CHAPTER 17

Fatty Acid Catabolism

A Personal Request
Please do On-Line Evaluation for this
course (Chem 371/650) Thank you!

Migratory Birds Travel Long Distances on

Energy From Fatty Acid Oxidation
Because they represent the most highly concentrated
form of stored biological energy, fatty acids are the
metabolic fuel of choice for sustaining the long flights
of migratory birds
American golden plovers fly from Alaska to Hawaii
nonstop 3300 km in 35 hours more than 250,000
wing beats
The ruby-throated hummingbird flies nonstop across
the Gulf of Mexico
These prodigious feats are accomplished by storing
large amounts of triacylglycerols prior to flight
These birds are often 70% fat by weight when
migration begins

Why Are Fatty Acids Used by

Organisms for Energy Storage?
Two Main Reasons:

The carbon in fatty acids (mostly -CH2-) is

reduced (so its oxidation yields the most
energy possible).
Fatty acids are not hydrated (as monoand polysaccharides are), so they can
pack more closely in storage tissues

How Are Fats Mobilized from

Dietary Intake and Adipose Tissue?
- Most of the fats in diet and in adipose
tissue are triglycerides
- Triglycerides represent the major energy
input in the modern American diet (but it
wasn't always this way)
- Triglycerides are also the major form of
stored energy in the body
- Hormones (Glucagon, Epinephrine, ACTH)
trigger the release of fatty acids from
adipose tissue

Scanning electron micrograph of an adipose cell (fat cell).

Globules of triacylglycerols occupy most of the volume of
such cells.

How are Fatty Acids Catabolized, and How

is Their Inherent Energy Captured by
Organisms?

, a lipoprotein aggregate

Pancreatic and Intestinal Lipases in Action..

Hydrolysis of triacylglycerols by
pancreatic and intestinal lipases.
Panreatic Lipases cleave fatty
acids at the C-1 and C-3
positions. Resulting
monoacylglycerols with fatty
acids at C-2 are hydrolyzed by
intestinal lipases. Fatty acids
and monoacylglycerols are
absorbed through the intestinal
wall and assembled into
lipoprotein aggregates termed
CHYLOMICRONS

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
metabolism of chylomicron
contents.

Mobilization of Triacylglycerols Stored

in Adipose Tissue Triggered by Hormones

Entry of Glycerol into The

Glycolytic Pathway

How Are Fatty Acids Broken Down?

Knoop showed that fatty acids must be degraded
by removal of 2-C units
Albert Lehninger showed that this occurred in
the Mitochondria.
F. Lynen and E. Reichart showed that the 2-C
unit released is acetyl-CoA, not free acetate
The process begins with oxidation of the
carbon that is "" to the carboxyl carbon, so
the process is called "-oxidation"

How Are Fatty Acids Broken Down?

Figure. Fatty acids are
degraded by repeated
cycles of oxidation at
the -carbon and
cleavage of the
C-C bond to yield
acetate units, in the
form of acetyl-CoA.

CoA activates FAs for oxidation

Acyl-CoA synthetase condenses fatty acids with
CoA, with simultaneous hydrolysis of ATP to
AMP and PPi
Formation of a CoA ester is expensive
energetically
Reaction just barely breaks even with ATP
hydrolysis
But subsequent hydrolysis of PPi drives the
reaction strongly forward
Note the acyl-adenylate intermediate in the
mechanism

Conversion of a Fatty Acid to a Fatty AcylCoA

Carnitine as a Carrier
Carnitine carries fatty acyl groups across the inner
mitochondrial membrane
Short chain fatty acids are carried directly into the
mitochondrial matrix
Long-chain fatty acids (>14 c) cannot be directly
transported into the matrix
Long-chain FAs are converted to acyl carnitines
and are then transported in the cell

Carnitine

Liver
TMAO (Clogs Arteries)

Fatty Acid Entry into Mitochondria via the

Acyl-Carnitine/Carnitine Transporter

Acyltransferase I is inhibited by malonyl-CoA, the first

intermediate in fatty acid synthesis. Think how this might help.

Three 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.

-Oxidation of Fatty Acids

A Repeated Sequence of 4 Reactions

Strategy: Create a carbonyl group on the -C
First 3 reactions do that; 4th cleaves the "keto ester.
Products: an acetyl-CoA and a fatty acid two
carbons shorter
The first three reactions are crucial and classic
- we will see them again and again in other
pathways

The -oxidation pathway

STEP 1: Acyl-CoA Dehydrogenase

Reaction

The mechanism of acyl-CoA dehydrogenase. Removal of a

proton from the -carbon is followed by hydride transfer from
the -carbon to FAD.

STEP 2: Enoyl-CoA Hydratase Reaction

Enoyl-CoA Hydratase Adds Water Across the Double Bond

The next step is the addition of the elements of H2O across the
new double bond in a stereospecific manner, yielding the
corresponding hydoxyacyl-CoA. The reaction is catalyzed by
enoyl-CoA hydratase, also called crotonase. These enzymes
convert trans-enoyl-CoA derivatives to L--hydroxyacyl-CoA.

STEP 3: -Hydroxyacyl-CoA Dehydrogenase

-Hydroxyacyl-CoA Dehydrogenase Oxidizes the Hydroxyl Group

The third reaction of this cycle is the oxidation of the hydroxyl

group at the -position to produce a -ketoacyl-CoA derivative.
This second oxidation reaction is catalyzed by -hydroxyacylCoA dehydrogenase, an enzyme that requires NAD+ as a
coenzyme. NADH produced in this reaction represents
metabolic energy. Each NADH produced by this reaction
drives the synthesis of 2.5 ATP.

