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Outline
27.1
Digestion of Proteins
27.2
Amino Acid Metabolism: An Overview
27.3
Amino Acid Catabolism: The Amino Group
27.4
The Urea Cycle
27.5
Amino Acid Catabolism: The Carbon Atoms
27.6
Biosynthesis of Nonessential Amino Acids
Goals
1. What happens during the digestion of proteins, and what
are the fates of the amino acids?
Be able to list the sequence of events in the digestion of
proteins, and describe the nature of the amino acid pool.
2. What are the major strategies in the catabolism of amino
acids?
Be able to identify the major reactions and products of amino
acid catabolism and the fate of the products.
3. What is the urea cycle?
Be able to list the major reactants and products of the urea
cycle.
4. What are the essential and nonessential amino acids, and
how, in general, are amino acids synthesized?
Be able to define essential and nonessential amino acids, and
describe the general strategy of amino acid biosynthesis.
27.1 Digestion of Proteins
• The end result of protein digestion is
simple—the hydrolysis of all peptide bonds
to produce a collection of amino acids.
27.1 Digestion of Proteins
• Food is converted into smaller,
more digestible portions,
increasing the surface area of
the food to be digested.
• In the acidic environment of the
stomach (pH 1–2), the tertiary
and secondary structures of
proteins begin to unfold.
• Gastric secretions include
pepsinogen, a zymogen that is
activated by acid to give the
enzyme pepsin. Pepsin is stable
and active at pH 1–2.
• Pepsin breaks peptide bonds.
27.1 Digestion of Proteins
• The polypeptides produced by pepsin enter the small
intestine, where the pH is about 7–8.
• Pepsin is inactivated, and a group of pancreatic
zymogens is secreted. The activated enzymes (proteases
such as trypsin, chymotrypsin, and carboxypeptidase)
then take over further hydrolysis of peptide bonds in the
partially digested proteins.
• The combined action of the pancreatic proteases in the
small intestine and other proteases in the cells of the
intestinal lining completes the conversion of dietary
proteins into free amino acids.
• After active transport across cell membranes lining the
intestine, the amino acids are absorbed directly into the
bloodstream.
27.2 Amino Acid Metabolism: An Overview
• The amino acid pool occupies a central
position in protein and amino acid
metabolism.
• All tissues and biomolecules are constantly
being degraded, repaired, and replaced.
• Amino acids continuously enter the pool from
digestion and breakdown of old protein.
• They are continuously being withdrawn for
synthesis of new nitrogen-containing
biomolecules.
27.2 Amino Acid Metabolism: An Overview
27.2 Amino Acid Metabolism: An Overview
• Each amino acid is degraded via its own
unique pathway, but the general scheme is
the same for each one.
General scheme for amino acid catabolism
• Removal of the amino group
• Use of nitrogen in synthesis of new nitrogen
compounds
• Passage of nitrogen into the urea cycle
• Incorporation of the carbon atoms into
compounds that can enter the citric acid cycle
27.2 Amino Acid Metabolism: An Overview
• Our bodies do not store nitrogen-containing
compounds and ammonia is toxic to cells.
• Amino nitrogen must either be incorporated into
urea and excreted, or used in the synthesis of
new nitrogen-containing compounds:
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Nitric oxide (NO, a chemical messenger)
Hormones
Nicotinamide (in coenzymes)
Heme (as part of hemoglobin in red blood cells)
Purine and pyrimidine bases (for nucleic acids)
27.2 Amino Acid Metabolism: An Overview
• Nitrogen oxide (NO) is a particularly
interesting molecule:
– Chemically, it is a free radical and therefore
very reactive.
– Biologically, it lowers blood pressure, kills
invading bacteria, and enhances memory.
– Nitric oxide is synthesized from oxygen and
the amino acid arginine.
– In blood vessels, NO activates reactions in
smooth muscle cells that cause dilation and a
resulting decrease in blood pressure.
27.2 Amino Acid Metabolism: An Overview
• The carbon atoms of amino acids are
converted to compounds that can enter the
citric acid cycle.
• They continue through the citric acid cycle to
give CO2 and energy stored in ATP.
