through the TCA
cycle. This in turn leads to increased release of
ketone bodies from the liver for use as fuel by
other tissues. In early stages of starvation, when
the last remnants of fat are oxidized, heart and
skeletal muscle will consume primarily ketone
bodies to preserve glucose for use by the brain.
152
 Synthesis of the Ketones
 Acetoacetate and β-hydroxybutyrate, in
particular, also serve as major substrates for the
biosynthesis of neonatal cerebral lipids.
 Ketone bodies are utilized by extrahepatic
tissues through the conversion of β-
hydroxybutyrate to acetoacetate and of
acetoacetate to acetoacetyl-CoA. The first step
involves the reversal of the β-hydroxybutyrate
dehydrogenase reaction, and the second
involves the action (shown below) of
acetoacetate:succinyl-CoA transferase, also
called β-ketoacyl-CoA-transferase.
153
3 TYPES OF KETONE BODIES

1. Acetoacetate: source of other 2

ketone bodies
2. Acetone
3. beta-hydroxybutyrate

154
Ketogenesis and Ketone Bodies

In ketogenesis:
• Large amounts of acetyl CoA accumulate.
• Two acetyl CoA molecules combine to
form acetoacetyl CoA.
• Acetoacetyl CoA hydrolyzes to
acetoacetate, a ketone body.
• Acetoacetate reduces to b-
hydroxybutyrate or loses CO2 to form
acetone, both ketone bodies.
155
Reactions of Ketogenesis

Ketone bodies

156
ketogenesis

157
158
 Utilization of the Ketones
• The latter enzyme (beta ketothiolase) is
present in all tissues except the liver.
Importantly, its absence allows the liver to
produce ketone bodies but not to utilize
them. This ensures that extrahepatic
tissues have access to ketone bodies as a
fuel source during prolonged fasting and
starvation.

159
Ketogenesis and Ketone Bodies

In ketogenesis:
• Body fat
breaks down
to meet energy
needs.
• Keto
compounds
called ketone
bodies form.
160
Ketone Bodies and Diabetes
• The blood glucose is
elevated within 30 min
following a meal containing
carbohydrates
• The elevated level of glucose
stimulates the secretion of
insulin, which increases the
flow of glucose into muscle
and adipose tissue for
synthesis of glycogen (+
stimulates glycolysis)
• As blood glucose levels
drop, the secretion of
glucagon increases, which
stimulates the breakdown of
glycogen in the liver to yield
glucose 161
 Ketone Bodies and Diabetes

In diabetes:
• Insulin does not function properly.
• Glucose levels in muscle, liver, and
adipose tissue are insufficient for
energy needs.
• As a result, liver cells synthesize
glucose from non-carbohydrate
sources (gluconeogenesis) and
fats are broken down to acetyl CoA.
• The level of acetyl CoA is elevated.
• Excess acetyl CoA undergoes
ketogenesis.
• Ketogenesis produces ketone
bodies.
• Ketone bodies accumulate in the
blood.

162
 Regulation of Ketogenesis
The fate of the products of fatty acid metabolism is
determined by an individual's physiological status.
Ketogenesis takes place primarily in the liver and may
by affected by several factors:

1. Control in the release of free fatty acids from adipose

tissue directly affects the level of ketogenesis in the
liver. This is, of course, substrate-level regulation.
2. Once fats enter the liver, they have two distinct fates.
They may be activated to acyl-CoAs and oxidized, or
esterified to glycerol in the production of
triacylglycerols. If the liver has sufficient supplies of
glycerol-3-phosphate, most of the fats will be turned to
the production of triacylglycerols.

163
3. The generation of acetyl-CoA by
oxidation of fats can be completely
oxidized in the TCA cycle. Therefore, if
the demand for ATP is high the fate of
acetyl-CoA is likely to be further
oxidation to CO2.
4. The level of fat oxidation is regulated
hormonally through phosphorylation of
ACC, which may activate it (in response
to glucagon) or inhibit it (in the case of
insulin).

164
 Clinical Significance of
Ketogenesis
• The production of ketone bodies occurs at a
relatively low rate during normal feeding and
under conditions of normal physiological status.
Normal physiological responses to carbohydrate
shortages cause the liver to increase the
production of ketone bodies from the acetyl-CoA
generated from fatty acid oxidation. This allows
the heart and skeletal muscles primarily to use
ketone bodies for energy, thereby preserving the
limited glucose for use by the brain.

165
 Clinical Significance of
Ketogenesis
• The most significant disruption in the level of ketosis,
leading to profound clinical manifestations, occurs in
untreated insulin-dependent diabetes mellitus. This
physiological state, diabetic ketoacidosis (DKA) results
from a reduced supply of glucose (due to a significant
decline in circulating insulin) and a concomitant increase
in fatty acid oxidation (due to a concomitant increase in
circulating glucagon). The increased production of
acetyl-CoA leads to ketone body production that
exceeds the ability of peripheral tissues to oxidize them.
Ketone bodies are relatively strong acids (pKa around
3.5), and their increase lowers the pH of the blood. This
acidification of the blood is dangerous chiefly because it
impairs the ability of hemoglobin to bind oxygen.

