Chapter 14 Lipid and Amino Acid Metabolism

Introduction
Chapter 14 • In this chapter, we will discuss the storage,
degradation, and synthesis of lipids and amino acids,
Lipid and Amino Acid and the relationships between the metabolism of
amino acids, lipids, and carbohydrates.
Metabolism
• Triglycerides (fats and oils) are important dietary
sources of energy. Fat also functions as a major
Chapter Objectives: form of energy storage (9 Cal/g).
• Learn about blood lipids and cholestero, fat mobilization and glycerol metabolism.
• Learn about the oxidation of fatty acids into acetyl CoA and energy production from fatty – Because it is water-insoluble, fat can be stored in
acids. larger quantities than carbohydrates.
• Learn about ketone bodies.
• Learn about fatty acid synthesis. – Carbohydrate reserves are depleted after about 1
• Learn about amino acid metabolism, transamination and deamination, the urea cycle, and day without food, but stored fat can provide
amino acids in energy production.
• Learn about the biosynthesis of amino acids. needed calories for 30-40 days.
Mr. Kevin A. Boudreaux • Amino acids are the building blocks for proteins,
Angelo State University they provide C and N for the synthesis of other
CHEM 2353 Fundamentals of Organic Chemistry
Organic and Biochemistry for Today (Seager & Slabaugh) biomolecules, and they are also sources of energy (4
[Link]/faculty/kboudrea Cal/g). 2

Digestion of Triglycerides
• During digestion, triglycerides are hydrolyzed to
glycerol, fatty acids, and monoglycerides:
O O
CH2 O C R CH2 OH CH2 O C R
O O
CH O C R CH OH HO C R CH OH
O fatty acid

CH2 O C R CH2 OH CH2 OH

triglyceride glycerol monoglyceride

• Phosphoglycerides are also hydrolyzed to their

component substances (glycerol, fatty acids,
phosphate groups, and aminoalcohols).

3 4

Chylomicrons Digestion and Absorption of Triglycerides

• The smaller molecules that are produced, along with
cholesterol, are absorbed into cells of the intestinal
mucosa (the innermost layer of the gastrointestinal
wall), where resynthesis of the triglycerides and
phosphoglycerides occurs.
• For transport within the aqueous environment of
lymph and blood, water-insoluble triglycerides,
phosphoglycerides, and cholesterol are complexed
with proteins to form lipoprotein aggregates called
chylomicrons. These aggregates can pass into the
lymph system and then into the bloodstream.
• Chylomicrons are modified by the liver into smaller
lipoprotein particles, the form in which most lipids
are transported to various parts of the body by the
bloodstream.
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Chapter 14 Lipid and Amino Acid Metabolism

Plasma Lipid Levels Classifying Lipoproteins by Density

• The behavior of blood lipids parallels that of blood • Lipoproteins may be classified by density. Because
sugar. lipids are less dense than proteins, increasing the lipid
– The concentration of plasma lipids increases after concentration makes the lipoprotein less dense.
a meal, and returns to normal as a result of – Chylomicrons carry triglycerides from the
storage in fat depots and oxidation to provide intestines to the liver, skeletal muscle, and adipose
energy. tissue.
– The concentration of plasma lipids rises within 2 – Very-low-density lipoproteins (VLDL) carry
hours after a meals, peaks after 4-6 hours, then newly synthesized triglycerides from the liver to
drops to normal levels. adipose tissue
– Low-density lipoproteins (LDL) carry cholesterol
from the liver to cells of the body (“bad
cholesterol”)
– High-density lipoproteins (HDL) collect
cholesterol from the body’s tissues, and bring it
back to the liver (“good cholesterol”).
7 8

