Metabolism of Fatty Acid

Objective
The reader will be able to learn on the following topics.

 Important of fatty acids to cells

 Hydrolysis (lipolysis) of triacylglycerol by enzyme lipase in adipose tissue
 Control of lipolysis in adipose tissue through cyclic AMP
 Fate of glycerol
 Fate of free fatty acids
 β-oxidation of saturated fatty acid with even carbon atom
 Regulation of β-oxidation
 Disorder associated with β-oxidation
 β-oxidation of saturated fatty acid with odd carbon atom
 Methylmalonic acidemia
 Oxidation of fatty acids in peroxisomes
 Zellweger syndrome
 α-oxidation of fatty acid
 Refsum’s disease
 ω-oxidation of fatty acid
 Biosynthesis of fatty acids
 Fatty acid synthase (FAS) multienzyme complex
 Fatty acid elongation and desaturation
 Regulation of fatty acid synthesis
 Role of diet in fatty acid metabolism
 Comparison of fatty acid synthesis and oxidation
 Synthesis of triacylglycerols
Why are fatty acids important to cells?

– fuel molecules
• stored as triacylglycerols

– building blocks
• phospholipids
• Glycolipids

– precursors of hormones and other

messengers

– used to target proteins to membrane sites

Hydrolysis (lipolysis) of triacylglycerol by
enzyme lipase in adipose tissue

Lipase
 + H2o

+
Control of lipolysis in adipose tissue through cyclic AMP
 Fate of Glycerol

The adipose tissue lacks the

enzyme glycerol kinase

(Glycerokinase), hence glycerol

produced in lipolysis cannot be

phosporylated here. lt is transported

to liver where it is activated to

glycerol 3 -phosphate
 Fate of free fatty acids

 The fatty acids released by lipolysis in the adipocytes enter the

circulation and are transported in a bound form to albumin.

 The free fatty acids enter various tissues and are utilized for the
energy by the oxidation process.

 Certain tissues cannot oxidize fatty acids, e.g. brain, erythrocytes,

adrenal medulla.
Stages of β-oxidation of saturated fatty acid with even carbon atom

1. Activation of fatty acids takes place on the outer

mitochondrial membrane or cytosol
2. Transport into the mitochondria

3. Degradation to two-carbon fragments (as acetyl CoA) in the

mitochondrial matrix (β oxidation proper)
Activation of fatty acid to acyl CoA by the enzyme thiokinase or
acyl CoA synthetase
Carnitine shuttle for transport of activated fatty acid (acyl CoA)
into mitochondria

Or
Translocase
 β-oxidation proper

Each cycle of β-oxidation

liberates a two carbon unit
acetyl CoA and occurs in a
sequence of four reactions

1. Oxidation

2. Hydration

3. Oxidation

4. Cleavage
 β-oxidation proper
Each round generates one molecule each of:
FADH2
NADH
Acetyl CoA
Fatty acyl CoA (2 carbons shorter each round)

Fates of the products

- NADH and FADH2 - are used in ETC
- acetyl CoA - enters the citric acid cycle
- acyl CoA – undergoes the next cycle of
oxidation
 ATP Generation per one oxidized palmitate

Palmitoyl CoA + 7 HS-CoA + 7 FAD+ + 7 NAD+ + 7 H2O

8 Acetyl CoA + 7FADH2 + 7 NADH + 7 H+

ATP generated
8 acetyl CoA 10x8=80
7 FADH2 7x1.5=10.5
7 NADH 7x2.5=17.5
108 ATP
ATP expended to activate palmitate -2
Net yield: 106 ATP
 Regulation of β-oxidation

1. Availability of free fatty acid

2. Insulin

3. Epinephrine and glucagon

4. Malonyl CoA inhibit Carnitine acyl transferase I (CAT-I) so ß-oxidation

is inhibited
 Disorder associated with β-oxidation

 Sudden infant death syndrome (SIDS)

 Occurs due to blockage in ß-oxidation because of deficiency of medium
chain acyl CoA dehydrogenase.

 The enzyme defect has a frequency of 1 in 10,000 births.

 Jamaican vomiting sickness

 It is characterized by severe hypoglycemia, vomiting, convulsions, coma

and death.

 Occurs due to hypoglycin A (unusual toxic amino acid) which inhibits the
enzyme acyl CoA dehydrogenase and thus block the ß -oxidation of fatty
acids. .
 β-oxidation of saturated fatty acid with odd carbon atom

The only difference is that in the last and final β-oxidation cycle, a three-carbon
fragment is left behind (in place of 2 carbon unit). This compound is propionyl
CoA which is converted to succinyl CoA
Methylmalonic acidemia
 OXIDATION OF FATTY ACIDS IN
PEROXISOMES
Peroxisomes - organelles containing
enzyme catalase, which catalyzes
the dismutation of hydrogen
peroxide into water and molecular
oxygen

Acyl CoA dehydrogenase

transfers electrons to O2
to yield H2O2
instead of capturing the
high-energy electrons by
ETC, as occurs in
mitochondrial
b-oxidation.
Zellweger syndrome is a rare disorder characterized by
the absence of peroxisomes in almost all the tissues. As a
result, the long chain fatty acids (C26-C36) are not
oxidized. They accumulate in tissues, particularly in brain,
liver and kidney. Hence the disorder is also known as
cerebrohepatorenal syndrome.
 α-oxidation of fatty acid

 It is a process by which fatty acids are oxidised by removing carbon

atoms, one at a time, from the carboxyl end.

