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Lipid
Structure and Metabolism
I.
Introduction and Classification
II.
Nomenclature and Structure
III.
Biological Membrane
IV.
Metabolism
A.
Oxidation of Fatty Acids
B.
Ketone Body Formation
C.
Biosynthesis of Fatty Acids
D.
Lipogenesis and Lipolysis
Introduction
“Biological molecules that are insoluble in aqueous solutions and soluble
in organic solvents, have some relation to fatty acids as esters, and have
potentiality of utilization by living organisms are classified as lipids.”
They perform four major physiological functions:
1.
Serve as structural components of biological membranes
2.
Provide energy reserves, predominantly in the form of
triacylglycerols
3.
Both lipids and lipid derivatives serve as vitamins and
hormones
4.
Lipophilic bile acids aid in lipid solubilization
Classification
Bloor’s Classification
A.
Simple lipid - ester of fatty acids with various alcohols
1.
Natural fats and oils (triglycerides)
2.
Waxes
(a) True waxes: cetyl alcohol esters of fatty acids
(b) Cholesterol esters
CH3
CH3
(c) Vitamin A esters
(d) Vitamin D esters
B.
E
E
CH3
E
E
OH
CH3
CH3
Compound lipid - esters of fatty acids with alcohol plus other
groups
1.
Phospholipids and spingomyelin: contains phosphoric
acid and often a nitrogenous base
2.
Spingolipids (also include glycolipids and cerebrosides):
contains aminoalcohol spingosine, carbohydrate, N-base;
glycolipids contains no phosphate
3.
Sulfolipids : contains sulfate group
4.
Lipoproteins : lipids attached to plasma/other proteins
5.
Lipopolysaccharides: lipids attached to polysaccharides
Classification cont.
C.
Derived lipids – hydrolytic products of A & B with lipid
characters
1.
Saturated & unsaturated fatty acids
2.
Monoglycerides and diglycerides
3. Alcohols (b-carotenoid ring, e.g., vitamin A,
carotenoids)
D.
certain
Miscellaneous lipids
1.
Aliphatic hydrocarbons: found in liver fat and certain
hydrocarbon found in beeswax and plant waxes
2.
Carotenoids
3.
Squalene : found in shark and mammalian liver and in
human sebam; an important intermediate in biosynthesis
of cholesterol
4.
Vitamin E and K
Figure 43
Nomenclature and Structure
Fats and oils:
 Vegetable oils are triglycerides that are liquid at room temp
due to their higher unsaturated or shorter-chain fatty acids
 Triglycerides are most abundant natural lipids
 Natural fats have D-configuration
 Usually R1 and R3 are saturated and R2 is unsaturated
 Natural fats are mixture of two or more simple triglycerides
Fatty acids
“ A fatty acid may be defined as an acid that occurs in a natural
triglyceride and is a mono carboxylic acid ranging in chain length
From four carbon to 24 carbon atoms and including , with
exceptions, only the even-numbered members of the series ”
Figure 44
Some Natural Fatty Acids
Hydroxy acids : ricinoleic acid and dihydroxy stearic acid (castor
oil) cerebronic acid (C23H46[OH]COOH, 2 – hydroxy tetracosanoic
acid) (cerebroside of animal tissues)
Cyclic acids: Hydnocarpic and chaunmoogric acids (chaulmoogra
oil, used in treatment of leprosy)
Linoleic acid, linolenic acid and arachidonic acid are essential
fatty acids
Figure 45
Obviously other combinations are possible, and are
known as configurational isomers. They each will differ;
for example the following:
H3C
CHCOOH
CH3CH2CH2COOH
H3C
Butyric acid
Isobutyric acid
Oleic acid is D9; linoleic acid is D9,12, g-linolenic acid
is D6,9,12, arachidonic acid is D5,8,11,14.