A Low-Density Lipoprotein Composition of Lipoproteins

d < 0.95 g/mL

d = 0.95-1.006 g/mL d = 1.019-1.063 g/mL d > 1.063 g/mL

9 10

Cholesterol and LDL’s Cholesterol and LDL’s

CH3 CH3
CH(CH2)3CHCH3
O OH OH O
HO O
• There are several medications which have been used to
CH3
N
H
N OH O
O
either lower the total cholesterol level in the blood-
CH3
Atorvastatin
(Lipitor) O
Lovastatin
(Mevacor) stream, or to lower the concentration of the LDL
Cholesterol
H
(“bad”) cholesterol levels:
HO F
– Resin drugs (Questran, Colestid) bind with bile acids in the
• Cholesterol is involved in the formation of cell digestive tract and remove them from operation; the liver
membranes, the insulation of nerves, the synthesis of synthesizes more bile acids from cholesterol, so less
cholesterol available to be released into the blood from LDL.
a number of hormones, and the digestion of food.
– Lopid, or large doses of niacin reduce the production of
– LDL’s transport cholesterol into the wall of an triglycerides, which are involved in the formation of LDL;
artery, causing the formation of plaques (an less cholesterol circulates in the blood.
accumulation and swelling in artery walls), and – Statins (Mevacor, Zocor, Pravachol, Lipitor) block the
leading to atherosclerosis. synthesis of cholesterol in the liver by inhibiting HMG-CoA
– HDL’s are able to remove cholesterol from reductase, causing liver cells to remove cholesterol from the
circulating blood; they also help the body to reabsorb
plaques in the arteries and transport it to the liver cholesterol from plaque that has formed in blood vessels.
for excretion or reuse.
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Chapter 14 Lipid and Amino Acid Metabolism

Glycogen and Glucose Stores

• Carbohydrates from dietary sources and glycogen
catabolism are used preferentially for energy
production by some tissues, such as the brain and
active skeletal muscles.
• Body stores of glycogen are depleted after only a
few hours of fasting, which requires fatty acids
stored in triglycerides to be used as energy sources.
– Even when glycogen supplies are adequate,
resting muscle and liver cells use energy from
triglycerides because this conserves glycogen
stores and glucose for use by brain cells and red
blood cells.
• Brain cells do not obtain nutrients from blood.
• Red blood cells do not have mitochondria, and
cannot do fatty acid oxidation.
13 14

Fat Mobilization Glycerol Metabolism

• When cells need fatty acids for energy, the endocrine • The glycerol hydrolyzed from triglycerides can
system produces several hormones, including provide energy to cells. It is converted to
epinephrine, which interact with adipose tissue, dihydroxyacetone phosphate in two steps:
stimulating the hydrolysis of triglycerides to fatty
acids and glycerol, which enter the bloodstream.
This process is called fat mobilization.
– In the blood, mobilized fatty acids form a
lipoprotein with the plasma protein called serum
albumin. \
– In this form, the fatty acids are transported to the – Dihydroxyacetone phosphate is one of the
tissue cells that need them. chemical intermediates in glycolysis. It is
– The glycerol is water soluble, so it dissolves in the converted to pyruvate, and thus contributes to
blood and is also transported to cells that need it. cellular energy production.
– The pyruvate can also be converted to glucose
through gluconeogenesis.
15 16

The Formation of Fatty Acyl CoA

• Fatty acids that enter tissue cells cannot be oxidized
to produce energy until they pass through the
membrane of the mitochondria. This cannot occur
until the fatty acid is converted into fatty acyl CoA by
reaction with coenzyme A, with energy provided by
ATP:

– This reaction is catalyzed by acyl CoA synthetase.

