Lecture 18

Lipid Metabolism
Metabolism of Fatty acids - II

Dr. S. Annie Jeyachristy

Lecturer in Biochemistry
Faculty of Medicine
AIMST University
 OBJECTIVES

To provide an overview of
β-oxidation of fatty acids
Energetics of β-oxidation of fatty acids
alpha and omega-oxidation of fatty acids
metabolic defects of fatty acid oxidation
an overview of breakdown of triacylglycerols in adipose tissues
eicosanoid metabolism.
 BREAKDOWN OF FATTY ACIDS
Fatty acid degradation – oxidation of long-chain fatty acids.
Occurs in mitochondrial matrix.
Process known as β-Oxidation.
Fatty acids are converted to their acyl coenzyme A (CoA) derivatives
and then degraded by successive removal of acetyl CoA (two-carbon)
units from the end of the fatty acid.
Significance of the pathway
Reoxidation of FADH2
Reoxidation of NADH.
Oxidation of acetyl coA in the TCA cycle
I. Activation of fatty
acids

(Thiokinase)

Occurs in cytosol
Only step that requires ATP
Thiokinases are found in ER, peroxisomes and inside and on outer
membrane of mitochondria
II. Transport of fatty acids into mitochondria – carnitine shuttle system
Carnitine is β– OH-γ-trimethylammonium butyrate; has methionine paring action in animals;
obtained from diet or synthesized from AA, lysine and methionine; found in inner
mitochondrial membrane

III. β-oxidation of fatty acids
Removal of successive two carbon atoms
from the carboxyl end of the FA
Acetyl CoA then enters into TCA cycle
to give CO2 and H2O
Reducing equivalents enters ETC & OP

5
2

4 3
 Energetics of palmitic acid oxidation
Calculation for the ATP production when (16 carbon) is completely oxidized.

S. Mechanism ATP yield

No.
1. -oxidation (7 cycles) II step liberates 2 ATP(2x7) 14
IV step gives 3 ATP(3x7) 21
2. From 8 acetyl CoA Oxidized by citric acid cycle, 96
each acetyl CoA
Provides 12 ATP
3. Total energy from one molecule of palmitate 131
4. Energy utilized for activation in the I step -2
5. Net yield of oxidation of one molecule of palmitate 129
Oxidation of Fatty Acids with Odd-Numbered
Carbon Chains
Most fatty acids in natural lipids contain even-chain fatty
acids.
Small proportion have odd-numbered chains.
Upon complete -oxidation, yield acetyl CoA(2C) and a single
mole of Propionyl CoA (3C).
Propionyl CoA → methylmalonyl CoA Succinyl CoA
----------> Oxaloacetate ---------> TCA cycle
 Oxidation of Unsaturated Fatty Acids
Complete degradation of unsaturated fatty acids requires additional
processing.
Saturated portion of CoA esters of these fatty acids are degraded by
the enzymes normally responsible for β-oxidation from the CoA
terminus.
Presence of double bond in the fattyacid spares the action of acyl CoA
dehydrogenase thereby FADH2 is not formed.
The net result is for each double bond present in the unsaturated fatty
acid, the ATP production on oxidation is less by two numbers.
Process repeated until the whole chain is degraded.
Unsaturated fatty acids yield slightly less amount of energy as
saturated ones of same C length.
Omega-Oxidation of Fatty Acid
Another minor pathway is omega (ω)-
oxidation.
Occurs in microsomes involving NADPH
and cytochrome P-450
Preferred substrates are fatty acids of 10
or 12 carbon atoms.
Pathways involves oxidation of the
methyl C (ω C) to COOH → dicarboxylic
acid.
Either end can be attached to CoASH and
molecule undergoes β-oxidation in the
mitochondrion.
Pathway yields dicarboxylic acids such as
succinic and adipic acids
Dicarboxylic aciduria
 Alpha-Oxidation Pathway for Phytanic
Acid
Minor pathway - found active in brain tissue
Oxidation Occurs in endoplasmic reticulum.
Involves hydroxylation of α- instead of β-carbon
Reduction and elimination of CO2.

Pathway mainly used for fatty acids that have a

methyl group at the β-carbon.
α-oxidation (defective in
Phytol, a fatty
Refsum’s acid present in the tissues of
Disease
ruminants, dairy products and plant food stuff is
converted to pristanic acid which can then
Decarboxylation
undergo β-oxidation.
Oxidation
Phytanic acid contains methyl group on the β-
carbon that blocks β-oxidation
6cycles of
Β-oxidationRefsum’s Disease due to defective conversion of
phytanic acid to pristanic acid → Accumulate
large quantities of phytanic acid in tissues and
serum - severe neurological and other symptoms.
 Metabolic defects of fatty acid oxidation
Defects in β-Oxidation (carnitine deficiency, transferases &
translocase deficiency of carnitine transport system)
Organic acidurias (methyl malonic aciduria, propionic acidemia,
dicarboxylic aciduria)
Refsum’s disease
 Comparison of Fatty Acid Synthesis and Degradation

