The oxidation of long-chain fatty acids to acetyl-CoA is a

central energy-yielding pathway in many organisms and

tissues. In mammalian heart and liver, for example, it
provides as much as 80% of the energetic needs under all
physiological circumstances.
The electrons removed from fatty acids during oxidation pass
through the respiratory chain, driving ATP synthesis; the
acetyl-CoA produced from the fatty acids may be completely
oxidized to CO2 in the citric acid cycle, resulting
in further energy conservation.
In some species and in some tissues, the acetyl-CoA has
alternative fates. In liver, acetyl-CoA may be converted to
ketone bodies water-soluble fuels exported to the brain
and other tissues when glucose is not available.

Digestion, Mobilization, and

Transport
of Fats
Processing
of dietary lipids in

vertebrates. Digestion and absorption of

dietary lipids occur in the
small and the
intestine,
fatty acids released
from triacylglycerols
are packaged into
chylomicrons
by combination with
specific
apolipoproteins and
delivered to muscle
and adipose tissues.

Structure of glycocholic acid.

Chylomicrons deliver
triacylglycerols to tissues, where
lipoprotein lipase releases free
fatty acids for entry into cells.
Triacylglycerols stored in adipose
tissue are mobilized by a
hormone-sensitive triacylglycerol
lipase.
The released fatty acids bind to
serum albumin and are carried in
the blood to the heart, skeletal
muscle, and other tissues that use
fatty acids for fuel.
Molecular structure of a chylomicron. The surface is a layer of
phospholipids, with head groups facing the aqueous phase.
Triacylglycerols sequestered in the interior (yellow) make up more
than 80% of the mass. Several apolipoproteins that protrude from
the surface (B-48, C-III, C-II) act as signals in the uptake and

Mobilization of triacylglycerols stored in adipose tissue.

When low levels of glucose in the blood trigger the release of
glucagon and/or epinephrine, 1 the hormone binds its receptor
adipocyte
membrane and thus 2
in the
stimulates adenylyl cyclase, via a
G protein, to produce cAMP. This
activates Potein Kinase A, which
phosphorylates 3 the hormonesensitive lipase and 4 perilipin
molecules on the surface of the
lipid droplet. Phosphorylation of
perilipin permits hormone
sensitive lipase access to the
surface of the lipid droplet, where
5 it hydrolyzes triacylglycerols to
free fatty acids. 6 Fatty acids
leave the adipocyte, bind serum
albumin in the blood, and are
transporter.
In the myocyte,
carried in the8 blood;
they are fatty acids are oxidized to CO2,
and
the energy
ofalbumin
oxidation
is conserved
in ATP, which fuels
released
from the
and
7
muscle
enter a myocyte via a specific

Once inside cells, fatty acids are activated at the outer

mitochondrial membrane by conversion to fatty acylCoA
thioesters. Fatty acylCoA to be oxidized enters mitochondria in
three steps, via the carnitine shuttle.

Fatty acid entry into mitochondria via the acyl-carnitine/

carnitine transporter. After fatty acylcarnitine is formed at the
outer membrane or in the inter membrane space, it moves into
the matrix by facilitated diffusion through the transporter in the
inner membrane. In the matrix, the acyl group is transferred to
mitochondrial coenzyme A, freeing carnitine to return to the
intermembrane space through the same transporter.
Acyltransferase I is inhibited by malonyl-CoA, the first

Key concept map for

fatty acid and
triacylglycerol
metabolism.

Oxidation of Fatty Acids

Oxidation of Fatty Acids

Stages of fatty acid oxidation.

Stage 1: A long-chain fatty acid is
oxidized to yield acetyl residues in
the form of acetyl- CoA. This
process is called oxidation.
Stage 2: The acetyl groups are
oxidized to CO2 via the citric acid
cycle.
Stage 3: Electrons derived from the
oxidations of stages 1 and 2 pass
to O2 via the mitochondrial
respiratory chain, providing the
energy for ATP synthesis by
oxidative phosphorylation.

reduced electron carriers

Donate
electrons

The major pathway for catabolism of fatty acids is a

mitochondrial pathway called -oxidation, in which twocarbon fragments are successively removed from the carboxyl
end of the fatty acyl CoA, producing acetyl CoA, NADH, and
FADH2.
Transport of long-chain fatty acids (LCFA) into the
mitochondria:

acylcarnitine

Inner mitochondrial membrane is impermeable to CoA.

