Biochemistry II
CHEM152
CHAPTER 17
Fatty Acid Catabolism
CHAPTER 17:
Fatty Acid Catabolism
Key topics:
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How fats are digested in animals
How fats are mobilized and transported in tissues
How fats are oxidized
How “ketone bodies” are produced
Oxidation of fatty acids is a major energy
source in many organisms
• About one-third of our
energy needs comes from
dietary triacylglycerols
• About 80% of energy needs
of mammalian heart and
liver are met by oxidation of
fatty acids
• Many hibernating animals,
such as grizzly bears, rely
almost exclusively on fats as
their source of energy
Fats provide efficient fuel storage
• The advantage of fats over
polysaccharides:
– Fatty acids carry more energy
per carbon because they are
more reduced
– Fatty acids carry less water
along because they are
nonpolar
• Glucose and glycogen are for
short-term energy needs, quick
delivery
• Fats are for long-term (months)
energy needs, good storage, slow
delivery
fat storage in white
adipose tissue
Dietary fatty acids are absorbed in the
vertebrate small intestine
Dietary fatty acids are absorbed in the
vertebrate small intestine
• Fatty acids use bile salts (fat emulsifiers)
to aid in absorption by acting as
detergents
• Fat breakdown in digestive system
involves intestinal lipases (extracellular)
• Fats hydrolyzed to fatty acids can help
emulsify more fats
- adding to the work of bile salts
Fats existing the digestive system
• Fats (triacylglycerols) are degraded (intestinal lumen) and
remade in (intestinal mucosa)
Lipids are transported
in the blood as chylomicrons
• Single monolayer structure; not bilayer
Hormones trigger mobilization
of stored triacylglycerols
• Phosphorylation
activates breakdown in
fats like
phosphorylation actives
glycogen breakdown
• Activation of 3 different
lipases (intracellular)
Hydrolysis of fats yields
fatty acids and glycerol
• Hydrolysis of triacylglycerols is catalyzed by lipases
• Some lipases are regulated by hormones glucagon and
epinephrine
• Epinephrine means: “We need energy now”
Glucagon means: “We are out of glucose”
Glycerol from fats enters glycolysis
• Glycerol kinase activates glycerol
by phosphorylation at the
expense of ATP
• Subsequent reactions
recover more than enough
ATP to cover this cost
• Glycerol is oxidized to the
glycolytic intermediate DHAP
and fed into glycolysis
• Allows limited anaerobic
catabolism of fats
Transport or attachment to phospholipids
requires conversion to fatty acyl-CoA
• Activates fatty acids by
addition of CoA
(thioester)
• Reduces fatty acid
inside of cells from
acting as detergents
Fatty Acid Transport into Mitochondria
• Fats are degraded into fatty acids and glycerol in the
cytoplasm of adipocytes
• Fatty acids are transported to other tissues for fuel
• -oxidation of fatty acids occurs in mitochondria
Fatty Acid Transport into Mitochondria
• Small (< 12 carbons) fatty acids diffuse freely across
mitochondrial membranes
• Larger fatty acids (most free fatty acids) are
transported via acyl-carnitine/carnitine transporter
• Carnitine shuttles fatty acids into the mitochondrial
matrix
Fatty Acid Transport into Mitochondria
• Larger fatty acids (most
free fatty acids) are
transported via acylcarnitine/carnitine
transporter
• Carnitine shuttles fatty
acids into the
mitochondrial matrix
Stages of Fatty Acid Oxidation
• Stage 1 consists of oxidative
conversion of two-carbon units into
acetyl-CoA via β-oxidation with
concomitant generation of NADH
and FADH2
– involves oxidation of β carbon to
thioester of fatty acyl-CoA
• Stage 2 involves oxidation of acetylCoA into CO2 via citric acid cycle
with concomitant generation NADH
and FADH2
• Stage 3 generates ATP from NADH
and FADH2 via the respiratory chain
The -Oxidation Pathway
Each pass removes one acetyl moiety in the form of acetyl-CoA.