Reduction
Dehydrogenation
(NADPH)
(FAD)

Hydration Dehydration

Reduction
Dehydrogenation
(NADPH)
(NAD+)

Condensa-
Thiolytic
tion
cleavage
 Synthesis Degradation
Intermediates Linked to SH in Linked to CoASH
Proteins (Acyl
Carrier Proteins)

Site Cytosol Mitochondria

Redox NADP+ / NADPH NAD+ / NADH

Coenzymes
Enzymes Multienzyme Independent
complex proteins
Sequential units 2 C units split off 2 C units added, as
as acetyl CoA 3 carbon malonyl
CoA
 Degradation of triacylglycerols
During fasting, insulin decreases, glucagon increases, cAMP levels increases in
adipose cells, stimulates lipolysis, - breakdown of TAG.
Low insulin: glucagon ratio causes the activation of hormone-sensitive lipase
(adipose TAG lipase) that initiates TAG breakdown. Insulin inhibits this process.
Hormones – thyroid, ACTH, TSH, GH, glucocorticosteroids – stimulate cAMP
and activates hormone-sensitive lipase.
FA and glycerol are then released into the blood.
 Eicosanoids
Name refers to their origin from C20 polyunsaturated FA, Arachidonic acid
Arachidonic acid is the main precursor for eicosanoids, including
prostaglandins, prostacyclins, thromboxanes and leukotrienes
Very potent agonists and elicit wide range of both physiological and
pathological responses
Eicosanoid synthesis begins with arachidonate (in 2 nd position) release from
membranes
Released arachidonate is then processed by one of three pathways
cyclooxygenase
lipoxygenase
cytochrome P450 system
HETE – Hydroxy eicosa tetra enoic acid
 Cyclooxygenase pathway I

This pathway leads to the production of prostaglandins,

thromboxane and prostacyclin
Involves oxidative cyclization of arachidonic acid to yield PGH 2 by
endoperoxide synthase with 2 catalytic activities - cyclooxygenase
(COX) & peroxidase actions
Fatty acid cycloxygenase – requires 2 mol of O 2
Peroxidase – requires reduced glutathione
First product PGH2 is converted to various other prostaglandins and
thromboxanes by cell-specific synthases
PGs produced are responsible for mediating pain, heat, redness and
swelling in inflammation and fever in infection
Cyclooxygenase pathway
DERIVATIVE TISSUES ACTIONS
TXA2 Platelets platelet aggregation,
vasoconstriction, Mobilizes
cellular Ca2+, smooth muscle
contraction
PGI2 Vascular Inhibits platelet aggregation,
endothelium vasodilation
PGF2α Most tissues Vasoconstriction, Smooth
muscle contraction (bronchial)
(+)Uterine contraction
PGE2 Most tissues Vasodilation, relaxes smooth
(esp. kidney) muscle, induces labor
 Drugs that affect COX pathway

• COX-1/2 – inhibited irreversibly by aspirin & reversibly by

acetaminophen (tylenol), ibuprofen (Motrin, Nuprin, Advil),
indomethacin & phenylbutazone (all are NSAIDs)
• COX-2 – inhibited by corticosteroids and specific COX-2
inhibitors celecoxib, rofecoxib (Celebrex, Vioxx etc.).
• Used to treat pathological inflammatory responses
Aspirin and NSAIDS

Low dosage aspirin very

effective in inhibiting
platelets aggregation &
hence useful in patients
prone for
atherosclerosis/thrombosis
 Lipoxygenase pathway I
This pathway leads to production of 5-
hydroperoxyeicosatetraenoic acid (5-HPETE) catalyzed by 5-
lipoxygenase (polymorphonuclear leukocytes)
5-HPETE is converted into LTA4 and then other leukotrienes
There are two other lipoxygenases (12- and 15- in platelets &
eosinophilic leukocytes respectively)
Lipoxygenase pathway
 Leukotrienes

LTC4 LTD4 LTE4

Produced in leukocytes, platelets, mast cells and heart and
lung vascular tissues from LTA4. Contract smooth muscle
& increase bronchconstrict/vasoconstrict, involved in
anaphylaxis

LTB4
Involved with increased chemotaxis of PM leukocytes,
vascular permeability, leukocyte aggregation & interleukin
1 & 2 synthesis
 LEARNING OUTCOMES

Explain the role of carnitine in the transport of fatty acids into

mitochondria for oxidation
Describe how fatty acids can be used as fuels via oxidative conversion
(especially B-oxidation) to acetyl CoA.
Compare fatty acid synthesis with its breakdown
Differentiate between omega and alpha-oxidation of fatty acids.
Describe the genetic deficiency of enzymes involved in fatty acid
oxidation.
Outline the metabolic pathway of eicosanoids.
Outline the functions of eicosanoids.