– This reaction is referred to as activation of the
fatty acid because the fatty acyl CoA is a high-
energy compound.
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Chapter 14 Lipid and Amino Acid Metabolism

b-Oxidation: The Fatty Acid Spiral The Fatty Acid Spiral

• The fatty acyl CoA molecules that enter the
mitochondria then undergo a catabolic process
called b-oxidation, in which the second (beta)
carbon away from the carbonyl group of the fatty
acyl CoA molecule is oxidized to a ketone:

• There are four reactions in this pathway. The fatty

acyl CoA from the 18-carbon fatty acid stearic acid
will be used as an example:
19 20

The Fatty Acid Spiral The Fatty Acid Spiral

• In the final step of b-oxidation (Step 4), the bond • Every run through the spiral produces one molecule
between the a- and b-carbons is broken by reaction each of acetyl CoA, NADH, and FADH2, until the
with coenzyme A. A new fatty acyl CoA is formed, fatty acyl CoA is only four carbons long:
which is two carbons shorter than the original
molecule, and a unit of acetyl CoA is released:

• The new fatty acyl compound enters the b-oxidation

process at Step 1, and the process is repeated.
• With every pass through the “fatty acid spiral,” the
chain is shortened by two carbons, until the fatty
acyl CoA is completely degraded into acetyl CoA
units. 21 22

The Fatty Acid Spiral The Fatty Acid Spiral

• In the last spiral, the four-carbon chain of butyryl • The complete conversion of a fatty acyl CoA to two
CoA passes through the b-oxidation sequence, and carbon fragments of acetyl CoA always produces
produces one FADH2, one NADH, and two acetyl one more molecule of acetyl CoA than of FADH2 or
CoA’s: NADH.
– Thus, the breakdown of 18-C stearic acid requires
8 passes through the spiral, and produces 9 acetyl
CoA’s, but only 8 FADH2’s and 8 NADH’s.

• Net reaction:

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Chapter 14 Lipid and Amino Acid Metabolism

The Energy from Fatty Acids The Energy from Fatty Acids
How much energy do we get from a fatty acid?
• The activation of stearic acid by coenzyme A to
form stearoyl CoA comes from the hydrolysis of 2
ATP’s (total=-2 ATP’s).
• As a stearoyl CoA molecule (18 C’s) passes through
the b-oxidation spiral, 9 acetyl CoA’s, 8 FADH2’s,
and 8 NADH’s are produced.
– Acetyl CoA can enter the citric acid cycle /
electron transport chain and form 10 ATP’s
(total=9x10=90 ATP’s)
– Each FADH2 yields 1.5 ATP’s (total=8x1.5=12
ATP’s), and each NADH yields 2.5 ATP’s
(total=8x2.5= 20).
– Thus, from one 18-C stearic acid molecule, 120
molecules of ATP are formed. 25 26

An Energy Comparison: Fatty Acids vs. Glucose An Energy Comparison: Fatty Acids vs. Glucose
• Stearic acid (18 C’s) vs. Glucose (6 C’s): • Stearic acid (18 C’s) vs. Glucose (6 C’s):
– The complete oxidation of a single glucose – On a mass basis, one mole of stearic acid weighs
molecule produces 32 ATP’s. 284 g, and yields 120 mol of ATP.
– Since three glucose molecules have 18 C’s – Three moles of glucose weighs 540 g and yields
(3x6=18), three glucose molecules would produce 96 mol of ATP.
96 ATP’s. – On this basis, 284 g of glucose would produce 50
– A stearic acid molecule (also 18C’s) produces mol of ATP.
120 ATP’s. – On an equal-mass basis, lipids contain more than
– On the basis of an equal number of carbons, lipids twice the energy of carbohydrates.
are nearly 25% more efficient than carbohydrates • This is partially because lipids, which are primarily
as energy-storage systems. hydrocarbons, are a more reduced form of the fuel,
while glucose, which contains a lot of OH groups, is
already partially oxidized.