1)
2)
3)
4)
Steps
Dehydrogenation
Hydration
Oxidation of –OH
Thiolase (cleavage)
Fatty acid oxidation reaction summary
Step 1: Dehydrogenation of Alkane to Alkene
• Catalyzed by isoforms of
acyl-CoA dehydrogenase
(AD) on the innermitochondrial membrane
– Very-long-chain AD (12–18 carbons;
occurs in peroxisome)
– Medium-chain AD (4–14 carbons)
– Short-chain AD (4–8 carbons)
• Analogous to succinate
dehydrogenase reaction in
the CAC
– Electrons from bound FAD
transferred directly to the electrontransport chain via electrontransferring flavoprotein (ETF)
Step 1: Dehydrogenation of Alkane to Alkene
• Results in trans double
bond, different from
naturally occurring
unsaturated fatty acids
• Dehydrogenation of fatty
acyl-CoA produces double
bond between the a and 
carbon bonds (C-2 and C3)
yielding a trans-D2-enoyl
CoA
FAD Cofactor
Flow of Electrons from Biological Fuels
into the Electron-Transport Chain
Step 2: Hydration of Alkene
• Catalyzed by two isoforms
of enoyl-CoA hydratase:
• Water adds across the
double bond yielding
alcohol
• Analogous to fumarase
reaction in the citric acid
cycle
– Same stereospecificity
Step 3: Dehydrogenation of Alcohol
• Catalyzed by -hydroxyacylCoA dehydrogenase
• The enzyme uses NAD
cofactor as the hydride
acceptor
• Only L-isomers of
hydroxyacyl CoA act as
substrates
• Analogous to malate
dehydrogenase reaction in
the citric acid cycle
Step 4: Transfer of Fatty Acid Chain
• Catalyzed by acyl-CoA
acetyltransferase (thiolase)
via covalent mechanism
– The carbonyl carbon in ketoacyl-CoA is electrophilic
– Active site thiolate acts as
nucleophile and releases
acetyl-CoA
– Terminal sulfur in CoA-SH acts
as nucleophile and picks up
the fatty acid chain from the
enzyme
• The net reaction is thiolysis
of carbon-carbon bond
Fatty Acid Catabolism for Energy
• For palmitic acid (C16)
– Repeating the above four-step
process six more times (7 total)
results in eight molecules of
acetyl-CoA
• FADH2 is formed in each cycle (7 total)
• NADH is formed in each cycle (7 total)
• Each round produces an acetyl-CoA and
shortens the chain by two carbons
• Acetyl-CoA enters citric acid cycle and
further oxidizes into CO2
– This makes more GTP, NADH, and FADH2
• Electrons from all FADH2 and NADH enter
ETF
NADH and FADH2 serve as sources of ATP
Similar mechanisms introduce carbonyls
in other metabolic pathways
Oxidation of Unsaturated Fatty Acids
• Naturally occurring Unsaturated
Fatty acids contain cis double
bonds
– Are NOT a substrate for enoyl-CoA
hydratase
• Two additional enzymes are
required
– Isomerase: converts cis double
bonds starting at carbon 3 to trans
double bonds
– Reductase: reduces cis double
bonds not at carbon 3
• Monounsaturated fatty acids
require the isomerase
• Polyunsaturated fatty acids
require both enzymes
Oxidation of Polyunsaturated Fatty Acids
• Naturally occurring Unsaturated
Fatty acids contain cis double
bonds
– Are NOT a substrate for enoyl-CoA
hydratase
• Two additional enzymes are
required
– Isomerase: converts cis double
bonds starting at carbon 3 to trans
double bonds
– Reductase: reduces cis double
bonds not at carbon 3
• Monounsaturated fatty acids
require the isomerase
• Polyunsaturated fatty acids
require both enzymes
First double bond requires isomerization
Second requires reduction/isomerization
Oxidation of odd-numbered fatty acids
• Most dietary fatty acids are evennumbered
• Many plants and some marine
organisms also synthesize oddnumbered fatty acids
• Propionyl-CoA forms from oxidation of odd-numbered fatty
acids
• Bacterial metabolism in the rumen
of ruminants also produces
propionyl-CoA
Carboxylation of Propionyl-CoA
Isomerization to Succinyl-CoA  CAC
Isomerization in propionate oxidation
requires coenzyme B12
Complex Cobalt-Containing Compound:
Coenzyme B12
Isomerization in propionate oxidation
requires coenzyme B12
Oxidation of odd-numbered fatty acids
Regulation of Fatty Acid
Synthesis and Breakdown
-Oxidation in Plants Occurs
Mainly in Peroxisomes
• Mitochondrial acyl-CoA
dehydrogenase passes electrons
into respiratory chain via electrontransferring flavoprotein
– Energy captured as ATP
• Peroxisomal/glyoxysomal acyl-CoA
dehydrogenase passes electrons
directly to molecular oxygen
– Energy released as heat
– Hydrogen peroxide eliminated
by catalase
Comparison of β oxidation in mitochondria
and in peroxisomes and glyoxysomes
The peroxisomal/glyoxysomal system differs from the
mitochondrial system in three respects:
1. The peroxisomal system prefers
very-long-chain fatty acids
2. In the first oxidative step electrons
pass directly to O2, generating H2O2
3. The NADH formed in the second
oxidative step cannot be reoxidized
in the peroxisome or glyoxysome, so
reducing equivalents are exported
to the cytosol, eventually entering
mitochondria
ω-Oxidation in the ER of Liver Cells
• Minor pathway in mammals, more
important in invertebrates
• Involves oxidation of the carbon
most distant from carboxyl group
• Located in ER of liver
– Steps involve introduction of hydroxyl
group via molecular oxygen followed
by a series of oxidations (alcohol to
aldehyde to carboxylic acid.