166
 Physiological aspects
1. Use by other cells ( muscle, liver) to
preserve glucose for use by the brain
2. Acetoacetate and Β-hydroxybutyrate
serve as major substrate for the
biosynthesis of neonatal cerebral lipids
3. Ketone bodies are utilized by
extrahepatic tissues
167
168
 Ketosis

Ketosis occurs:
• In diabetes, diets
high in fat, and
starvation.
• As ketone bodies
accumulate.
• When acidic ketone
bodies lowers blood
pH below 7.4
(acidosis).
169
 Lipogenesis: Synthesis of F.A
Lipogenesis:
• Is the synthesis of fatty acids from acetyl
CoA.
• Occurs in the cytosol.
• Uses reduced coenzyme NADPH (NADH
with a phosphate group).
• Requires an acyl carrier protein (ACP).

170
 Malonyl CoA

In lipogenesis, acetyl CoA combines with

bicarbonate to form malonyl CoA. ATP
hydrolysis provides energy.
O
||
CH3—C—S—CoA + HCO3- + ATP
Acetyl CoA
O O
|| ||
-O—C—CH —C—S—ACP + ADP + P
2 i
Malonyl CoA
171
 Formation of Acetyl and
Malonyl ACP

Acetyl CoA and malonyl CoA combine

with acyl carrier protein (ACP) to form
acetyl-ACP and malonyl-ACP:
O
||
CH3—C—S—ACP
Acetyl-ACP
O O
|| ||
-O—C—CH —C—S—ACP
2
Malonyl-ACP
172
 Condensation and Reduction

In reactions 1 and 2 of
fatty acid synthesis:
• Condensation by a
synthase combines
acetyl-ACP with malonyl-
ACP to form acetoacetyl-
ACP (4C) and CO2
(reaction 1).
• Reduction converts a
ketone to an alcohol
using NADPH (reaction
2). 173
 Dehydration and Reduction

In reactions 3 and 4 of
fatty acid synthesis:
• Dehydration forms a
trans double bond
(reaction 3).
• Reduction converts the
double bond to a
single bond using
NADPH (Reaction 4).
174
 Lipogenesis Cycle Repeats

Fatty acid synthesis

continues:
• Malonyl-ACP
combines with the
four-carbon butyryl-
ACP to form a six-
carbon-ACP.
• The carbon chain
lengthens by two
carbons each cycle.
175
 Lipogenesis Cycle Completed

• Fatty acid
synthesis is
completed when
palmitoyl ACP
reacts with water
to give palmitate
(C16) and free
ACP.

176
Summary of Lipogenesis

177
 Fatty Acid Formation

• Shorter fatty acids undergo fewer cycles.

• Longer fatty acids are produced from
palmitate using special enzymes.
• Unsaturated cis bonds are incorporated
into a 10-carbon fatty acid that is
elongated further.
• When blood glucose is high, insulin
stimulates glycolysis and pyruvate
oxidation to obtain acetyl CoA to form fatty
acids. 178
Comparing b-oxidation and Fatty
Acid Synthesis

179
 process of cholesterol
2.Cholesterol synthesis
synthesis • 1. Acetyl-CoAs are converted to 3-
hydroxy-3-methylglutaryl-CoA (HMG-
CoA)
• 2. HMG-CoA is converted to
mevalonate
• 3. Mevalonate is converted to the
isoprene based molecule, isopentenyl
pyrophosphate (IPP), with the
concomitant loss of CO2
• 4. IPP is converted to squalene
• 5. Squalene is converted to
cholesterol.

Vitamin D is synthesized from an intermediate of

Cholesterol biosynthesis.
Cholesterol biosynthesis provide substrate(7-
dehydrocholesterol) for the photochemical
production of vitamin D3 in the skin by
irradiation with UV rays of the sun

7-Dehydrocholesterol Previtamin D3

Vitamin D3 ( cholecalciferol)
180
 PHYSIOLOGICAL IMPORTANCE OF CHOLESTEROL
• It is an important steroid • It is an important
because other molecules component in the plasma
are synthesized from it membrane and facilitate
E.g.: fluidity of the membrane.
Bile salts; which increase fat • It is a precursor of
absorption in the hormones especially
intestines (emulsification) reproductive ones like
Bile acids; which play a progesterone, estrogen
direct role in the control of and testosterone.
pancreatic lipase and
facilitate absorption of fat- From cholesterol(c-27) 1 pregnenolone(c-21)
soluble vitamins (vitamin 2

D) from the intestines. Aldosterone(C-21) 3

Progesterone(c-21)
1.Side chain cleavage enzyme
4
2. 3β-ol dehydrogenase
3.Hydrolase enzyme(zona glomerulosa) Cortisol(c-21)
4.Hydrolase enzyme(zona fasiculata) 181
 Exercises
1. b-oxidation of saturated branched fatty
acids: example of 5,12 dimethyl-
pentadecanoic acid.
This acid has a odd-number of carbon atoms
and 2 ramifications, that means at the end
of the last b-oxidation there will be 3
succinyl-CoA.