Therefore, a specialized carrier, Carnithine, transports the
long-chain acyl group from the cytosol into the mitochondrial
matrix. This rate-limiting transport process is called the
carnitine shuttle. [Note: Long-chain fatty acyl CoA
synthetase is in the outer mitochondrial membrane; active

Inhibitor of the carnitine shuttle: Malonyl CoA inhibits

CPT-I, thus preventing the entry of long-chain acyl groups
into the mitochondrial matrix. Therefore, when fatty acid
synthesis is occurring in the cytosol (as indicated by the
presence of malonyl CoA), the newly made palmitate cannot
be transferred into the mitochondria and degraded.
Sources of carnitine: Carnitine can be obtained from the
diet, where it is found primarily in meat products. Carnitine
can also be synthesized from the amino acids lysine and
methionine by an enzymatic pathway found in the liver and
kidney but not in skeletal or heart muscle.
Entry of short- and medium-chain fatty acids (plentiful
in human milk) into the mitochondria: Fatty acids shorter
than 12 carbons can cross the inner mitochondrial membrane
without the aid of carnitine or the CPT system.
Once inside the mitochondria, they are activated to their CoA
derivatives

The Oxidation of Saturated Fatty Acids Has

Four Basic Steps

In the first stage of oxidation, four reactions remove

each acetyl-CoA unit from the carboxyl end of a
saturated fatty acylCoA:
(1)dehydrogenation of the - and - carbons (C-2 and
C-3) by FAD-linked acyl-CoA dehydrogenases,
(2)hydration of the resulting trans -2 double bond by
enoyl-CoA hydratase, catalyze the addition of
H2O to the trans double bond of the 2-enoyl-CoA
generated during oxidation.
(3)dehydrogenation of the resulting L--hydroxyacylCoA by NAD- linked - hydroxyacyl-CoA
dehydrogenase, and
(4)CoA-requiring cleavage of the resulting -ketoacylCoA by thiolase, to form acetyl-CoA and a fatty
acylCoA shortened by two carbons.

*three isozymes
VLCAD
MCAD
SCAD

The -oxidation pathway. (a) In

each pass through this four-step
sequence, one acetyl residue
(shaded in pink) is removed in the
form of acetyl-CoA from the
carboxyl end of the fatty acyl chain
in this example palmitate (C16),
which enters as palmitoyl-CoA. (b)
Six more passes through the
pathway yield seven more
molecules of acetyl-CoA, the
seventh arising from the last two

Oxidation of Unsaturated Fatty Acids Requires

Additional Reactions
Oxidation of a
monounsaturated fatty
acid. Oxidation of Oleic
acid, as oleoyl-CoA (9),
requires an
additional enzyme, enoylCoA isomerase, to
reposition the double bond,
converting the cis isomer
*
to a trans isomer, a
normal intermediate in
oxidation.
Note: most of the fatty
acids in the triacylglycerols
and phospholipids
of animals and plants are
unsaturated, having one or
more double bonds. These

* cannot serve as a substrate for enoyl-CoA hydratase, which acts only on trans

Complete Oxidation of Odd-Number Fatty Acids Requires

Three Extra Reactions
Oxidation of propionyl-CoA
produced by oxidation of oddnumber fatty acids.

Propionyl-CoA is first carboxylated

to form the D stereoisomer of
methylmalonyl-CoA by
propionyl-CoA carboxylase,
which contains the cofactor biotin.
The D-methylmalonyl- CoA thus
formed is enzymatically epimerized
to its L stereoisomer by
methylmalonyl-CoA epimerase .
The L-methylmalonyl-CoA then
undergoes an
intramolecular rearrangement to
form succinyl-CoA, which can enter
the citric acid cycle. This
rearrangement is catalyzed by

Vitamin B12 (synthesized only by a few species of

microorganisms; daily requirement 3 g/day) deficiency
results in serious disease called Pernicious Anemia due to
(in most cases) from failure to absorb vitamin B12
efficiently from the intestine, where it is synthesized by
intestinal bacteria or obtained from digestion of meat .
Individuals with this disease do not produce sufficient amounts
of intrinsic factor, a glycoprotein essential to vitamin B12
absorption.
The pathology in pernicious anemia includes reduced
production
of erythrocytes, reduced levels of hemoglobin, and severe,
progressive impairment of the central nervous system.
Administration of large doses of vitamin B12 alleviates these
symptoms in at least some cases.
Common signs and symptoms of pernicious anemia are:

KETONE BODIES: AN ALTERNATE FUEL

FOR
CELLS
In humans and
most
other mammals, acetyl-CoA formed in the

liver during oxidation of fatty acids can either enter the citric
acid cycle or undergo
conversion to the ketone bodies, acetone, acetoacetate, and
D--hydroxybutyrate, for export to other tissues.
Ketone bodies are important sources of energy for the
peripheral tissues because
1) they are soluble in aqueous solution and,
therefore, do not need to be incorporated into
lipoproteins or carried by albumin as do the other lipids;
2) they are produced in the liver during periods when
the amount of acetyl CoA present exceeds the oxidative
capacity of the liver; and
3) they are used in proportion to their concentration in the blood
by extrahepatic tissues, such as the skeletal and cardiac muscle
and renal cortex. Even the brain can use ketone bodies to help
meet its energy needs if the blood levels rise sufficiently; thus,

Synthesis of ketone bodies by the

liver: ketogenesis

Use of ketone bodies by the peripheral

tissues: ketolysis

Liver mitochondria can convert acetyl CoA derived

from fatty acid oxidation into the ketone bodies,
acetoacetate and 3-hydroxy butyrate.
Peripheral tissues possessing mitochondria can
oxidize 3-hydroxybutyrate to acetoacetate, which
can be reconverted to acetyl CoA, thus producing
energy for the cell. Unlike fatty acids, ketone
bodies are utilized by the brain and, therefore, are
important fuels during a fast. The liver lacks the
ability to degrade ketone bodies, and so

Ketone body formation and export from the liver. In

untreated diabetes, when the insulin level is insufficient,
extrahepatic tissues cannot take up glucose efficiently from the
blood, either for fuel or for conversion
Under CoA
these
levelstooffat.
malonyl(the
conditions,
starting material for fatty acid
synthesis) fall,
inhibition of carnitine
acyltransferase I is relieved, and
fatty acids enter mitochondria to
be degraded to acetyl- CoA
*
which cannot pass through the
citric acid cycle because cycle
intermediates have been drawn
off for use as substrates in
gluconeogenesis. The resulting
accumulation of acetyl-CoA
accelerates the formation of
ketone
bodies beyond the capacity of
extrahepatic tissues to oxidize
*The released coenzyme A allows
continued oxidation of fatty acids.
them. The increased blood levels

Fatty Acid Synthesis

Generally a linear hydrocarbon chain with a terminal carboxyl

group, a fatty acid can be saturated or unsaturated. Two fatty
acids are essential (must be obtained from the diet): linoleic and
-linolenic acids. Fatty acids are synthesized in the cytosol of
liver following a meal containing excess carbohydrate and
protein. Carbons used to synthesize fatty acids are provided by
acetyl CoA, energy by ATP, and reducing equivalents by NADPH.
Biosynthesis of fatty acids requires the participation of a threecarbon intermediate, malonyl-CoA. The formation of malonylCoA from acetyl-CoA is an
irreversible process, catalyzed by acetyl-CoA carboxylase.

The acetyl-CoA carboxylase reaction. Acetyl-CoA

carboxylase has three functional regions: biotin carrier protein
(gray); biotin carboxylase, which activates CO2 by attaching it to
a nitrogen in the biotin ring in an ATP-dependent transcarboxylas
reaction; and
e, which
transfers
activated CO2
(shaded green)
from biotin to
acetyl-CoA,
producing
malonyl-CoA.

Fatty Acid Synthesis Proceeds in a Repeating

Reaction
Sequence
The long
carbon chains
of fatty acids are assembled in a

repeating four-step sequence.

A saturated acyl group produced by this set of reactions becomes
the substrate for subsequent condensation with an activated
malonyl group.
With each passage through the cycle, the fatty acyl chain is
extended by two carbons.
When the chain length reaches 16 carbons, the product
(palmitate, 16:0) leaves the cycle.
Carbons C-16 and C-15 of the palmitate are
derived from the methyl and carboxyl carbon
ACP
atoms, respectively, of an acetyl-CoA
used directly to prime the system;the rest
of the carbon atoms in the chain are
derived from acetyl-CoA via malonyl-CoA.
All the reactions in the synthetic process are catalyzed by a
multienzyme complex, fatty acid synthase.