CH3(CH2)7 C H
CH3(CH2)7 C H
H C (CH2)7COOH
trans
Elaidic acid
HOOC(CH2)7 C H
cis
Oleic acid
Natural unsaturated fatty acids are all cis isomers. The
schematic form of linoleic acid is as follows:
COOH
Linoleic acid
Figure 46
Hydrolysis
If Alkali is used (saponification):
Triolein + 3NaOH
Glycerol + 3C17H33COO-Na+ (Sodium oleate, soap)
Phospholipids
 They are first and foremost structural components
of membranes
 Serves as emulsifying agents and surface active
agents
 They are amphipathic molecules
 They are of two types : phosphoglycerides and
spingomyelins (contains spingosine instead of
glycerol)
 Ceramide is the core structural unit of spingolipids
which is a fatty acid amide derivative of spingosine
Figure 47
Table 10.2
Major Classes of Phospholipids
Figure 48
Components of Sphingolipid
Steroids
 Contains cyclopentanoperhydrophenanthrene ring
 It is the nonsaponifiable fraction of lipids
 Main constituent of animal tissues and abundant
in brain, nerve tissue and glandular tissue
 Chief component of gallstones
 Normal blood level is 200 mg/ml a portion of which
is plasma protein bound
Figure 49
The Structure of cholesterol
21
22
H3C
18
20
CH3
27
24
23
CH3
25
CH3
26
12
19
11
CH3
1
10
A
3
8
B
5
4
HO
C
9
2
7
6
17
13
14
D
16
15
Figure 50
α and β Forms of Cholesterol
Key Words of Today’s Lecture
Lipid
Triglycerol
Fatty Acid
Phospholipid
Spingolipid
Cholesterol
Eicosanoids
 Extremely powerful hormone like molecules but are not
hormones rather autocrine regulators
 Derived from arachidonic acid which is synthesized from
linoleic acid by adding a two carbon unit and inserting two
additional double bonds
 Phospholipase A2 release arachidonic acid from membrane
phopholipid to initiate eicosanoid synthesis
 Prostaglandins , thromboxanes and leukotrienes are the
three types of eicosanoids
Figure 51
Selected Examples of Eicosanoids
Key Features of Eicosanoids
 Prostaglandins contains a cyclopentane ring with hydroxy
group at C - 11 and C - 15 (pain, fever, ovulation, uterine
contraction, gastric secretion inhibition)
 Thromboxanes possess a cyclic ether in their structures;
TxA2 is the most prominent member of this group and is
primarily produced by platelet (clotting)
 Leukotrines are hydroxy derivatives possessing conjugated
trienes ; early discovery was in leukocites. LTC4, LTD4
and LTE4 are “ slow - releasing substance of anaphylaxis ”
( SRS - A ) , cause fluid leakage from blood vessels to
inflamed area. LTB4 is a potent chemotactic agent
Figure 52
Biological Actions of Selected
Eicosanoid Molecules
Lipoproteins
“Proteins covalently linked to lipid found in the blood plasma”
Key concepts
Plasma lipoproteins transport lipid through the bloodstream. On the
basis of density, lipoproteins are classified into four major classes:
 Chylomicrons: Large lipoproteins of extremely low density; transport
dietary triglycerols and cholesteryl esters from intestine to the tissues
(muscle/ adipose)
 VLDL (0.95-1.006 g/cc) : synthesized in the liver ; transport lipids to
tissues; coverted to LDL with depletion of triglycerol, apoproteins and
phospholipids
 LDL (1.006 - 1.063 g/cc): carry cholesterol to tissues; engulfed by cells
after binding to LDL receptors
 HDL (1.063 - 1.210 g/cc ): produced in liver; scavenge cholesterol from
cell membrane as cholesteryl ester which is transported to liver from
where the excess cholesterol is disposed of as bile acids
Atherosceloresis is A chronic disease in which soft masses
called atheromas, accumulate on the inside of arteries”
Figure 53
General Structure of Plasma
Lipoproteins
Figure 54
A Summary of the Relative Amounts of Cholesterol,
Cholesteryl Ester, Phospholipid, and Protein in Four
major Classes of Plasma Lipoproteins
Membrane Lipids
According to the fluid mosaic medel, membrane is a lipid bilayer;
proteins float within the bilayer and determines the membrane’s
biological function
Chemical Composition of Some Cell Membranes
Membrane
Human erythrocyte plasma membrane
Mouse liver cell plasma membrane
Amoeba plasma membrane
Mitochondrial inner membrane
Spinach chloroplast lamellar membrane
Halobacterium purple membrane
Protein Lipid
(%)
(%)
49
46
54
76
70
75
43
54
42
24
30
25
Carbohydrate
(%)
8
2-4
4
1-2
6
0
Figure 55
Structure of Lipid Bilayer
Figure 56
Membrane Structure
Majority of membrane lipids are phospholipids which are largely
responsible for following biological events of membranes:
1.