 The process is important in brain.

 The process occurs in the endoplasmic reticulum.

 Does not require CoA.

 Does not generate energy.

 It is mainly used for fatty acids (phytanic acid ) that have a methyl
group at the beta-carbon, which blocks beta oxidation.
Refsum’s Disease
 ω-oxidation of fatty acid

 It is a minor pathway taking place in microsomes.

 ω-oxidation becomes important when β-oxidation is defective.

 Biosynthesis of fatty acids

• Occurs mainly in liver, kidney, adipose tissue and

lactating mammary glands.
• Occurs in cytoplasm
• FA synthesis and degradation occur by two completely
separate pathways.
• When glucose is plentiful, large amounts of acetyl CoA(
as source of carbon atom) are produced by glycolysis
and can be used for fatty acid synthesis.
• NADPH provides the reducing equivalents and ATP
supplies energy for FA formation.
 Three stages of fatty acid
synthesis:

1. Transport of acetyl CoA from mitochondria into

cytosol and supply of NADPH

2. Conversion of acetyl CoA to malonyl CoA

3. Reactions of fatty acid synthase (FAS)

multienzyme complex or Assembly of fatty acid
chain
1. Transport of acetyl CoA from mitochondria into cytosol and
supply of NADPH

Isocitrate + α ketoglutarate +
Cytoplasmic isocitrate dehydrogenase

Ketene bodies
2. Conversion of acetyl CoA to malonyl CoA
3. Reactions of fatty acid synthase (FAS) multienzyme complex or Assembly
of fatty acid chain
Summary of paltimate synthesis
Fatty acid synthase (FAS) multienzyme complex
Fatty Acid Elongation and Desaturation
The common product of fatty acid synthesis is
palmitate (16:0).
Longer fatty acids and unsaturated fatty acids are
synthesized in the endoplasmic reticulum.
The reactions of elongation are similar to the ones
seen with fatty acid synthase (new carbons are
added in the form of malonyl CoA).
For the formation of unsaturated fatty acids there
are various desaturases that catalizing the
formation of double bonds.
 Regulation of fatty acid synthesis

Acetyl CoA carboxylase plays an essential role in

regulating fatty acid synthesis.
The Acetyl CoA carboxylase is controlled by hormones:
 glucagon,
 epinephrine, and
 insulin.

Another regulatory factors:

 citrate,
 palmitoyl CoA,
 AMP and
ATP
Acetyl CoA carboxylase is switched off by phosphorylation
and activated by dephosphorylation

Insulin stimulates fatty acid synthesis by causing

dephosphorylation of carboxylase.
Glucagon and epinephrine have the reverse effect (keep the
carboxylase in the inactive phosphorylated state and
inhibit fatty acid synthesis).

Protein kinase is
activated by AMP
(inhibit FA synthesis)
and inhibited by ATP
(Stimulate FA
synthesis).
Acetyl CoA carboxylase is allosterically stimulated by citrate.
The level of citrate is high when both acetyl CoA and ATP are
abundant. They activate the fatty acid synthesis.
Palmitoyl CoA inhibits carboxylase and inhibits the fatty acid
synthesis

NADPH activates the FA synthesis.

Role of diet in fatty acid metabolism

Fed state:
• Insulin level is increased

• Inhibits hydrolysis (lipolysis)of stored TGs and stimulate the synthesis of

FA and ß-oxidation.

Starvation:
• Epinephrine and glucagon are produced and stimulate hydrolysis (lipolysis) of
stored TGs and the level of free fatty acids rises which undergoes the ß-
oxidation pathway to provide energy.
• They also inhibit FA synthesis.
Comparison of fatty acid synthesis and oxidation
Synthesis of triacylglycerols
Liver Liver & Adipose tissue

Fatty acids and glycerol must be

activated prior to the synthesis of

triacylglycerols.

Conversion of fatty acid to acyl

CoA occurs by thiokinase.

A saturated fatty acid

is usually present on carbon 1,
an unsaturated fatty acid is
found on carbon 2, and carbon 3
may have either.
 Reference books

 Textbook of Biochemistry for Medical Student (DM Vasudevan)

 Textbook of Biochemistry ( U. Satyanarayana)

 Harper’s
THANK YOU