• About 10–20% of our energy is produced in
this way.
• If not needed immediately for energy, the
carbon-carrying intermediates enter storage
as triacylglycerols, glycogen, or ketone
bodies.
27.3 Amino Acid Catabolism: The Amino Group
• In transamination, the amino group of the
amino acid and the keto group of an aketo acid change.
27.3 Amino Acid Catabolism: The Amino Group
• A number of transaminase enzymes are
responsible for “transporting” an amino group from
one molecule to another.
• Most are specific for a-ketoglutarate as the amino
group acceptor and work with several amino acids.
• The a-ketoglutarate is converted to glutamate, and
the amino acid is converted to an a-keto acid.
27.3 Amino Acid Catabolism: The Amino Group
• Transamination is a key reaction in many
biochemical pathways.
• The reactions are reversible and go easily in
either direction, depending on the
concentrations of the reactants.
• Amino acid concentrations are regulated by
keeping synthesis and breakdown in balance.
• Oxidative deamination: Conversion of an
amino acid —NH2 group to an a-keto group,
with removal of NH4+.
27.3 Amino Acid Catabolism: The Amino Group
• The glutamate from transamination serves as
an amino group carrier.
• Glutamate can be used to provide amino
groups for the synthesis of new amino acids,
but most of the glutamate formed in this way
is recycled to regenerate a-glutarate.
27.3 Amino Acid Catabolism: The Amino Group
• The ammonium
ion formed in
this reaction
proceeds to the
urea cycle
where it is
eliminated in
the urine as
urea.
27.4 The Urea Cycle
• Ammonia is highly toxic to living things
and must be eliminated in a way that does
no harm.
• Fish are able to excrete ammonia through
their gills directly into their watery
surroundings.
• Mammals must find other ways to get rid
of ammonia, and must first convert
ammonia, in solution as ammonium ion, to
nontoxic urea via the urea cycle.
27.4 The Urea Cycle
• The conversion of ammonium ion to urea
takes place in the liver.
• From there, urea is transported to the
kidneys and transferred to urine for
excretion.
• Like many other biochemical pathways,
urea formation begins with an energy
investment. Ammonium ion, bicarbonate
ion, and ATP combine to form carbamoyl
phosphate in the mitochondrial matrix.
27.4 The Urea Cycle
• Two ATP are invested and one phosphate
is transferred to form carbamoyl
phosphate, an energy-rich phosphate
ester like ATP.
27.4 The Urea Cycle
Steps 1 and 2 of the Urea Cycle: Building
Up a Reactive Intermediate
• The first step of the urea cycle transfers
the carbamoyl group, H2NC=O, from
carbamoyl phosphate to ornithine, an
amino acid not found in proteins, to give
citrulline, another nonprotein amino acid.
• This exergonic reaction introduces the first
urea nitrogen into the urea cycle.
27.4 The Urea Cycle
Steps 1 and 2 of the Urea Cycle: Building
Up a Reactive Intermediate
• In step 2, a molecule of aspartate
combines with citrulline in a reaction
driven by conversion of ATP to AMP and
pyrophosphate followed by the additional
exergonic hydrolysis of pyrophosphate.
• Both nitrogen atoms destined for
elimination as urea are now bonded to the
same carbon atom in argininosuccinate.
27.4 The Urea Cycle
Steps 3 and 4 of the Urea Cycle:
Cleavage and Hydrolysis of the Step 2
Product
• Step 3 cleaves argininosuccinate into two
pieces: arginine, an amino acid, and
fumarate, which is an intermediate in the
citric acid cycle.
• In Step 4 the hydrolysis of arginine takes
place to give urea and regenerate the
reactant in Step 1 of the cycle, ornithine.
27.4 The Urea Cycle
27.4 The Urea Cycle
We can summarize the results of the urea
cycle as follows:
• Formation of urea from the carbon of CO2,
NH4+, and one nitrogen from the amino
acid aspartate, followed by biological
elimination through urine
• Breaking of four high-energy phosphate
bonds to provide energy
• Production of the citric acid cycle
intermediate, fumarate
27.4 The Urea Cycle
27.4 The Urea Cycle
Gout: When Biochemistry Goes Awry
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Gout is caused by the precipitation of sodium urate crystals in joints. The pain of gout
results from a cascade of inflammatory responses.