Membrane fluidity
2.
Selective permeability
3.
Self-sealing capability
4.
Asymmetry
Key Words of Today’s Lecture
Eicosanoids
Prostaglandins
Thromboxanes
Leukotrienes
Plasma Lipoproteins
Membrane Lipids
Metabolism
The hydrophobic and highly reduced structure of triglycerols allows
them to serve as a compact and rich source of energy (e.g., in
average U.S. diet, 30 – 40% of calories are provided by fat). The
metabolism of lipids include the degradation and synthesis and
regulation of these processes. A major emphasis is placed on the
role of the central metabolite in lipid metabolism: acetyl-CoA.
Figure 57
Oxidation
1. ACTIVATION
Thiokinases also known as Acyl-CoA ligase
activate the fatty acids to fatty acyl-CoA
Thiophorases activate by interconversion
O
E
+ RCH2CH2COOH
+ ATP
Mg++
[RCH2CH2C
E
+ PPi
O
O
[RCH2CH2C
AMP]
AMP]
E
RCH2CH2C
+ HSCoA
SCoA + AMP + E
O
Mg
RCH2CH2COOH + ATP + HSCoA
++
RCH2CH2C
E
SCoA + AMP + PPi
2. Acyl-CoA Translocation:
Role of Carnitine
Acyl - CoA ligase is found in the outer mitochondrial membrane.
Mitochondrial inner membrane is impermeable to most acyl-CoA and
carnitine is used to transport these acyl groups as follows:
CoASH
Fatty Acyl-Carnitine
CH3
CoASH
H3C
Fatty Acyl-CoA
Carnitine
Outer Membrane
Fatty Acyl-CoA
Inner Membrane
N+
CH3
O
H2
C
H
C
H2
C
OH
Carnitine
 Each acyl - CoA is converted to acylcarnitine; carnitine
acyltransferase I catalyze this reaction
 A carrier protein within the mitochondrial inner membrane
transfers acylcarnitine into the mitochondrial matrix
 Acyl - CoA is regenerated by carnitine acyltransferase II
 Carnitine is transported back into the inner membrane by
carrier protein and the cycle goes on
O-
Figure 58
β-Oxidation of Acyl-CoA
Stoichiometry for
Palmitic Acid Oxidation
O
CH3(CH2)14C
CoA + 7FAD + 7NAD+ + 7CoASH + 7H2O
S
O
8 CH3C
S
CoA + 7FADH2 + 7NADH+ + 7CoASH + 7H+
Each FADH2 yield 1.5 ATP and NADH 2.5 ATP during electron
transport and oxidative phosphorylation, acetyl CoA yields 10ATP
thus a total of 108ATP of which 2 ATP is utilized in conversion of
palmitic acid to Palmityl-CoA, thus 106 molecules ATP per
molecule of palmitic acid is synthesized
Oxidation of Unsaturated Fatty
Acids
 Similar pathway as above
 Usually natural unsaturated fatty acids have cis
configuration, which is transformed to trans by the action of
an isomerase, as enoyl hydrates acts only on trans double
bonds.
