Biochemistry:

Amino acid oxidation

and urea production
22 may 2016

Dra. Erin C. McKiernan

emckiernan@ciencias.unam.mx
unknown image source
 Digestion of
proteins

https://2012books.lardbucket.org/books/
introduction-to-chemistry-general-organic-and-
biological/s23-02-stage-i-of-catabolism.html
Digestion of
https://www.boundless.com/biology/
proteins textbooks/boundless-biology-
textbook/animal-nutrition-and-the-
digestive-system-34/digestive-system-
processes-197/digestion-and-
absorption-754-11987/
Proenzymes (zymogens) and active enzymes

https://www.studyblue.com/notes/note/n/protein-digestion-and-amino-acid-absorption/deck/8804464
Digestion of proteins

https://archive.cnx.org/contents/47e14543-2793-423b-baa4-dc0e4548245f@1/ou-human-physiology-
chemical-digestion-and-absorption-a-closer-look
Dipeptide/tripeptide absorption depends on H+ gradient

The primary
transporter
responsible for
short peptide
uptake is
called PepT1
and is a
symporter that
carries
peptides in
conjunction
with protons.

http://users.atw.hu/blp6/BLP6/
HTML/C0299780323045827.htm
Absorption of some amino acids depends on Na+ gradient
Oxidative degradation of amino acids happens:

1. During normal synthesis and degradation of cellular

proteins (protein turnover), some amino acids not
needed and degraded.

2. When ingested amino acids exceed body’s needs

for protein synthesis, excess is catabolized; amino
acids cannot be stored.

3. During starvation or uncontrolled diabetes, when

carbs not available or properly utilized, cellular
proteins are used as fuel.

Lehninger, Principles of Biochemistry, Ch. 18

In general:

1. Amino acids lose their amino groups to form alpha-

keto acids, “carbon skeletons”.

2. Alpha-keto acids undergo oxidation to CO2 and

H2O, or to compounds that enter gluconeogenesis.

3. Gluconeogenesis provides fuel for brain, skeletal

muscle, and other tissues.

Lehninger, Principles of Biochemistry, Ch. 18

 specific to each amino acid

http://iweb.langara.bc.ca/biology/mario/Biol2315notes/biol2315chap3.html
Amino acid catabolism
Lehninger, Principles of
Biochemistry, Ch. 18

every amino acid

contains an amino
group, and the
pathways for amino
acid degradation
therefore include a
key step in which the
amino group is
separated from the
carbon skeleton and
shunted into the
pathways of amino
group metabolism
Transfer of Alpha-Amino Groups to Alpha-Ketoglutarate

The first step in the

catabolism of most L-amino
acids, once they have
reached the liver, is removal
of the alpha-amino groups,
promoted by enzymes
called aminotransferases or
transaminases.

In these transamination
reactions, the alpha-amino
group is transferred to
the alpha-carbon atom of
alpha-ketoglutarate, leaving
behind the corresponding
alpha-keto acid analog of
the amino acid.

Lehninger, Principles of Biochemistry, Ch. 18

Transamination
Transamination is the transfer of an amine group from an amino
acid to a keto acid (amino acid without an amine group), thus
creating a new amino acid and keto acid as shown below. Keto
acids (e.g. pyruvate) are what remain after amino acids have had
their nitrogen group removed by deamination or transamination.
Transamination is used to synthesize nonessential amino acids.

https://docs.google.com/document/d/1USW37gL6ZjTHKjJXBuVVAyw4Uwbe_E-yUxM7L1uMTYo/edit
Deamination

Deamination is the removal of the amine group. The potential

problem with deamination is that too much ammonia is toxic,
causing a condition known as hyperammonemia

https://docs.google.com/document/d/1USW37gL6ZjTHKjJXBuVVAyw4Uwbe_E-yUxM7L1uMTYo/edit
Ammonia is
a toxic waste
product

Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2).
DOI:10.15347/wjm/2014.008. ISSN 20018762. - All used images are in public domain., Public
Domain, https://commons.wikimedia.org/w/index.php?curid=6703008
Fates of ammonia

http://www.slideshare.net/drashokkumarj/formation-of-ammonia-and-urea-cycle
Production of glutamine from glutamate and ammonia

Excess ammonia in tissues is added to glutamate to form glutamine, a

process catalyzed by glutamine synthetase. After transport in the
bloodstream, the glutamine enters the liver and NH4+ is liberated in
mitochondria by the enzyme glutaminase.

Lehninger, Principles of Biochemistry, Ch. 18

Glutamine synthetase reaction

http://slideplayer.com/slide/10932032/
Glutamine transports
ammonia safely in
bloodstream

Ammonia is quite toxic to

animal tissues. In most
animals much of the free
ammonia is converted to a
nontoxic compound before
export from the
extrahepatic tissues into
the blood and transport to
the liver or kidneys.
Glutamine is a nontoxic
transport form of ammonia.

Lehninger, Principles of Biochemistry, Ch. 18

 Lehninger, Principles of Biochemistry, Ch. 18
Glutaminase reaction

The amide nitrogen is

released as ammonium ion
in the mitochondria, where
the enzyme glutaminase
converts glutamine to
glutamate and NH4+. The
NH4+ from intestine and
kidney is transported in the
blood to the liver. In the
liver, the ammonia from all
sources is disposed of by
urea synthesis.