Understanding the many possible causes of the crystal formation is far from
complete.
Uric acid is an end product of the breakdown of purine nucleosides. Loss of its acidic
H gives urate ion.
Anything that increases the production of uric acid or inhibits its excretion in the urine
is a possible cause of gout.
One significant cause of increased uric acid production is accelerated breakdown of
ATP, ADP, or AMP. Alcohol abuse, inherited fructose intolerance, glycogen storage
diseases, and circulation of poorly oxygenated blood accelerate uric acid production
by this route
Conditions that diminish excretion of uric acid include kidney disease, dehydration,
hypertension, lead poisoning, and competition for excretion from anions produced by
ketoacidosis.
One treatment for gout relies on allopurinol, a structural analog of hypoxanthine, a
precursor of xanthine in the formation of urate. Allopurinol inhibits the enzyme for
conversion of hypoxanthine and xanthine to urate. Since hypoxanthine and xanthine
are more soluble than sodium urate, they are more easily eliminated.
27.4 The Urea Cycle
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The Importance of Essential Amino Acids and Effects of Deficiencies
“Essential” nutrients, must be harvested daily from the foods we eat.
There are nine essential amino acids: histidine, isoleucine, leucine, lysine,
methionine, phenylalanine, threonine, tryptophan, and valine.
Histidine: Deficiency can cause pain in bony joints and may have a link to rheumatoid
arthritis.
Isoleucine, Leucine, and Valine: These hydrophobic amino acids are essential for the
production and maintenance of body proteins.
Lysine: Deficiency can lead to poor appetite, reduction in body weight, anemia, and a
reduced ability to concentrate, as well as pneumonia, kidney disease (nephritis), and
acidosis, as well as with malnutrition and rickets in children.
Methionine: Methionine deficiency may ultimately lead to chronic rheumatic fever in
children, hardening of the liver (cirrhosis), and nephritis.
Phenylalanine: Deficiency of phenylalanine can lead to behavioral changes such as
psychotic and schizophrenic behavior.
Threonine: This amino acid is key in the formation of collagen, elastin, and tooth
enamel. Its deficiency can result in irritability in children .
Tryptophan: It has been used to help relieve insomnia, migraines and mild
depression. A deficiency of tryptophan can lead to a broad array of emotional and
behavioral problems.
27.5 Amino Acid Catabolism: The Carbon Atoms
• The carbon atoms of each protein amino acid
arrive by distinctive pathways at pyruvate,
acetyl-CoA, or one of the citric acid cycle
intermediates.
• Eventually, all of the amino acid carbon
skeletons can be used to generate energy.
• Amino acids that are converted to acetoacetylCoA or acetyl-CoA enter the ketogenesis
pathway, and are called ketogenic amino acids.
• Those amino acids that proceed by way of
oxaloacetate to the gluconeogenesis pathway
are known as glucogenic amino acids.
27.5 Amino Acid Catabolism: The Carbon Atoms
27.5 Amino Acid Catabolism: The Carbon Atoms
27.6 Biosynthesis of Nonessential Amino Acids
• Humans are able to synthesize about half
of the 20 amino acids found in proteins.
• These are known as the nonessential
amino acids because they do not have to
be supplied by our diet.
• The remaining amino acids, the essential
amino acids, are synthesized only by
plants and microorganisms. Humans must
obtain the essential amino acids from
food.
27.6 Biosynthesis of Nonessential Amino Acids
• Meats contain all of the essential amino
acids.
• Foods that do not have all of them are
described as having incomplete amino
acids.
• Dietary deficiencies of the essential amino
acids can lead to a number of health
problems.
• Food combinations that together contain all
of the amino acids are complementary
sources of protein.
27.6 Biosynthesis of Nonessential Amino Acids
• We synthesize the nonessential amino acids
in pathways containing one to three steps.
• Synthesis of essential amino acids by other
organisms is complicated, requiring many
steps and a substantial energy investment.