27 28

Changes Caused by Fasting

• Under normal conditions, most acetyl CoA produced
during fatty acid metabolism is processed through
the citric acid cycle.
• During fasting, the balance between carbohydrate
and fatty acid metabolism is lost, and fatty acids
become the body’s primary energy source.
– Because minimal amounts of cellular glucose are
available, the level of glycolysis decreases, and a
reduced amount of oxaloacetate is synthesized.
– Oxaloacetate is also used for gluconeogenesis to a
greater extent as the cells make their own glucose.
– The lack of oxaloacetate reduces the activity of
the citric acid cycle, and acetyl CoA produced by
fatty acid oxidation builds up faster than it can be
processed by the citric acid cycle.
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Chapter 14 Lipid and Amino Acid Metabolism

Ketone Bodies Diabetes and Ketosis

• As the concentration of acetyl CoA builds up, the • Diabetes mellitus also produces an imbalance in
excess is converted in the liver to the ketone bodies carbohydrate and lipid metabolism. Even though
acetoacetate, b-hydroxybutyrate, and acetone. blood glucose reaches hyperglycemic levels, a
deficiency of insulin prevents the glucose from
entering tissue cells in sufficient amounts to meet
cellular energy needs.
– This results in an increase in fatty acid
metabolism, and the excessive production of
acetyl CoA, and a substantial increase in the level
• These ketone bodies are carried by the blood to body of ketone bodies in the blood of untreated
tissues, mainly the brain, heart, and skeletal muscles, diabetics.
where they may be oxidized to meet energy needs.
• A concentration of ketone bodies higher than 20 mg
• Under normal conditions, the / 100 mL of blood is called ketonemia (“ketones in
concentration of ketone bodies the blood”).
in the blood averages
0.5 mg/100 mL.
31 32

Diabetes and Ketosis Ketoacidosis

• At a level of about 70 mg/100 mL of blood, the renal • Two of the ketone bodies are acids, and their
threshold for ketone bodies is exceeded, and ketone accumulation in the blood results in a particular
bodies are excreted in the urine, resulting in acidosis (low blood pH) called ketoacidosis.
ketonuria (“ketones in the urine”). – If this condition is uncontrolled, the person
• Acetone levels in the blood can reach levels so high becomes severely dehydrated because the kidneys
that it is expelled through the lungs, producing excrete excessive amounts of water in response to
acetone breath. low blood pH.
• When ketonemia, ketonuria, and acetone breath exist – Prolonged ketoacidosis leads to general
simultaneously, the condition is called ketosis. debilitation, coma, or death.
• Patients suffering from diabetes-related ketosis are
usually given insulin as a first step in treatment. The
insulin restores normal glucose metabolism and
reduces the rate of formation of ketone bodies.
• Acid-base balance can be restored by the
intravenous administration of sodium bicarbonate.
33 34

Fatty Acid Synthetase System

• Excess nutrients are converted to fatty acids, and
then to body fat. The process for fatty acid synthesis
is separate from that of fatty acid degradation, and
occurs in the cytoplasm rather than in the
mitochondria.
– In both processes, the reactions occur in two-C
fragments from acetyl CoA.
• Acetyl CoA is generated in the mitochondria, and
transported to the cytoplasm for fatty acid synthesis
in the form of citrate (Step 1 of the citric acid cycle).
• Fatty acid synthesis occurs in a complex series of
reactions catalyzed by an complex called the fatty
acid synthetase system. This system consists of six
enzymes and a protein called the acyl carrier protein
(ACP), to which all intermediate are attached.
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Chapter 14 Lipid and Amino Acid Metabolism

The Synthesis of Palmitic Acid Fatty Acids and the Liver

• The reaction shown below for the synthesis of • The liver is the most important organ involved in fatty
palmitic acid from acetyl CoA requires a large input acid and triglyceride synthesis. It is able to modify
of energy in the form of 7 ATP’s and 14 NADPH’s body fats by lengthening or shortening the chain, or
(a phosphate derivative of NADH): saturating or unsaturating the chain.
– The only fatty acids that cannot be synthesized by
the body are those that are polyunsaturated.
– Linoleic and linolenic acids from the diet can be
converted to other polyunsaturated fatty acids.
• The human body can convert glucose to fatty acids,
but cannot convert fatty acids to glucose.
• Fatty acids are incorporated into triglycerides and
stored in the form of fat in adipose tissues. – Humans have no enzyme that catalyzes the
conversion of acetyl CoA to pyruvate, which is
• This large input of energy is stored in the required for gluconeogenesis.
synthesized fatty acids, and is one of the reasons it is
difficult to lose excess weight due to fat. – Plants, and some bacteria do possess such enzymes.
37 38