Step 4: The Fourth Reaction of Oxidation: Thiolase

aka -ketothiolase
Cysteine thiolate on enzyme attacks the carbonyl group
Thiol group of a new CoA attacks the shortened
chain, forming a new, shorter acyl-CoA

Mechanism of STEP 4 Thiolase Rxn:

Summary of -Oxidation

Repetition of the cycle yields a succession of

acetate units
Thus, Palmitic acid (16 C) yields eight acetylCoAs
Complete -oxidation of 1 Palmitic acid yields
108 molecules of ATP
Large energy yield is a consequence of the highly
reduced state of the carbon in fatty acids
This makes fatty acids the fuel of choice for
migratory birds and many other animals

Yield of ATP during Oxidation of

One Molecule of Palmitoyl-CoA to
CO2 and H2O

Fatty Acid Oxidation is an Important Source

of Metabolic Water for Some Animals
Large amounts of metabolic water are generated by
-oxidation
For certain animals including desert animals (such
as gerbils),
and killer whales (which do not drink seawater),
and camels (whose hump is a large fat deposit)
the oxidation of stored fatty acids can be a
significant source of dietary water
Metabolism of fatty acids from such stores provides
needed water, as well as metabolic energy, during
periods when drinking water is not available

How Are Unsaturated Fatty Acids

Oxidized?

Consider monounsaturated fatty acids:

Oleic acid, palmitoleic acid
Normal -oxidation for three cycles
cis-3 acyl-CoA cannot be utilized by acyl-CoA
dehydrogenase
Enoyl-CoA isomerase converts this to trans- 2
acyl CoA
-oxidation continues from this point

Oleic-S-CoA Ester

The -oxidation pathway (Saturated FA)

Oxidation of a Monounsaturated Fatty Acid

- Most Unsaturated fatty acids

consumed my mammals are
Unsaturated with CIS Geometry.
- Oxidation requires an additional
enzyme, enoyl-CoA isomerase, to
reposition the double bond,
converting the cis isomer to a
trans isomer, a normal intermediate
in oxidation. Now Enoyl-CoA
Hydratase Can Work on it.

Degradation of Polyunsaturated Fatty Acids

Requires 2,4-Dienoyl-CoA Reductase
Degradation of polyunsaturated fatty acids is
slightly more complicated
The process is the same as for oleic acid,
through 3 cycles of -oxidation
Enoyl-CoA isomerase then converts the cis-3
double bond to a trans-2 double bond
Which permits 1 more round of -oxidation
But the resulting trans-2, cis-4 structure is a
problem
2,4-Dienoyl-CoA reductase solves this problem

Oxidation of a Polyunsaturated Fatty Acid

The example here is linoleic acid, as linoleoyl-CoA

(9,12). Oxidation requires a second auxiliary
enzyme in addition to enoyl-CoA isomerase:
NADPH-dependent 2,4-dienoyl-CoA reductase.
The combined action of these two enzymes converts
a trans-2,cis-4-dienoyl-CoA intermediate to the
trans-2-enoyl-CoA substrate necessary for
oxidation.

The -oxidation pathway

Complete Oxidation of Odd-Number Fatty Acids

(Plants and Marines) Requires 3 Extra Reactions
- Long-Chain Odd Fatty Acid Breakdown
Starts with Same Pathway as Even
Ones, Beginning at the Carboxy End.
- But Last Cycle of -Oxidation Yields
5-Carbon Fatty-Acyl CoA.
- This is Oxidized and Cleaved to
Give Acetyl-CoA and Propionyl-CoA.
- Acetyl-CoA Goes to Citric Acid Cycle.
- Propionyl-CoA Enters A Different Pathway
Involving 3 Enzymes.

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 downregulated. Two enzymes are key to the
coordination of fatty acid metabolism: acetyl-CoA carboxylase (ACC), the first
enzyme in the synthesis of fatty acids (see Figure 21-1), and carnitine acyltransferase I,
which limits the transport of fatty acids into the mitochondrial matrix for oxidation.

Triacylglycerols as Glucose Source in Seeds

Oxidation is one stage in a pathway that converts

stored triacylglycerols to glucose in germinating seeds.

Ketone Bodies and Diabetes

"Starvation of cells in the midst of plenty"

Glucose is abundant in blood, but uptake by cells
in muscle, liver, and adipose cells is low
Cells, metabolically starved, turn to
gluconeogenesis and fat/protein catabolism
In type I diabetics, Oxaloacetate is low, due to
excess gluconeogenesis, so Acetyl-CoA from
fat/protein catabolism does not go to TCA, but
rather to ketone body production
Acetone can be detected on breath of type I
diabetics

So Mammals Form Ketone Bodies in

Liver Mitochondria A Minor Pathway
In Healthy Individuals
- Healthy, well-nourished individuals produce
ketone bodies at a relatively low rate.
- When acetyl-CoA accumulates (as in
starvation or untreated diabetes), thiolase
catalyzes the condensation of two
acetyl-CoA molecules to acetoacetyl-CoA,
the parent compound of the 3 ketone
bodies

Conversion of Ketone Bodies to Acetyl-CoA

Figure 20-22

So Ketone Body Are Overproduced in Diabetes

And Starvation & Are Exported From the Liver

Conditions that promote gluconeogenesis (untreated diabetes, severely reduced food intake), slow citric
acid cycle (by drawing off oxaloacetate) and enhance the conversion of acetyl-CoA to acetoacetate.
The released coenzyme A allows continued oxidation of fatty acids.

Suggested Problems

1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 13, 14, 16, 17,

18, 19, 20, 21, 23, 26

Conversion of Ketone Bodies to Acetyl-CoA

Figure 20-22