182
 CALCULATION OF ENERGY
NBERS OF CARBONS EG. C16 if n=number
of carbon
ACETYLCOA= N/2
ROUND=ACETYLCOA-1
 FADHH+ =ACETYLCOA-1
 NADHH+= ACETYLCOA-1
TOTAL OF
ENERGY=FADHH++NADHH+12(ACETYLCOA)
FATTYACIDS WITH EVEN NUMBERS OF CARBONS

183
5,12DIMETHYLPENTADECANOIC ACID

1ST ACETYLCOA
184
185
186
 Complete Oxidation of Odd-Number Fatty Acids - Requires
Three Extra Reactions
• Cattle and other ruminant
animals form large amounts of
the three carbon propionate
(CH3-CH2-COO-).
1
1. carboxylation of propionyl-CoA
to D-methylmalonyl-CoA by
propionyl-CoA carboxylase
2. convert D-methymalonyl-CoA to
L-methylmalonyl-CoA by
2 methylmalonyl-CoA epimerase
TCA 3. L-methylmalonyl-CoA to
succinyl-CoA by methylamlonyl-
CoA epimerase
• succinyl-CoA enter TCA

3
187
• Energy from 5,12 dimethyl pentadecanoic
acid
• Nbers of acetylcoA=4
Energy=4x12=48
Round=7-1=6
FADH2+=6 ATP=6X2=12
NADH2+=6 ATP=6X3=18
SuccinylcoA ATP=6X3=18
Total Energy produced=48+12+18+18=96
Balance =96-4=92
1 ATP for activation 3ATP for transformation
propionyl to succinylcoA 188
 Exercises
2. The human body completely oxidizes the
stearic acid and a molecule of galactose to
produce the maximum amount of energy
ATP needed in various cellular activities:
Explain and show how the lipids produce
more energy than carbohydrates by
calculating the energy yield (rendement
énergétique) per carbon atom for lipids
and for carbohydrates.
189
ATP
ADP

190
191
As we know :
 The complete aerobic respiration of galactose
produces the total number of 38ATP.
Energy yield by 1C atom for a monosaccharide
(hexose): 38 ATP/6 = 6.3 ATP / 1 C
 the complete oxidation of stearic acid produces
the total of 148 ATP (Balance=147ATP)
Energy yield by 1C atom for the stearic acid
(fatty acid): 147ATP/18 = 8.16 ATP / 1 C

All these above mentioned statements mean

that Lipids produce more energy (8.16 ATP/1C)
than carbohydrates (6.3 ATP/1C). 192
 Conversion of lipids into carbohydrate
and proteins and vice-versa

 Firtly, lipids must be converted into the

molecules of acetyl-CoA through Beta
oxidation. Then these acetyl-CoA enter
the glyoxylic acid cycle as follow:
 Acetyl-CoA reacts with glyoxylic acid to
produce malic acid. Malic acid will be
transformed into isocitric acid the
reactions of Kreb’s cycle as follow:

193
Glyoxilate cycle

194
.

195
Krebs cycle

196
 Conversion of lipids into carbohydrate
and proteins

 Isocitric acid is cleaved (by isocitratase)

into glyoxylic acid and succinic acid. By
the reactions of Kreb’s cycle, this succinic
acid will transformed into oxaloacetic acid.
This latter undergoes decarboxylation and
phosphorylation to produce
phosphoenolpyruvic acid (PEP). PEP
enters glyconeogenesis to produce
glucose.
197
 Conversion of lipids into carbohydrate and
proteins

 Two glyoxylic acid cycles are needed to

produce 2 molecules of PEP (two C3) in
order to synthesize one molecule of
glucose (C6).
The molecules of Glc can undergo
glycolysis to produce pyruvic acid which
can produce Alanine by transamination.
Pyruvic acid can undergo carboxylation to
produce oxaloacetic acid, then
transamination to produce aspartic acid. 198
 Conversion of lipids into carbohydrate and
proteins and vice-versa

The next slide indicates how the

carbohydrates can undergo glycolysis
to produce pyruvic acid, the acetyl-
CoA and synthesis of lipids.

199
Conversion of lipids into carbohydrate and proteins

200
 Conversion of lipids into carbohydrate and
proteins and vice-versa
 By deamination or transamination, aminoacids
(from proteins) transformed into pyruvic acid
(Alnine, serine, cysteine), oxaloacetic acid
(aspartic acid), alpha-ketoglutaric acid (glutamic
acid). By the Kreb’s cycle, this latter will be
transformed into oxaloacetic acid.
 Pyruvic and oxaloacetic acids can undergo the
gluconeogenesis for synthesis of glucose.

201
 .

THANK YOU

202