Addition of two carbons to a

growing fatty acyl chain: a fourstep sequence.
Each malonyl group and acetyl (or
longer acyl) group is activated by a
thioester that links it to fatty
acid synthase, a multienzyme
complex.
1. Condensation of an activated
acyl group (an acetyl group from
acetyl-CoA is the first
acyl group) and two carbons derived
from malonyl-CoA, with elimination
of CO2 from the malonyl group,
extends the acyl chain by two
carbons. The mechanism of the first
step of this reaction is given to
illustrate
the role of decarboxylation in
facilitating condensation. The -keto

3. elimination of H2O (dehydration) creates a

double bond, and 4. the double bond is reduced
to form the corresponding saturated fatty acyl
group.

The overall process of palmitate synthesis.

The fatty acyl chain grows by two-carbon units
donated by activated malonate, with loss of CO2
at each step. The initial acetyl group is shaded
yellow, C-1 and C-2 of malonate are shaded pink,
and the carbon released as CO2 is shaded green.
After each two-carbon addition, reductions
convert the growing chain to a saturated fatty
acid of four, then six, then eight carbons, and so

Subcellular localization of lipid metabolism. Yeast and

vertebrate cells differ from higher plant cells in the
compartmentation of lipid metabolism. Fatty acid synthesis takes
place in the compartment in which NADPH is available for
reductive synthesis (i.e., where the [NADPH]/[NADP] ratio is high).

Coordinated regulation of fatty acid synthesis

and breakdown
When the diet provides a ready source of carbohydrate as fuel,
oxidation of fatty acids is unnecessary and is therefore down
regulated.
Two enzymes are key to the coordination of fatty acid metabolism:
acetyl-CoA carboxylase (ACC), the first enzyme in the synthesis of
fatty acids , and carnitine acyl transferase I, which limits the
transport of fatty acids into the mitochondrial matrix for oxidation.
Ingestion of a high-carbohydrate meal raises the blood glucose level
and thus 1 triggers the release of insulin. 2 Insulin-dependent protein
phosphatase dephosphorylates ACC, activating it. 3 ACC catalyzes
the formation of malonyl-CoA (the first intermediate of fatty acid
synthesis), and 4 malonyl-CoA inhibits carnitine acyltransferase I,
thereby preventing fatty acid entry into the mitochondrial matrix.
When blood glucose levels drop between meals, 5 glucagon release
activates cAMP-dependent protein kinase (PKA), which 6
phosphorylates and inactivates ACC. The concentration of malonylCoA falls, the inhibition of fatty acid entry into mitochondria is
relieved, and 7 fatty acids enter the mitochondrial matrix and 8
become the major fuel. Because glucagon also triggers the

(allosteric activator)

The reaction catalyzed by acetyl-CoA

carboxylase is the rate-limiting step in the
biosynthesis of fatty acids, and this enzyme is
an important site of regulation.
Coordinated regulation of fatty acid
synthesis and breakdown

(feedback inhibitor)

Summary of the energy yield from the oxidation of palmitoyl CoA (16
carbons). CC = acetyl CoA. *Activation of palmitate to palmitoyl CoA

Comparison of the synthesis and degradation of long-chain,

even-numbered, saturated fatty acids

SPECIAL TOPIC: BIOLOGICAL MEMBRANE

Major Components of Plasma Membranes in Various

Organisms

Fluid mosaic model for membrane structure. The

fatty acyl chains in the interior of the membrane form
a fluid, hydrophobic region. Integral proteins float in
this sea of lipid,
interactions
withheld
theirby hydrophobic
nonpolar amino acid side
chains. Both proteins and
lipids are free to move
laterally in the plane of
the bilayer, but
movement of either from
one face of the bilayer to
the other is restricted.
CHO moieties exposed on

QUESTIONS:

ibe the processing of dietary lipids in vertebrates in terms of Digestion, Mobilizat

nsport of Fats.
ment on Chylomicron, Carnitine shuttle, Pernicious Anemia, Ketone bodies, Acetyl
ylase reaction, Subcellular localization of lipid metabolism
evels of glucose in the blood triggers the mobilization of triacylglycerols stored in
tissue? Explain with a suitable diagram.
are the different stages of fatty acid oxidation?
ibe the -oxidation pathway for palmitic acid (C16).
oxidation of unsaturated fatty acids requires additional reactions?
in the cause of Diabetic ketoacidosis?
ibe the pathway for palmitic acid synthesis (C16).
y discuss the coordinated regulation of fatty acid synthesis and breakdown.
marize the energy yield from the oxidation of palmitoyl CoA.
pare the synthesis and degradation of long-chain, even-numbered, saturated fat