Lipid catabolism (fatty acid oxidation)

Lipid catabolism

1. LECTURE NOTES: PHARM. BIOCHEMISTRY


DR. USMAN SALEEM 1

Fatty Acid Oxidation
Over View
As early as 1904, Franz Knoop, proposed that the body utilizes fatty acids as an energy source by breaking them
down into fragments. Prior to fragmentation, the -carbon (the second carbon atom from the COOH group) is
oxidized:


The name -oxidation has its origin in Knoop’s prediction.
Definition
The biochemical pathway that degrades fatty acids to acetyl CoA by removing two carbons at a time and
yielding energy.
Location
The -oxidation of fatty acids occur in several tissues, including liver, muscle, and adipose tissue. The
erythrocytes and brain cannot use fatty acids and so continue to rely on glucose during normal periods of
fasting. Erythrocytes lack mitochondria, and fatty acids do not cross the blood-brain barrier efficiently.
Short and medium-chain fatty acids diffuse freely into mitochondria while long chain fatty acids are transported
into mitochondrion by a carnitine shuttle to be oxidized.
Steps of -Oxidation for Fatty Acids.

A. Activation of Fatty Acid
Long chain fatty acids that enter tissue cells cannot be oxidized to produce energy until they pass through
the mitochondrial membrane. This cannot occur until the fatty acid is converted into fatty acyl CoA by
reaction with coenzyme A (CoA-SH).

2. LECTURE NOTES: PHARM. BIOCHEMISTRY


DR. USMAN SALEEM 2


This reaction is catalyzed by acyl CoA synthetase and is referred to as activation of the fatty acid because
the fatty acyl CoA is a high-energy compound. The energy needed for its synthesis is provided by the
hydrolysis of ATP to AMP and PPi.
The activated fatty acid must be transported into the mitochondrion so that the rest of the oxidation process
can proceed.
B. Transport of Fatty Acyl-CoA into Mitochondria
The acyl-CoA can cross the outer mitochondrial membrane but not the inner membrane. In the intermembrane
space, the acyl group is transferred to carnitine by transesterification to form acyl-carnitine; this reaction is
catalyzed by the enzyme carnitine acyltransferase-I, which is located on the outer face of the inner membrane.
The acyl-carnitine passes through the inner membrane via a specific carnitine/acyl-carnitine transporter
called carnitine translocase. Once in the matrix, the acyl group is transferred from carnitine to
mitochondrial CoA-SH by another enzyme called carnitine acyltransferase-II located on the inner face of the
membrane.

C. -Oxidation
Once the fatty acid in the form of acyl CoA is inside the mitochondrion, it is degraded in a catabolic
process called -oxidation.
The -oxidation of saturated fatty acids involves a cycle of four enzyme-catalyzed reactions.
1) Oxidation by FAD
2) Hydration
3) Oxidation by NAD
4) Cleavage

1) Oxidation by FAD: The acyl-CoA is oxidized to an , unsaturated acyl-CoA (also called a -enoyl-
CoA). This reaction is catalyzed by an FAD-dependent acyl-CoA dehydrogenase. The product has the trans
arrangement at the double bond.
2) Hydration: The unsaturated acyl-CoA is hydrated to produce a -hydroxyacyl-CoA. This reaction is
catalyzed by the enzyme enoyl-CoA hydratase.
3) Oxidation by FAD: A second oxidation reaction is catalyzed by β-hydroxyacyl-CoA dehydrogenase,
an NAD
+
-dependent enzyme. The product is a β-ketoacyl-CoA.

3. LECTURE NOTES: PHARM. BIOCHEMISTRY


DR. USMAN SALEEM 3

4) Cleavage: The enzyme thiolase catalyze the cleavage of the terminal C2 fragment (an acetyl CoA) from
the chain and the rest of the molecule is bonded to a new molecule of coenzyme A (acyl CoA).

The new fatty acyl-CoA that is two carbons shorter than the original molecule enters the-oxidation process
and sequence is repeated until the fatty acyl-CoA is completely degraded to acetyl CoA.


Fig: The -Oxidation of Saturated Fatty Acids
Stearic Acid: R = –CH2 – (CH2)12 – CH3

4. LECTURE NOTES: PHARM. BIOCHEMISTRY


DR. USMAN SALEEM 4

When a fatty acid with an even number of carbon atoms undergoes successive rounds of the -oxidation
cycle, the product is acetyl-CoA. The number of molecules of acetyl-CoA produced is equal to half the
number of carbon atoms in the original fatty acid. For example, stearic acid contains 18 carbon atoms and
gives rise to 9 molecules of acetyl-CoA.

The Energy Yield from the Oxidation of Fatty Acids
To calculate the energy yield from fatty acid, we shall use the oxidation of stearic acid, the C18
saturated fatty acid, as an example.
 As a stearyl CoA molecule (18 carbons) passes through the -oxidation spiral, 9 acetyl
CoA, 8 FADH2, and 8 NADH molecules are produced.
 When the FADH2 and NADH molecules enter the electron transport chain, each FADH2
yields 2 ATP molecules, and each NADH yields 3 ATP molecules.
 The oxidation of each acetyl CoA by the citric acid cycle yield 12 ATP molecules.
 Two high energy phosphate bonds are consumed in the activation of stearic acid in which
ATP is split into AMP and PPi.
 Thus, from the complete oxidation of a stearic acid, we obtain a total of 146 ATP
molecules.

The Balance Sheet for Oxidation of One Molecule of Stearic Acid
Chemical Step Happens
Number of
ATP
molecules
produced
Activation (stearic acid  stearyl CoA)
Dehydrogenation (acyl CoA  trans-enoyl CoA), producing FADH2
Dehydrogenation (hydroxylacyl CoA  ketoacyl CoA , producing NADH + H
+
Oxidation of acetyl CoA by citric acid cycle, producing 12 ATP
Once
8 times
8 times
9 times
-2
16
24
108
Total: 146

5. LECTURE NOTES: PHARM. BIOCHEMISTRY


DR. USMAN SALEEM 5

Summery
 Fatty acids are activated and transported to the mitochondrial matrix for further catabolism.
 The breakdown of fatty acids takes place in the mitochondrial matrix and proceeds by successive
removal of two-carbon units as acetyl-CoA. Each cleavage of a two-carbon moiety requires a four-step
reaction sequence called -oxidation.
 The b-oxidation of unsaturated fatty acids proceeds in the same way. An extra step is involved, in
which the cis double bond is isomerized to a trans bond, but otherwise the spiral is the same.