Pharm 13: PHARMACEUTICAL BIOCHEMISTRY

LECTURE | FINALS | USM College of Medicine and Allied Health Sciences | Barbadillo, J.A 2BSPh-A
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Lipid Metabolism
The fatty acid and glycerol hydrolysis products from TAG
hydrolysis are absorbed by the cells of the body and are either
DIGESTION AND LIPID METABOLISM broken down to acetyl CoA for energy or stored as lipids (they are
again repackaged as TAGs).
TRIACYLGLYCEROL

• 98% of total dietary lipids

• insoluble in water
• undergo physical rather than chemical changes in the stomach.

CHYME

• is a thick semi-liquid material made up of partially digested food

and gastric secretions (hydrochloric acid and several enzymes).
• the conversion of high-fat materials into chyme takes longer than
breakup of low-fat materials.
• upon arrival from stomach triggers in small intestine through the
action of the hormone cholecystokinin, which contains no
enzymes, acts as emulsifier.

FATTY ACID MICELLE

• is a micelle in which fatty acids and/or monoacylglycerols and

some bile are present.
• are very small compared to the original triacylglycerol globules,
which contain thousands of triacylglycerol molecules.

CHYLOMICRON

• is a lipoprotein that transports triacylglycerols from intestinal cells,

via the lymphatic system, to the bloodstream.
• Triacylglycerols constitute 95% of the core lipids present in a
chylomicron.
• are too large to pass through capillary walls directly into the
bloodstream.
• enter the lymphatic system through tiny lymphatic vessels in the
intestinal lining and enter the blood stream through the thoracic
duct (a large lymphatic vessel just below the collarbone), where
the fluid of the lymphatic system flows into a vein, joining the
TRIACYLGLYCEROL STORAGE AND MOBILIZATION
bloodstream.
• Once reached the bloodstream, the TAGs they carry are again
ADIPOCYTE
hydrolyzed to produce glycerol and free fatty acids.
• TAG release from chylomicrons and their ensuing hydrolysis is
• is a triacylglycerol-storing cell.
mediated by lipoprotein lipases. These enzymes are located on
the lining of blood vessels in muscle and other tissues that use
fatty acids for fuel and in fat synthesis.
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Pharm 13: PHARMACEUTICAL BIOCHEMISTRY (Adapted from the book)
ADIPOSE TISSUE
• is tissue that contains large numbers of adipocyte cells.
• is located primarily directly beneath the skin (subcutaneous),
particularly in the abdominal region, and in areas around vital
organs.
• subcutaneous adipose tissue also serves as an insulator against
excessive heat loss to the environment and provides organs with
protection against physical shock.
• are among the largest cells in the body.
• most of the cytoplasm has been replaced with a large
triacylglycerol droplet.
• Use of the TAGs stored in adipose tissue for energy production is
triggered by several hormones, including epinephrine and
glucagon.
• Hormonal interaction with adipose cell membrane receptors
stimulates production of cAMP from ATP inside the adipose cell.
DIHYDROXYACETONE
HORMONE SENSITIVE LIPASE
• Hormonal interaction with adipose cell membrane receptors
stimulates production of cAMP from ATP inside the adipose cell.
In a series of enzymatic reactions, the cAMP activates hormone-
sensitive lipase (HSL) through phosphorylation.
• is the lipase needed for triacylglycerol hydrolysis, a prerequisite
for fatty acids to enter the bloodstream from an adipose cell.
TRIACYLGLYCEROL MOBILIZATION
• is the hydrolysis of triacylglycerols stored in adipose tissue,
followed by release into the bloodstream of the fatty acids
and glycerol so produced.
• is an ongoing process.
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Barbadillo, J.A 2BSPh-A
• On the average, about 10% of the TAGs in adipose tissue
are replaced daily by new triacylglycerol molecules.
GLYCEROL METABOLISM
• one molecule of glycerol is produced for each triacylglycerol
completely hydrolyzed.
• primarily involves processes considered in the previous
chapter.
• After entering the bloodstream, glycerol travels to the liver or
kidneys, where it is converted, in a two-step process, to
dihydroxyacetone phosphate.
• The first step involves phosphorylation of a primary hydroxyl
group of the glycerol. In the second step, glycerol’s
secondary alcohol group (C-2) is oxidized to a ketone.
• is an intermediate in both glycolysis and gluconeogenesis.
• can be converted to pyruvate, then acetyl CoA, and finally
carbon dioxide, or it can be used to form glucose.
• its formation from glycerol represents the first of several
situations we will consider wherein carbohydrate and lipid
metabolism are connected.
OXIDATION OF FATTY ACIDS
1. The fatty acid must be activated by bonding to coenzyme A.
2. The fatty acid must be transported into the mitochondrial
matrix by a shuttle mechanism.
3. The fatty acid must be repeatedly oxidized, cycling through a
series of four reactions, to produce acetyl CoA, FADH2, and
NADH.
FATTY ACID OXIDATION
• site: mitochondrial membrane
• fatty acid is converted to a high-energy derivative of
coenzyme A.
• reactants are the fatty acid, coenzyme A, and a molecule of
ATP.
• requires the expenditure of two high-energy phosphate
bonds from a single ATP molecule; the ATP is converted to
AMP rather than ADP, and the resulting pyrophosphate (PPi)
is hydrolyzed to 2Pi.
• activated fatty acid–CoA molecule is called acyl CoA.
Pharm 13: PHARMACEUTICAL BIOCHEMISTRY (Adapted from the book) Barbadillo, J.A 2BSPh-A
FATTY ACID TRANSPORT

