Amino Acids

Metabolism
&

Urea cycle
 Major Functions of Amino Acids
Derived from Dietary Protein
Oxidation
Glycogenic amino acids: --Blood glucose--Energy
Ketogenic amino acids: -Acetyl CoA-Stored fat-Energy

Biosynthesis of nitrogen-containing metabolites

Heme Blood cell

Choline PL
Glycosamine Sugar
Nucleotides DNA
Protein synthesis Protein
Biogenic amines Neurotransmitters
Carnitine Heart
Creatine phosphate « Energy »
 Substrates for the Urea Cycle
-amino acid -ketoglutarate NADH   H2N-CO-OPO32-

-keto acid glutamate NAD+ 

• Above, amino groups are transferred to glutamate,

from which ammonium is produced, and then used to
make carbamoyl phosphate.
• Below, amino groups are transferred to produce
aspartate.
-amino acid -ketoglutarate aspartate

-keto acid glutamate oxaloacetate

1
 Urea Cycle • Aspartate and
carbamoyl
phosphate
each deliver an
amino group to
the cycle.
• Notice that the
carbamoyl
phosphate
production and
condensation
occur in the
Fig. 23.16
mitochondrial
matrix.
2
 NH4+ from Oxidative Deamination of Glutamate
O O O O
+
NH3 NAD+ NADH + H+
H O
CH2 CH2 + NH4+
CH2 glutamate CH2
dehydrogenase
O O O O
glutamate -ketoglutarate
• Hexameric glutamate dehydrogenase is is controlled
allosterically.
– High energy levels inhibit (ATP and GTP).
– Low energy levels activate (ADP and GDP).
• NADP+ can replace NAD+.
• NH4+ , which is toxic to humans, is produced in the
mitochondria and used to make carbamoyl phosphate.
3
 O
H NH 2
N O O
O O Pi + CH 2 +
H 3N H
H2N O P O CH 2
CH 2
O CH 2 + ATP
+
H NH 3
carbamoyl O O

phosphate O O aspartate
4 citrulline 1
+ O
NH 3 + O
H 2N
CH 2 H
CH 2 UREA H
N
N
H CH 2
+ AMP + PPi
ornithine CH 2

H
CH 2
+
NH 3 CYCLE CH 2
CH 2
O O 2 Pi
O O (1-3 in cytosol, 4 +
H NH 3
in mitochondial matrix)
2 ~ P used +
O O
H 2N
3 2 argininosuccinate
H NH 2
H2N N
NH2 CH 2
O O
CH 2 H O
UREA CH 2
+
H2O H NH 3
O H
O O O fumarate
arginine
1. ARGININOSUCCINATE SYNTHASE 2. ARGININOSUCCINASE
5 3. ARGINASE 4. ORNITHINE TRANSCARBAMOYLASE
 Connection to Krebs Cycle
+ ATP -keto acid
aspartate
citrulline -amino acid
1

UREA Oxaloacetate
CYCLE argininosuccinate
+ AMP + PPi NADH

2 2 Pi
NAD+
Malate
arginine
fumarate
H20

• Fumarate is oxidized to oxaloacetate by Krebs cycle

enzymes, producing NADH.
• Oxaloacetate accepts an amino group instead of
6 being condensed with acetyl CoA.
 Summary of Reactions and Energetics - 1

H20 + aa + NAD+  -keto acid + NH4+ + NADH + H+

and
H20 + fumarate + aa + NAD+  aspartate + -keto acid
+ NADH + H+
then
aspartate + NH4+ + HCO3- + 3 ATP 
urea + fumarate + 2 H20 + 2 ADP + AMP + 4 Pi + H+

Four high energy phosphate bond equivalents are

used for these reactions (- 4 ~P).
Two NADH are produced.

8
 Summary of Reactions and Energetics - 2

Now consider NADH oxidation:

2 H+ + 2 NADH + O2 2 NAD+ + 2 H20 (+5 ~P)

The net reaction is then

2 aa + HCO3- + O2 
2 -keto acid + urea + H+ + 2 H20 (+1~P)

9
 Hyperammonemia

• Normal blood [NH4+] is 10-40 mM.

• Deficiencies of carbamoyl phosphate synthetase or
of any enzyme in the urea cycle cause high [NH4+].
• Affects CNS and can lead to irreversible brain
damage.
• Treatment strategies depend on which enzyme is
deficient.

10
 Ketogenic and Glucogenic Amino Acids

Fig. 23.21

• After removal of the amino group, the keto acids are used to make
13 Krebs cycle intermediates, pyruvate, acetyl CoA and acetoacetyl CoA.