The Amino Acid Pool

• The most important function of amino acids (about
75% of amino acid utilization) is to provide building
blocks for the synthesis of proteins in the body.
• The maintenance of body proteins must occur
constantly because tissue proteins break down from
normal wear and tear, from injuries, and from
diseases.
• The amino acids that are used in this maintenance
come from the amino acid pool of the body. These
amino acids can come from:
– proteins that are eaten and hydrolyzed during
digestion
– the body’s own degraded tissues
– the synthesis in the liver of certain amino acids.
39 40

Protein Turnover and Half-Life Other Compounds from Amino Acids

• The process in which body proteins are continuously • The frequent turnover of proteins allows the body to
hydrolyzed and resynthesized is called protein continually renew important molecules and respond
turnover. to changing needs.
– The turnover rate, or life expectancy, of body • There is also a constant draw on the amino acid pool
proteins is a measure of how fast they are broken for the synthesis of other N-containing biomolecules,
down and resynthesized, expressed as a half-life. such as the bases in DNA and RNA, the heme in
• The half-life of liver proteins is about 10 days: over a hemoglobin and myoglobin, the aminoalcohols in
10-day period, half the proteins in the liver are phospholipids, and neurotransmitters.
hydrolyzed to amino acids and replaced.
• Plasma proteins = 10 days
• Hemoglobin = 120 days
• Muscle protein = 180 days
• Collagen = as high as 1000 days
• Enzyme and polypeptide hormones = as short as a few
minutes. (Insulin = 7-10 minutes)
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Chapter 14 Lipid and Amino Acid Metabolism

Amino Acid Metabolic Pathways Amino Acid Metabolic Pathways

• Amino acids in excess of immediate body
requirements cannot be stored for later use.
– The N atoms are converted to either ammonium
ions, urea, or uric acid (depending on the
organism), and excreted.
– Their carbon skeletons are converted to pyruvate,
acetyl CoA, or one of the intermediates in the
citric acid cycle and used for energy production,
the synthesis of glucose through gluconeogenesis,
or conversion to triglycerides.

43 44

The Fate of Nitrogen Atoms

• The N atoms in amino acids are either excreted or
used to synthesize other N-containing compounds.
There are three stages in nitrogen catabolism:
– Stage 1: Transamination
– Stage 2: Deamination
– Stage 3: Urea Formation

45 46

Stage 1: Transamination Stage 1: Transamination

• In the tissues, amino groups freely move from one • Specific example:
amino acid to another, under the influence of
enzymes called amino tranferases or trans
aminases. A key reaction for amino acids
undergoing catabolism is a transamination involving
the transfer of amino groups to a-ketoglutarate. The
carbon skeleton of the amino acid remains behind as
an a-keto acid:

• The net effect of this reaction is to exchange the

NH3+ on the amino acid with a =O.

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Chapter 14 Lipid and Amino Acid Metabolism

Stage 1: Transamination Stage 2: Deamination

• Another important example of transamination is the • This phase of amino acid catabolism uses the
production of aspartate, which is used in Stage 3, glutamate produced in Stage 1. The enzyme
urea formation, from the transfer of an amino to glutamate dehydrogenase catalyzes the removal of
oxaloacetate: the amino group as an ammonium ion and
regenerates a-ketoglutarate, which can participate in
transamination again.
– This reaction is the principal source of NH4+ in
humans.
– Because the deamination results in the oxidation
of glutamate, it is called oxidative deamination.