• acyl CoA is too large to pass through the inner mitochondrial

membrane to the mitochondrial matrix, where the enzymes
needed for fatty acid oxidation are located.
• shuttle mechanism involving the molecule carnitine effects
the entry of acyl CoA into the matrix.
• acyl group is transferred to a carnitine molecule, which
3. SECOND DEHYDROGENATION
carries it through the membrane. The acyl group is then
transferred from the carnitine back to a CoA molecule. • Removal of two hydrogen atoms converts the b-hydroxy
group to a keto group, with NAD+ serving as the oxidizing
agent. The required enzyme exhibits absolute
stereospecificity for the L isomer.

4. THIOLYSIS
• The fatty acid carbon chain is broken between the a and b
carbons by reaction with a coenzyme A molecule. The result
is an acetyl CoA molecule and a new acyl CoA molecule that
is shorter by two carbon atoms than its predecessor

• new acyl CoA molecule (now shorter by two carbons) is recycled

REACTIONS OF THE b-OXIDATION PATHWAY through the same set of four reactions again. This yields another
acetyl CoA, a two-carbon shorter new acyl CoA, FADH2, and
• a sequence of four reactions repeatedly cleaves two carbon NADH.
units from the carboxyl end of the acyl CoA molecule.

B-OXIDATION PATHWAY

• is a repetitive series of four biochemical reactions that

degrades acyl CoA to acetyl CoA by removing two carbon
atoms at a time, with FADH2 and NADH also being
produced.
• each repetition of the four-reaction sequence generates an
acetyl CoA molecule and an acyl CoA molecule that has two
fewer carbon atoms.

4 STEPS IN B OXIDATION

1. FIRST HYDROGENATION
• Hydrogen atoms are removed from the a and b carbons,
creating a double bond between these two carbon atoms.
FAD is the oxidizing agent, and a FADH2 molecule is a
product.

2. HYDRATION
• A molecule of water is added across the trans double bond,
producing a secondary alcohol at the b-carbon position.
Again, the enzyme involved is stereospecific in that only the
L-hydroxy isomer is produced from the trans double bond.

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Pharm 13: PHARMACEUTICAL BIOCHEMISTRY (Adapted from the book) Barbadillo, J.A 2BSPh-A
UNSATURATED FATTY ACIDS

• are common components of dietary triacylglycerols. Their

oxidation through the b-oxidation pathway requires two additional
enzymes besides those needed for oxidation of saturated fatty
acids.
• two—an epimerase that can change a D configuration to an L
configuration and a cis–trans isomerase—are needed for two
reasons.

1. First, the double bonds in naturally occurring unsaturated fatty

acids are nearly always cis double bonds, which yield on
hydration a D-hydroxy product rather than the L-hydroxy product
needed for Step 3 of the pathway. The epimerase enzyme effects
a configuration change from the D form to the L form.

2. Second, the double bonds in naturally occurring unsaturated fatty

acids often occupy odd-numbered positions. The hydratase in
Step 2 of the pathway can affect hydration of only an even-
numbered double bond. The cis trans isomerase produces a
trans-(2,3) double bond from a cis-(3,4) double bond.

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