The document summarizes nitrogen metabolism and amino acid catabolism. It discusses how proteins are broken down into amino acids in the stomach and small intestine, and how amino acids are either used for building proteins or oxidized for energy. It describes the key roles of the liver in degrading amino acids and processing excess nitrogen via the urea cycle. The urea cycle involves ornithine, citrulline, argininosuccinate, and other intermediates to ultimately produce urea which is excreted in urine. Defects in the urea cycle can cause hyperammonemia and other issues.

1. BC368
Biochemistry of the Cell II
Nitrogen Metabolism I
(Ch 18)
Amino Acid Oxidation and the
Production of Urea
May 1, 2015

2. Overview of amino acid metabolism
Proteins constantly
undergo turnover.

3. Overview of amino acid metabolism
No protein stores, so
essential amino acids
must come from diet.
Amino acids are also
used to synthesize
some non-protein
metabolites.
Proteins constantly
undergo turnover.

4. 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

5. Overview of amino acid catabolism
Special role for four amino acids:

6. Digestive events
are triggered of the
hormone gastrin,
released when food
enters the stomach.
Digestion and
Absorption

7. Low pH activates
digestive enzymes;
e.g., pepsin.
Resulting amino
acids are absorbed by
the intestinal mucosa,
enter the capillaries,
travel to the liver.
Digestion and
Absorption
Liver can degrade
all amino acids but
Leu, Ile, Val.

8. Fig 18-1
Divergent pathways of NH3 groups and carbon
skeletons
Fig 18-1

9. Removal of amino group via transamination
Amino groups can be
removed by
transamination.
In liver cytosol, amino
groups are passed to α-
KG, forming glutamate.
Transaminases (aka
aminotransferases)
require pyridoxal
phosphate cofactor.

10. Pyridoxal phosphate and transamination

11. Fig 18-1
Glutamate in the liver
cytosol enters the
mitochondrial matrix,
where its amino group
is removed by
glutamate
dehydrogenase.
Removal of amino group via oxidative
deamination
Amino group must be
processed for excretion or
recycled.
Fig 18-7

12. Transport of amino groups as glutamine
Peripheral tissues
may send their
amino groups as
glutamine through
the bloodstream to
the liver for
processing.
Fig 18-8
To liver via bloodstream

13. Fig 18-1
Transport of amino groups as alanine
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

14. Fig 18-1
Summary of
paths of
amino
groups
Fig 18-2

15. Fig 18-1
Fate of
NH4
+
excreted as NH3
(ammonotelic)

16. Fate of
NH4
+
excreted as uric acid
(uricotelic)

17. Fate of
NH4
+

18. Fate of
NH4
+
excreted as urea in H2O
(ureotelic)

19. 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?

20. Gout, the evil demon
The Disease of Kings and
the King of Diseases…
The Gout by James Gilray, 1799
Alternate fate of
NH4
+ = uric acid
from purines
Podagra
(swelling of
the big toe)
results from
crystals of
uric acid in
the synovial
fluid

21. XO= xanthine oxidase
Normal pathway of purine degradation
GMP
AMP

22. Treatment for gout
Trojan horse inhibitor
of xanthine oxidase
Fig 22-47

23. Treatment for gout
Trojan horse inhibitor
of xanthine oxidase
Gertrude Elion, 1918-1999
Fig 22-47

24. Treatment for gout
Trojan horse inhibitor
of xanthine oxidase
Fig 22-47

25. 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.

26. 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.

27. Urea cycle
Spans two compartments: matrix and cytosol
Occurs in the liver

28. Preparatory step: carbamoyl phosphate
synthetase I
Occurs in the matrix First N of urea
Fig 18-11

29. Step 1: Ornithine
transcarbamoylase
Also occurs in the matrix, but
citrulline is transported to cytosol
Ornithine is analogous to OA

30. Step 2: Argininosuccinate synthetase
Second N of urea!

31. Step 3: Argininosuccinase

32. Step 4: Arginase
Ornithine is transported back to
the matrix.

33. Krebs’ bicycle
Fig 18-12

34. 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) Carbamoyl phosphate synthetase
2) Ornithine transcarbamoylase
3) Arginase
4) Alanine aminotransferase
5) Pyruvate carboxylase

35. Fates of carbon skeletons
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.
Fig 18-15