The document summarizes the urea cycle and protein catabolism. It discusses: 1) Proteins are constantly degraded and resynthesized to remove damaged, unneeded, defective, or old proteins. 2) Amino acids have varying half-lives, and some residues are more stabilizing while others are destabilizing. 3) Amino acids are oxidized or reused. Ammonia produced from amino acid catabolism must be eliminated as it is toxic, especially to the central nervous system. 4) The urea cycle in the liver involves several steps to convert ammonia to less toxic urea for excretion, including transamination to shuttle amino groups to glutamate

1. Urea Cycle
Dr. Zahid Azeem
Assistant Professor of Biochemistry
AJ&K Medical College Muzaffarabad
For MBBS-batch 2017

2. • Turnover mean both degradation and synthesis
• Proteins are constantly degraded and
resynthesized
• Why degradation?
 To remove
a) Damaged Proteins
b) Un-needed Proteins
c) Defective Proteins
d) Old Proteins (Actually the half life of many proteins is
determined at the time of their synthesis)
Protein Turnover
2

3. Half life of aminoacids
Highly stabilizing residues (t1/2>20 hours)
Ala Cys Gly Met
Pro Ser Thr Val
Intrinsically destabilizing residues
(t1/2= 2 to 30 minutes)
Arg His Ile Leu
Lys Phe Trp Tyr
Destabilizing residues after chemical
modification (t1/2= 3 to 30 minutes)
Asn Asp Gln Glu
3

4. Amino acid oxidation and the production
of urea
Waste or reuse
Oxidation
4

5. Ammonia has to be eliminated
• Ammonia originates in the catabolism of amino acids
that are primarily produced by the degradation of
proteins – dietary as well as existing within the cell:
digestive enzymes
proteins released by digestion of cells sloughed-
off the walls of the GIT
muscle proteins
hemoglobin
intracellular proteins (damaged, unnecessary)
5

6. Ammonia has to be eliminated
• Ammonia is toxic, especially for the CNS, because it
reacts with -ketoglutarate, thus making it limiting
for the TCA cycle  decrease in the ATP level
• Liver damage or metabolic disorders associated with
elevated ammonia can lead to tremor, slurred
speech, blurred vision, coma, and death
• Normal conc. of ammonia in blood: 30-60 µM
6Dr zahid

7. Overview of amino acid catabolism in mammals
2 CHOICES
1. Reuse
2. Urea cycle
Fumarate
Oxaloacetate
7Dr. Inayat Abbasi

8. Nitrogen removal from amino acids
Transamination
Oxidative
deamination
Urea cycle
Aminotransferase
PLP
8

9. Nitrogen removal from amino acids
Step 1: Remove amino group
Step 2: Take amino group to liver for
nitrogen excretion
Step 3: Entry into mitochondria
Step 4: Prepare nitrogen to enter urea
cycle
Step 5: Urea cycle
9

10. Step 1. Remove amino group ;
Transamination
• Transfer of the amino group of an amino acid to an -keto
acid  the original AA is converted to the corresponding -
keto acid and vice versa: Transamination is catalyzed by
transaminases (aminotransferases) that require participation
of pyridoxalphosphate
10

11. 11

12. Step 2: Take amino group to liver for
nitrogen excretion; Oxidation
deaminationn
Glutamate
dehydrogenase
The glutamate dehydrogenase of mammalian liver
has the unusual capacity to use either NAD+ or
NADP+ as cofactor
Glutamate releases its amino group as
ammonia in the liver.
The amino groups from many of the
-amino acids are collected in the
liver in the form of the amino group
of L-glutamate molecules.
12

13. Oxidation
deamination
13

14. 14

15. 1. Glutamate
transferres one amino group WITHIN cells:
Aminotransferase → makes glutamate from -ketogluta-rate
Glutamate dehydrogenase → opposite
2. Glutamine
transferres two amino group BETWEEN cells → releases its
amino group in the liver
3. Alanine
transferres amino group from tissue (muscle) into the liver
Nitrogen carriers
15

16. Glucose-alanine cycle
Ala is the carrier of ammonia and of the carbon
skeleton of pyruvate from muscle to liver.
The ammonia is excreted and the pyruvate is used
to produce glucose, which is returned to the
muscle.
Alanine plays a special role in transporting
amino groups to liver.
According to D. L. Nelson, M. M. Cox :LEHNINGER. PRINCIPLES
OF BIOCHEMISTRY Fifth edition
16

17. Step 3: entry of nitrogen to mitochondria
17

18. Step 4: prepare nitrogen to enter urea cycle
Regulation
18

19. Step 5: Urea cycle aspartate
Ornithine
transcarbamoylase
Argininosuccinate
synthase
Argininosuccinate
lyase
Arginase 1
19Dr. Inayat Abbasi

20. Dr. Inayat Abbasi 20

21. OOA
Oxaloacetate → aspartate
21

22. The overall chemical balance of the
biosynthesis of urea
NH3 + CO2 + 2ATP → carbamoyl phosphate + 2ADP + Pi
Carbamoyl phosphate + ornithine → citrulline + Pi
Citrulline + ATP + aspartate → argininosuccinate + AMP + PPi
Argininosuccinate → arginine + fumarate
Arginine → urea + ornithine
Sum: 2NH3 + CO2 + 3ATP  urea + 2ADP + AMP + PPi + 2Pi
22

23. Deficiencies of urea cycle enzymes

24. Ammonia toxicity
Ammonia encephalopathy
• Increased concentration of ammonia in the blood
and other biological fluids → ammonia difuses into
cells, across blood/brain barrier → increased
synthesis of glutamate from -ketoglutarate,
increased synthesis of glutamine
 -ketoglutarate is depleted from CNS → inhibition of
TCA cycle and production of ATP
• Neurotransmitters – glutamate (excitatory neurotr.)
and GABA (inhibitory neurotr.), may contribute to the
CNS effects – bizarre behaviour
24

25. Deficiencies of urea cycle enzymes
• Infant born with total deficiency of one or more enzymes
survive at least several days.
• Many enzymes deficiencies are partial → enzymes have
altered Km values.
• Case are known of deficiencies of each enzymes.
• Interruption of the cycle at each point affected nitrogen
metabolism differently - some of the intermediates can
diffuse from hepatocytes → accumulate in the blood → pass
into the urine.
• If symptoms are not detected early enough → severe mental
retardation → brain damage is irreversible.
25

26. • Urea Level in Blood:
• In clinical practice, blood urea level is taken as
an indicator of renal function. The normal
urea level in plasma is from 20 t0 40 mg/dl.
Blood urea level is increased where renal
function is inadequate.
• Urinary excretion of urea is 15 to 30g/day (6-
15g nitrogen/day). Urea constitutes 80% of
urinary organic solids.
26

27. • Clinical importance of urea:
• An active man consuming 300grams
carbohydrates, 100grams of fats and 100 grams
of proteins excretes 16.5 grams of N daily. 95%N
is eliminated through kidneys and remaining 5%
through feces.
• Normal Urea level:
• Healthy adult in fasting condition has urea 20-
40mg/100ml of plasma. Pakistani individual
taking less protein may have normal level of urea
15-40mg/100ml of plasma.
27

28. Causes of Increased Urea Levels
(Uremia):
• Pre-renal Causes:
• Here the plasma volume is mostly reduced
such as salt and water depletion.
• Sever and prolonged diarrhea/dehydration.
• Hemorrhage and shock; shock due to sever
burns.
• Ulcerative colitis with severe chloride loss
28

29. Thank you for your attention