BC368
Biochemistry of the Cell II
Nitrogen Metabolism I
(Ch 18)
Amino Acid Oxidation and the
Production of Urea
May 1, 2015
Overview of amino acid metabolism
Proteins constantly
undergo turnover.
Overview of amino acid metabolism
Proteins constantly
undergo turnover.
Amino acids are also
used to synthesize
some non-protein
metabolites.
No protein stores, so
essential amino acids
must come from diet.
Amino acid catabolism in humans
Proteins are broken down in stomach and small
intestine to constituent amino acids.
Amino acids are either used as building blocks or
burned for energy (~10% of our energy needs).
Catabolism of amino acids increases
 for use in gluconeogenesis when glucose is unavailable
(e.g., starvation/diabetes)
 when protein content of diet exceeds need for building
blocks
 during times of stress
Overview of amino acid catabolism
Special role for four amino acids:
Digestion and
Absorption
Digestive events
are triggered of the
hormone gastrin,
released when food
enters the stomach.
Digestion and
Absorption
Low pH activates
digestive enzymes;
e.g., pepsin.
Resulting amino
acids are absorbed by
the intestinal mucosa,
enter the capillaries,
travel to the liver.
Liver can degrade
all amino acids but
Leu, Ile, Val.
Divergent pathways of NH3 groups and carbon
skeletons
Fig 18-1
Fig 18-1
Removal of amino group via transamination
Amino groups can be
removed by
transamination.
In liver cytosol, amino
groups are passed to αKG, forming glutamate.
Transaminases (aka
aminotransferases)
require pyridoxal
phosphate cofactor.
Pyridoxal phosphate and transamination
Removal of amino group via oxidative
deamination
Fig 18-1
Glutamate in the liver
cytosol enters the
mitochondrial matrix,
where its amino group
is removed by
glutamate
dehydrogenase.
Fig 18-7
Amino group must be
processed for excretion or
recycled.
Transport of amino groups as glutamine
Peripheral tissues
may send their
amino groups as
glutamine through
the bloodstream to
the liver for
processing.
To liver via bloodstream
Fig 18-8
Transport of amino groups as alanine
Fig 18-1
In concert with the
Cori cycle, skeletal
muscle may send
pyruvate through
bloodstream as alanine
(the glucose-alanine
cycle).
Operates when muscle
proteins are undergoing
catabolism.
Fig 18-9
Summary of
paths of
Fig 18-1
amino
groups
Fig 18-2
Fate of
+
NH
Fig 18-1 4
excreted as NH3
(ammonotelic)
Fate of
NH4+
excreted as uric acid
(uricotelic)
Fate of
NH4+
Fate of
NH4+
excreted as urea in H2O
(ureotelic)
Case Study
EM, the third child of parents unrelated by blood,
had one healthy sister and one brother who
demonstrated spasticity. EM appeared normal at
birth with good Apgar scores. Hypotonia was
observed after the third month of life. At 7 months of
age (weight, 6.0 kg; height, 67 cm), he was admitted
for evaluation of painful swollen joints. Neurological
examination revealed hyperreflexia and an inability
to lift his head. Laboratory tests revealed the
following:
• What is wrong with EM?
• What treatment would you recommend?
The Disease of Kings and
the King of Diseases…
Alternate fate of
NH4+ = uric acid
from purines
Gout, the evil demon
Podagra
(swelling of
the big toe)
results from
crystals of
uric acid in
the synovial
fluid
The Gout by James Gilray, 1799
Normal pathway of purine degradation
AMP
GMP
XO= xanthine oxidase
Treatment for gout
Trojan horse inhibitor
of xanthine oxidase
Fig 22-47
Treatment for gout
Gertrude Elion, 1918-1999
Trojan horse inhibitor
of xanthine oxidase
Fig 22-47
Treatment for gout
Trojan horse inhibitor
of xanthine oxidase
Fig 22-47
Purine Salvage Defect
Purines are recycled
through the purine salvage
pathway.
Key enzyme is HGPRT
(hypoxanthine-guanine
phosphoribosyltransferase).
Defect in HGPRT leads to
Lesch-Nyhan syndrome.
Purine Salvage Defect
Purines are recycled
through the purine salvage
pathway.
Key enzyme is HGPRT
(hypoxanthine-guanine
phosphoribosyltransferase).
Defect in HGPRT leads to
Lesch-Nyhan syndrome.
Urea cycle
Occurs in the liver
Spans two compartments: matrix and cytosol
Preparatory step: carbamoyl phosphate
synthetase I
Occurs in the matrix
First N of urea
Fig 18-11
Step 1: Ornithine
transcarbamoylase
Ornithine is analogous to OA
Also occurs in the matrix, but
citrulline is transported to cytosol
Step 2: Argininosuccinate synthetase
Second N of urea!
Step 3: Argininosuccinase
Step 4: Arginase
Ornithine is transported back to
the matrix.
Krebs’ bicycle
Fig 18-12
Twenty-four hours after birth, a formula-fed male infant becomes
somnolent and feeds poorly. Soon he begins to vomit and then
goes into a coma. It looks like sepsis, but he has no risk factors
and his sepsis work-up is negative. His serum ammonia and
ornithine are elevated while his citrulline levels are undetectable.
The maternal grandmother tells you that she had a son who died
as a baby from the same symptoms. Which of the following
enzymes is defective?
1)
2)
3)
4)
5)
Carbamoyl phosphate synthetase
Ornithine transcarbamoylase
Arginase
Alanine aminotransferase
Pyruvate carboxylase
Fig 18-15
Glucogenic amino
acids are degraded to
pyruvate or TCA
intermediate.
Ketogenic amino
acids are degraded to
acetoacetyl-CoA or
acetyl-CoA.
Some amino acids
are both.
Fates of carbon skeletons