– Each step through the path results in
dicarboxylic acids, one of which can
enter CAC
α-Oxidation of Branched Chain Fatty Acids
Takes Place in Peroxisomes
• Presence of methyl group on the 
carbon of a fatty acids make 
oxidation impossible
• Oxidation of branch chains occurs
in the peroxisome of animal cells
– Steps involve the hydroxylation of the
a carbon, in a reaction that involves
molecular oxygen, decarboxylation to
aldehyde, and oxidation to carboxylic
acids. This can now be further
oxidized via  oxidation.
Acetyl-CoA in the glyoxysome is then
converted to metabolic intermediates
Formation of Ketone Bodies in Liver
• Acetyl-CoA formed in the liver during
oxidation of fatty acids can either
– Enter citric acid cycle
– Undergo conversion to ketone bodies
• When glucose is not available, we
need a backup energy supply
• Ketone bodies are water-soluble,
readily available compounds made
from fatty acids
– Can be released quickly into blood and
provide energy where needed like
glucose
• Ketone bodies are made when
glucose is low
Formation of Ketone Bodies in Liver
• Acetyl-CoA formed in the liver during
oxidation of fatty acids can either
– Enter citric acid cycle
– Undergo conversion to ketone bodies
• When glucose is not available, we
need a backup energy supply
• Ketone bodies are water-soluble,
readily available compounds made
from fatty acids
– Can be released quickly into blood and
provide energy where needed like
glucose
• Ketone bodies are made when
glucose is low
Formation of Ketone Bodies in Liver
• The first step is reverse of the
last step in the -oxidation:
thiolase reaction joins two
acetate units
• Third condensation with acetylCoA make HMG-CoA, a
precursor of isoprenes and
cholesterol (steroid
biosynthesis)
• Reaction cause release of free
CoA
Formation of Ketone Bodies in Liver
• HMG-CoA is cleaved to
free acetoacetate and
acetyl-CoA
• Acetoacetate is a -keto
acid, which is unstable and
can undergo spontaneous
decarboxylation or
reduction to more stable
compound using NADH
– Diabetics produce large
amounts of ketones &
volatile acetone can be
detected on breath
Utilization of Ketone Bodies NOT in Liver
• Ketone bodies released by
liver are taken up by other
organs (non-liver) as a fuel
• Hydroxybutyrate is oxidized
back to acetoacetate
• Acetoacetate is activated to
thiol ester (CoA) by transfer
from succinyl –CoA
– Transferase reaction catalyzed
by -ketoacyl-CoA transferase,
also called thiophorase
• Final reaction tis cleaved by
thiolase yields 2 acetyl-CoA
that can enter CAC
Liver is the source of ketone bodies
• Production of ketone
bodies increases during
starvation (and diabetes)
• Ketone bodies are released
by liver to bloodstream
• Organs other than liver can
use ketone bodies as fuels
• High levels of acetoacetate
and -hydroxybutyrate
lower blood pH
dangerously (acidosis)
Chapter 17: Summary
In this chapter, we learned:
• Fats are an important energy source in animals
• Two-carbon units in fatty acids are oxidized in a four-step oxidation process into acetyl-CoA
• In the process, a lot of NADH and FADH2 forms; these can yield
a lot of ATP in the electron-transport chain
• Acetyl-CoA formed in the liver can be either oxidized via the
citric acid cycle or converted to ketone bodies that serve as
fuels for other tissues