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TUMS
Dr. Azin Nowrouzi
Tehran University of Medical Sciences
Fate of the C-Skeleton of Amino Acids
2
Outline of catabolism of 20 amino acids
Amino acid
Products
# enzymatic
steps
Cofactors
Glycogenic or
Lipogenic
Alanine
Pyruvate
1
PLP
G
Glycine
Pyruvate
2
N5,N10 CH2 THF
G
Serine
Pyruvate
1
Cysteine
Pyruvate
2
Threonine
Pyruvate
3
Aspartic acid
Oxaloacetate
1
PLP
G
Asparagine
Oxaloacetate
2
PLP
G
Histidine
α-ketoglutarate
5
THFA, PLP
G
Glutamic acid
α-ketoglutarate
1
PLP
G
G
PLP, NADH
G
G
4
Glutamine
α-ketoglutarate
2
PLP
G
Amino acid
Products
enzymatic Cofactors
steps
Glycogenic
or Lipogenic
Methionine
Succinyl CoA
9
ATP, CoA, NAD,
biotin, Vit B12
G
Valine
Succinyl CoA
10
PLP, NAD, CoA, Vit
B12
G
Isoleucine
Succinyl CoA
9
PLP, NAD, CoA, FAD, G, L
biotin, Vit B12
Leucine
Succinyl CoA,
Acetoacetyl coA
6
Thiamin PP, lipoic
acid, PLP, CoA, NAD,
FAD
L
Phenylalanine
Succinyl CoA,
fumarate
7
O2, NADPH,
tetrahydrobiopterin
G, L
Tyrosine
Succinyl CoA,
Fumerate
6
O2, NADPH,
tetrahydrobiopterin
G, L
Tryptophan
Succinyl CoA,
Alanine
9
O2, NADPH, NAD
G, L
Lysine
Acetoacetyl
CoA,
9
NADPH, NAD, NADP,
PLP, CoA, FAD
L
5
Degradation of Carbon Skeletons
• Seven products result from the catabolism of amino acid carbon skeletons:
– oxaloacetate, α-ketoglutarate, pyruvate, fumarate, acetyl coA,
acetoacetyl coA, succinyl coA
• Glycogenic
– Their catabolism produces pyruvate or one of the
intermediates of the Crebs cycle.
– These are substrates for gluconeogenesis
– So they can produce glycogen in liver and muscle.
• Lipogenic (or ketogenic)
– Their catabolism produces acetoacetate or its
precursors acetyl coA or acetoacetyl coA
6
Amino Acids that produce
Oxaloacetate
Amino Acids that produce
α-ketoglutarate
Amino Acids that produce
Pyruvate
Amino Acids that produce
Fumarate
Phenylketonuria (PKU) Disease
• Deficiency of Phe hydroxylase
• Occurs in 1:20,000 live births in U.S.
• Seizures, mental retardation, brain
damage
• Treatment: limit phenylalanine intake
• Screening of all newborns mandated in
all states
11
Amino Acids that produce
Acetyl CoA or Acetoacetyl CoA
Amino Acids that produce
Succinyl CoA
Catabolism of
Branched Chain Amino Acids
Transfer of nitrogen components from
tissues to the liver for urea synthesis
Fed state
16
Fasting (starvation)
(i) For the first 7 days, maintain blood glucose
(brain use 65% of glucose  400 - 600
Cal)
(ii) > 7 days: Protein proteolysis decreases
(protect essential proteins) therefore use
over a prolonged period compromises
organism.
(iii) → Switch to Ketone bodies
17
18
AA are released from muscle during the post- absorptive
state (O/N fast). Of the AA released by muscle Ala= 30% &
Gln= 25% (total> 50%)
But output (Ala+Gln) > abundance in muscle proteins which
contain 7-10% Ala & 6% Gln
Where does this Ala & Gln come from?
19
(i)Muscle:
Protein → Ala + aa
aa→ NH4+ + α keto acids
α keto acids → Ala (“simplest” aa).
ThereforeSources
total Ala released
> Ala derived
from
proteins
of Alanine
(from
Muscle)
(ii) Liver: Ala → NH4+ + α keto acids
NH4+ → urea
(iii) As well Glucose → Pyruvate (no N) → Ala (with N)
Therefore Ala serves as a vehicle for transport of NH4+
from muscle to liver (NH4+ is generated through
breakdown of aa  → energy).
(iv) Because free NH4+ is very toxic even at low levels
therefore Pyruvate + NH4+ → Ala (non-toxic)
(v) In liver: NH4+ → urea for excretion
20
Specialized Amino Acid Roles
1. Certain NEAA continue being synthesized even when
adequate levels are supplied in diet because of a
specialized role
2. ARG → urea synthesis
ASP → urea synthesis
GLU → conduit for disposal of N
3. ALA & GLN → key role in exchange between tissues
(liver & skeletal muscle)
4. Liver: major site gluconeogenesis (AA → Glucose)
major site urea synthesis (kidneys to a lesser
extent)
5. Skeletal Muscle: 60% total body protein, 50% total
body AA pool and is the major source to provide AA 21
carbons → hepatic gluconeogenesis
Amino Acid Degradation
1. Removal of alpha-amino groups
2. Nitrogen excretion
3. Fate of carbon skeletons
22
Removal of alpha-amino groups
• Mechanisms of –NH2 removal
A. Transamination
B. Oxidative deamination
C. Amino acid oxidases
D. Threonine or Serine dehydratase
23
A. Transamination
Removal of Nitrogen by aminotransferase
24
B. Oxidative Deamination
25
L- and D- Amino Acid Oxidases
• They are present in liver and kidneys.
• They have low activity
• Their physiologic value is not clear.
Amino Acid + H2O
α-ketoacid + NH3
D. Amino acid Dehydratase
Threonine
Urea
Serine and Threonine can be Directly Deaminated
27
Fate of Nitrogen in Different Organisms
Other excretion
products
creatinine
uric acid
28
Disposal of amino group
•
•
Urea cycle (Krebs-Henseleit cycle)
Provides 25-30 g of urea daily for urine formation in the kidneys
a) Carbamoyl Phosphate Synthetase
b) Ornitine Carbamoyl Transferase
c) Argininosuccinate Synthetase
d) Argininosuccinate Lyase
e) Arginase
•
Excretion of free ammonia
a) Glutamine synthetase
b) Glutaminase
29
Ammonium Ion is Converted
into Urea
Urea cycle
31
The Urea Cycle is Linked to the
Citric Acid Cycle
NH4+
32
Amino Acid Metabolism
33