• This process is an important method for the bio-

synthesis of the nonessential amino acids glutamate
and aspartate from a variety of other amino acids.
49 50

Stage 2: Deamination Stage 3: Urea Formation

• The NADH produced in this stage enters the • The ammonium ions released by the glutamate
electron transport chain and eventually produces 2.5 dehydrogenase in Step 2 are toxic, and must be
ATP molecules. prevented from accumulating. In the urea cycle,
• Other amino acids can be catabolized by oxidative which only occurs in the liver, NH4+ is converted to
deamination in the liver by enzymes called amino urea, which is less toxic, and can be allowed to
acid oxidases. concentrate until it is excreted in urine.
• The urea cycle process NH4+ in the form of
carbamoyl phosphate, the fuel for the urea cycle.
This compound is synthesized in the mitochondria
from NH4+ and HCO3-:

51 52

The Urea Cycle Stage 3: Urea Formation

• The net reaction for carbamoyl phosphate formation
and the urea cycle is:

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Chapter 14 Lipid and Amino Acid Metabolism

Stage 3: Urea Formation

• After urea is formed, it diffuses out of liver cells and
into the blood. It is then filtered out by the kidneys,
and excreted in the urine.
• Normal urine from an adult usually contains about
23-30 g of urea daily, although this varies with the
protein content of the diet.
• The direct excretion of NH4+ accounts for a small
but important amount of the total urinary nitrogen.
• The excretion of ammonium along with acidic ions
is a mechanism that helps the kidneys to control the
acid-base balance of body fluids.

55 56

The Fate of the Carbon Skeleton

• After the amino group is removed by transamination
or oxidative deamination, the remaining amino acid
carbon skeleton undergoes catabolism and is
converted into one of several products.
• After the amino group is gone, the skeletons of all
20 amino acids are degraded into either pyruvate,
acetyl CoA, acetoacetyl CoA (which is degraded to
acetyl CoA), or various substances that are
intermediates in the citric acid cycle.
• All these degraded forms of the carbon skeletons are
a part of or can enter the citric acid cycle, and thus
may be very important in the production of energy.

57 58

Amino Acid Metabolism Glucogenic and Ketogenic Amino Acids

• There are two types of amino acid carbon skeletons:
– Glucogenic amino acids have a carbon skeleton
that can be metabolically converted to pyruvate or
an intermediate of the citric acid cycle. These
amino acids can be used to make glucose.
– Ketogenic amino acids have a carbon skeleton
that can be metabolically converted to acetyl CoA
or acetoacetyl CoA. They cannot be converted
into glucose, but can be used to make ketone
bodies and fatty acids.
• After glycogen stores are used up, glucogenic amino
acids can be used to synthesize glucose. The amino
acids come from hydrolysis of proteins from body
tissues, primarily muscle. The body can meets its
energy needs for only a limited time by sacrificing
59 proteins. 60
Chapter 14 Lipid and Amino Acid Metabolism

Essential and Nonessential Amino Acids

• The liver produces most of the amino acids that the
body can synthesize. Amino acids that can be made
in the amounts needed by the body are called
nonessential amino acids, because they do not need
to be obtained from the diet.
• The essential amino acids cannot be made in large
enough amounts, and must be obtained from the diet.

61 62

Biosynthesis of Nonessential Amino Acids Biosynthesis of Nonessential Amino Acids

• The key starting materials for the synthesis of 10 • Tyrosine is produced from the essential amino acid
nonessential amino acids are intermediates in phenylalanine:
glycolysis and the citric acid cycle:

• Three nonessential amino acids (glutamate, alanine,

and aspartate) are synthesized from a-keto acids via
transamination:

– The transaminases adjust the relative proportions

of amino acids to meet the needs of the body,
since most of our diets do not contain amino acids
63 in the exact proportions needed by the body 64

Biosynthesis of Nonessential Amino Acids

• Asparagine and glutamine are formed from aspartate
and glutamate by reaction of the side-chain
carboxylate groups with ammonium ions:

• The synthesis of arginine, cysteine, glycine, proline,

and serine are considerably more complex.
65 66