• Nonessential amino acid One of 11 amino
acids that are synthesized in the body and
are therefore not necessary in the diet.
• Essential amino acid An amino acid that
cannot be synthesized by the body and thus
must be obtained in the diet.
27.6 Biosynthesis of Nonessential Amino Acids
27.6 Biosynthesis of Nonessential Amino Acids
• All of the nonessential amino acids derive their
amino groups from glutamate, the molecule that
picks up ammonia in amino acid catabolism and
carries it into the urea cycle.
• Glutamate can also be made from NH4+ and
a-ketoglutarate by reductive deamination, the
reverse of oxidative deamination.
• The same glutamate dehydrogenate enzyme
carries out the reaction.
27.6 Biosynthesis of Nonessential Amino Acids
• Glutamate also provides nitrogen for the
synthesis of other nitrogen-containing
compounds, including the purines and
pyrimidines that are part of DNA.
• The following four common metabolic
intermediates are the precursors for synthesis of
the nonessential amino acids:
27.6 Biosynthesis of Nonessential Amino Acids
• Glutamine is made from glutamate, and
asparagine is made by reaction of glutamine
with aspartate.
27.6 Biosynthesis of Nonessential Amino Acids
• The amino acid tyrosine is classified as
nonessential because we can synthesize it from
phenylalanine, an essential amino acid.
27.6 Biosynthesis of Nonessential Amino Acids
• In 1947 it was found that failure to convert
phenylalanine to tyrosine causes
phenylketonuria (PKU).
• PKU results in elevated blood serum and urine
concentrations of phenylalanine,
phenylpyruvate, and metabolites produced when
the body diverts phenylalanine to metabolism by
other pathways.
• Undetected, PKU causes mental retardation by
the second month of life. Widespread screening
of newborn infants is the only defense against
PKU and similar treatable metabolic disorders
that take their toll early in life.
Chapter Summary
1. What happens during the digestion of proteins,
and what is the fate of the amino acids?
• Protein digestion begins in the stomach and
continues in the small intestine. The result is
virtually complete hydrolysis to yield free amino
acids.
• The amino acids enter the bloodstream after active
transport into cells lining the intestine.
• The body does not store nitrogen compounds, but
amino acids are constantly entering the amino acid
pool from dietary protein or broken down body
protein and being withdrawn from the pool for
biosynthesis or further catabolism.
Chapter Summary, Continued
2. What are the major strategies in the catabolism of
amino acids?
• Each amino acid is catabolized by a distinctive pathway,
but in most of them the amino group is removed by
transamination (the transfer of an amino group from an
amino acid to a keto acid), usually to form glutamate.
• Then, the amino group of glutamate is removed as
ammonium ion by oxidative deamination. The ammonium
ion is destined for the urea cycle.
• The carbon atoms from amino acids are incorporated into
compounds that can enter the citric acid cycle. These
carbon compounds are also available for conversion to
fatty acids or glycogen for storage, or for synthesis of
ketone bodies.
Chapter Summary, Continued
3. What is the urea cycle?
• Ammonium ion (from amino acid catabolism) and
bicarbonate ion (from carbon dioxide) react to produce
carbamoyl phosphate, which enters the urea cycle.
• The first two steps of the urea cycle produce a reactive
intermediate in which both of the nitrogens that will be
part of the urea end product are bonded to the same
carbon atom. Then arginine is formed and split by
hydrolysis to yield urea, which will be excreted.
• The net result of the urea cycle is reaction of
ammonium ion with aspartate to give urea and
fumarate.
Chapter Summary, Continued
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What are the essential and nonessential amino
acids, and how, in general, are amino acids
synthesized?
Essential amino acids must be obtained in the diet
because our bodies do not synthesize them.
They are made only by plants and microorganisms,
and their synthetic pathways are complex.
Our bodies do synthesize the so-called nonessential
amino acids. Their synthetic pathways are quite
simple and generally begin with pyruvate,
oxaloacetate, a-ketoglutarate or 3-phosphoglycerate.
The nitrogen is commonly supplied by glutamate.