Some glutamate may be processed in the liver by glutamate

dehydrogenase, releasing more ammonia and producing carbon skeletons
for metabolic fuel. However, most glutamate enters the transamination
reactions required for amino acid biosynthesis and other processes.
Alanine Transports Ammonia from Skeletal Muscles to the Liver

Alanine plays a special role in

transporting amino groups to
the liver in a nontoxic form,
via a pathway called the
glucose-alanine cycle.

In muscle and other tissues

that degrade amino acids
for fuel, amino groups are
collected in the form of
glutamate by transamination.

Glutamate can transfer its

alpha-amino group to
pyruvate, a readily available
product of muscle glycolysis,
by the action of alanine
aminotransferase.
Lehninger, Principles of Biochemistry, Ch. 18
Transamination of alanine (reversible)

alanine pyruvate
Glucose-alanine cycle Lehninger, Principles of Biochemistry, Ch. 18

Alanine serves as a carrier of ammonia and of the carbon skeleton of

pyruvate from skeletal muscle to liver. The ammonia is excreted and the
pyruvate is used to produce glucose, which is returned to the muscle.
Fates of ammonia

http://www.slideshare.net/drashokkumarj/formation-of-ammonia-and-urea-cycle
Excretory forms of nitrogen

From Lehninger
Urea cycle Lehninger, Principles of Biochemistry, Ch. 18

If not reused for the synthesis of new amino acids or other nitrogenous
products, amino groups are channeled into a single excretory end
product. In ureotelic organisms, the ammonia deposited in the
mitochondria of hepatocytes is converted to urea in the urea cycle
Urea cycle Lehninger, Principles of Biochemistry, Ch. 18

The enzymes
catalysing
these
reactions are
distributed
between the
mitochondrial
matrix and
the cytosol.
Urea cycle simplified
Urea cycle

urea production occurs in

liver (hepatocytes)

5 reactions: 2 mitochondrial
and 3 cytosolic

https://en.wikipedia.org/wiki/Urea_cycle
1. Formation of carbamoyl phosphate

http://nptel.ac.in/courses/102103015/module6/lec7/2.html
2. Formation of citrulline

http://www.slideshare.net/guest8cd1aaf/urea-cycle
3. Formation of argininosuccinate

http://www.slideshare.net/guest8cd1aaf/urea-cycle
4. Formation of arginine and fumarate

http://www.slideshare.net/guest8cd1aaf/urea-cycle
5. Cleavage of arginine to form urea

http://osp.mans.edu.eg/medbiochem_mi/Cources/Biochemistry/2nd_year_medicine/
Protein_metabolism/files/Lecture_03.htm
Links between urea and citric acid (Krebs) cycles
Because the fumarate produced in the argininosuccinase reaction is
also an intermediate of the citric acid cycle, the cycles are, in principle,
interconnected

Lehninger, Principles of
Biochemistry, Ch. 18

communication
between them
depends on the
transport of
key intermediates
between the
mitochondrion
and cytosol
Urea https://en.wikipedia.org/wiki/Urea

Urea is an organic compound with the chemical formula CO(NH2)2. This

amide has two –NH2 groups joined by a carbonyl (C=O) functional group.
The liver forms it by combining two ammonia molecules (NH3) with a
carbon dioxide (CO2) molecule in the urea cycle.
Urea excretion

causes of elevated BUN: dehydration, high-protein diet, urinary tract

obstruction, renal failure, diabetic nephropathy

causes of low BUN: over-hydration, low-protein diet, liver failure

Fates of ammonia

http://www.slideshare.net/drashokkumarj/formation-of-ammonia-and-urea-cycle
Ammonium can act as urinary buffer

http://fblt.cz/en/skripta/vii-vylucovaci-soustava-a-acidobazicka-rovnovaha/7-acidobazicka-rovnovaha/
http://slideplayer.com/slide/5712411/
Summary of amino acid catabolism
Ketogenesis
(formation of
ketone bodies)

provide energy when

FFA or glucose less
available (depends on
tissue)

transported from liver to

tissues where converted
back to acetyl CoA to
enter Krebs cycle
Ketone body
formation and
export from liver

During starvation,
gluconeogenesis
depletes citric acid
cycle intermediates,
diverting acetyl-CoA to
ketone body production

excess ketone body

formation also occurs in
uncontrolled diabetes

From Lehninger
Diabetic ketoacidosis

DKA results from insulin

insufficiency; body burns fatty
acids and produced acidic
ketone bodies

symptoms: nausea, vomiting,

fruity breath, frequent urination,
fatigue, confusion,
unconsciousness

http://dtc.ucsf.edu/living-with-diabetes/
complications/diabetic-ketoacidosis/
http://www.slideshare.net/RajeshChaudhary10/amino-acid-pool
Amino acid synthesis
Non-essential amino acids: can be synthesized in the
body. These five are alanine, aspartic acid, asparagine,
glutamic acid and serine.

Conditionally essential amino acids: synthesis can be

limited under special pathophysiological conditions.
These six amino acids are arginine, cysteine, glycine,
glutamine, proline and tyrosine.

Essential amino acid: cannot be synthesized de novo

(from scratch) by the organism, and thus must be
supplied in its diet. The nine amino acids humans cannot
synthesize are phenylalanine, valine, threonine,
tryptophan, methionine, leucine, isoleucine, lysine, and
histidine.
https://en.wikipedia.org/wiki/Essential_amino_acid
From Lehninger
From Lehninger