 An epimerase is needed to form L-isomer as D-isomer of 3hydroxy fatty acyl-CoA is formed when enoyl hydrases acts
on D2,3 unsaturated fatty acid
Figure 59
Oxidation of Odd-chain Fatty Acids
Conversion of Propionyl-CoA to Succinyl-CoA
End product of b-oxidation of an odd-number fatty acid is acetylCoA and a propionyl-CoA. The propionyl-CoA is then converted to
succinyl-CoA, a citric acid cycle intermediate
Ketone Bodies
Most of the acetyl-CoA product during fatty acid oxidation is utilized
by the citric acid cycle or in isoprenoid synthesis. In a process
called ketogenesis, acetyl–CoA molecules are used to synthesize
acetoacetate, b-hydroxy butyrate and acetone, a group of molecules
called the ketone bodies
Ketone body formation occurs within mitochondria
Ketone bodies are used to generate energy by several
Tissues, e.g., cardiac and skeletal muscle and brain
Figure 60
Ketone Body Formation
Figure 61
Conversion of Ketone
Bodies to Acetyl-CoA
Ketosis
In normal metabolic pathway, acetoacetate and bhydroxybutyrate are the ketone bodies which are
converted to acetyl - CoA. However, during
starvation and in uncontrolled diabetes, conc. of
acetoactate is very high and supply of oxaloacetate
(a TCA component) is insufficient, thus acetoacetate
spontaneously decarboxylated to acetone KETOSIS
 A 4-carbon acid (oxaloacetate) is needed to react with excess
acetyl-CoA and form citrate
 When OAA is not available excess acetyl - CoA in liver are
condensed to form ketone bodies
 OAA is limited during scarcity of glucose for glycolysis. In
starvation and diabetes, glycogen is broken down. Fatty acids of
fat depots are metabolized to supply ATP needs producing
excess of the ketone bodies
Key Words of Today’s Lecture
b-Oxidation
Carnitine
Acyl-CoA & acetyl-CoA
Propionyl-CoA & Succinyl-CoA
Ketone Bodies
Ketosis
Which is responsible for the
transporting of fatty acid across the
mitochondrial inner membrane?
1.
NADH
2.
Plasmin
3.
Cyctochrome Q
4.
Carnitine
The oxidation of fatty acids requires the
following five enzymes:
1. Fatty acyl-CoA dehydrogenase, 2. betahydroxyacyl-CoA dehydrogenase, 3. betaketothiolase, 4. Enoyl hydrase, 5. Thiokinase.
Which is the order of the enzyme involved?
A. 1, 2, 3, 4, 5
B. 2, 3, 4, 5, 1
C. 5, 2, 4, 1, 3
D
5, 1, 4, 2, 3
E. 3, 2, 4, 1, 5
Ketosis is ascribed in part to:
A. Slowdown in fat metabolism
B. An insufficient intermediates of TCA cycle
C. An underproduction of acetyl-SCoA
D. A vigorous protein synthesis
E. An inhibition of glycogen synthesis
Beta-oxidation of octanoic acid in mitochondria yields:
A. 1 FADH2, 1 NADH and 1 acetyl-CoA
B. 2 FADH2, 2 NADH and 2 acetyl-CoA
C. 2 FADH2, 2 NADH and 3 acetyl-CoA
D. 3 FADH2, 3 NADH and 3 acetyl-CoA
E. 3 FADH2, 3 NADH and 4 acetyl-CoA
Which of the following is not true regarding the oxidation of the mole of palmitate (16)
by the β-oxidation pathway?
A. 8 moles of acetyl-CoA are formed
B. 1 mole of the ATP is needed
C. 8 moles of FADH2 are formed
D. The reactions occur in the mitochondria
E. AMP and PP are formed
A fatty acid with an odd number of carbons will enter the citric acid cycle as acetylCoA and:
A. α-ketoglutarate
B. Malate
C. Succinyl-CoA
D. Citrate
E. Butyrate
Which of the following statements apply to the β-oxidation of fatty acids?
A. The process takes place in the cytosol of mammalian cells.
B. Carbon atoms are removed from the acyl chain one at a time.
C. Before oxidation, fatty acids must be converted to their CoA derivatives.
D. NADP+ is the electron acceptor.
Carnitine is:
A. One of the amino acids commonly found in protein.
B. Present only in carnivorous animals.
C. Essential for intracellular transport of fatty acids.
D. An essential cofactor for the citric acid cycle.
E. A 15-carbon fatty acid.
Biosynthesis of Lipids
Formation of Malonyl-SCoA
This is considered as activation step as the breaking of the CO2 bond of
malonyl-SCoA releases lot of energy that “drives” the reaction forward
Mg++
HCO3- + ATP + biotinyl-enzyme
ADP + Pi + carboxy-biotinyl-enzyme
O
carboxy-biotinyl-enzyme + H3C
O
C
SCoA
HOOCH2C
C
SCoA + biotinyl-enzyme
O
O
-
HCO3 + ATP +H3C
C
SCoA
Mg++
ADP + Pi + HOOCH2C
biotinyl-enzyme
O
-
H2C
C
O
OO
C
N
SCoA
NH
NH3+
O
S
(CH2)4
C
H
N
(CH2)4
carboxy-biotinyl-enzyme
C
C
H
O
C
SCoA
Figure 62
Fatty Acid Biosynthesis
Figure 63
Diagrammatic View of
Fatty Acid Biosynthesis
Stoichiometry for Palmitic Acid
Synthesis
O
O
CH3C
SCoA + HOOCCH2C
SCoA + 14NADPH + 14H+
O
CH3(CH2)14C
+
OH + 14NADP + 8CoASH + 6H2O + 7CO2
From acetyl-CoA
O
8 CH3C
SCoA + 7CO2 + 7ATP + 14NADPH + 14H+
O
CH3(CH2)14C
+
OH + 14NADP + 7CO2 + 8CoASH + 6H2O + 7ADP + 7Pi
Lipogenesis and Lipolysis
 Fatty acid may be converted to triacylglycerol, degradated to
generate energy, or utilized in membrane synthesis
 When serum glucose level is high after meal, insuline promotes
triacylglycerol synthesis by facilitating the transport of glucose
into adipocytes - lipogenesis
 Adiposites can not synthesize triacylglycerol when glucose level
is low (between meal), when several hormones stimulate the
hydrolysis of triacyl-glycerol within adipose tissue to form
glycerol and fatty acids – lipolysis.
Figure 64
Triacylglcerol Synthesis
Figure 65
Biosynthesis of Phosphatidic
Acid and Triglyceride
Lipolysis
Lipolysis occur during fasting, vigorous exercise, and in response to
stress.
Binding
of
several
hormones
(e.g.,
glucagon
and
epinephrine) to specific adipocyte plasma membrane receptors
initiates a reaction sequence similar to the activation of glycogen
phosphorylase. As a result of cAMP synthesis, the enzyme
triacylglycerol lipase (hormone-sensitive lipase) is activated when it
is phosphorylated by protein kinase which is activated by cAMP
NH2
N
N
H
O
O
N
R
R
HO
S
P
R
O
O
H
OH
N
Figure 66
Lipolysis – Diagrammatic View
Figure 67
Synthesis of Selected Steroids
Key Words of Today’s Lecture
Biosynthesis of lipid
Malonyl-SCoA
Fatty Acid Synthesis
Triacylglycerol
Phosphatidic Acid
Lipogenesis & Lipolysis
Steroid Synthesis
In the extra Mitochondria synthesis of fatty acid, CO2 is
utilized:
A. In the conversion of acetyl-CoA to malonyl-CoA
B. In the conversion of malonyl-CoA to malonic acid
C. To prevent the oxidation of biotin
D. In the formation of acetyl-CoA from pyruvate
E. In the deamination of amino acid
Which statement about lipogenesis and lipolysis is true
A. Fatty acid may be converted to triacylglycerol
B. After meal, insuline promotes lipogenesis
C. Between meal, several hormones stimulate lipolysis
D. B & C
E. A, B & C
A.Which statement is NOT true to the biosynthesis of palmitic acid:
A. Carboxylation of acetyl CoA to form malonyl CoA initiates its biosynthesis
B. 1 molecule of Acetyl CoA, 7 molecules of malonyl CoA and 14 NADPH are
needed to synthesize 1 molecule of palmitic acid
C. 8 molecules of malonyl CoA and 14 NADPH are needed to synthesize 1
molecule of palmitic acid
D. Its biosynthesis occurs in citosol
E. NADPH is the coenzyme in the reduction steps
O
17--Hydroxylase 17-a-Hydroxy 17,20-Lyase
Progesterone
progesterone
O
4-Androstenedione
17-b-Hydroxysteroid
dehydrogenase
Testosterone
?