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Urea Cycle
1. GDH is the major agency responsible for ammonium
production.
2. Ammonium is toxic (N = 15 - 40M , max 70M)
Urine: organic acids and orotic acid
3. Liver: Principal site but also in small intestine
4. Excretion NH4+ by kidneys important for acid-base balance
but Normally 80-90% N urine as urea.
5. Hyperammonium >500M plasma [NH4+] = TOXIC
related to inborn errors of metabolism (genetic defects) as
well as induced (liver failure)
Usually detected in the newborn period.
Blood: measure ammonium, AA, lactate
Excreted %
Urea
86.0
Creatinine
4.5
Ammonium
2.8
Uric acid
1.7
Other compounds
5.0
Urea Cycle
1. The urea cycle was the first metabolic process to be
described as a cycle by Sir Hans Krebs who also
described the TCA cycle.
2. Role of Urea cycle: rid the body of toxic NH 4 + therefore
permitting the use of AA as an energy source.
3. Liver major site of urea synthesis, major source of
arginase, (small amounts in small intestine) and is the
only tissue with the complete set of all 5 enzymes
required
Urea Cycle
Urea Cycle
I.
Compartmentation:
mitochondria (rxn 1&2) cytosol (rxn 3-5)
Mathematics of equation
1. 2 N per urea molecule:
1 NH4+ (start) + 1 transferred from ARG
2. 4 high energy phosphate: 2 ATP ADP + Pi
1 ATP AMP + Ppi
Therefore 2 ATP / amino (N) group
Overall catabolism:
Catabolize 1 Leu 32 ATP (from TCA cycle)
Make urea from N 2 ATP
NET ENERGY 30 ATP produced
Regulation through Mg
2+
Nutritional Regulation
long term regulation
(i) Five Urea Cycle enzymes & NAG synthase
all with low P diets & with high P diets
Therefore regulated nutritionally (over the long term)
(ii) Note also during starvation due to AA catabolism
therefore although muscle and liver protein the
level of these enzymes due to increased urea
synthesis
-increased enzyme synthesis
-decrease enzyme degradation
(iii) Changes take place over 3-7 days.
orotic acid
V
III
IV
Presentation
Severe Illness: First week
Usually normal first 24h
Symptoms of hyperammonemia within 1-3 days
Include: Feeding intolerance
Vomiting
Lethargy
Irritability
Respiratory Distress (hyperventilation)
Seizures
Coma
Outcome
Mortality
Improvements in treatment have increased 1 year survival rate.
Once past the neonatal period, long term survival rate =
50% OTC (Type II)
75% CPS (Type I)
95% AS and AL (Steps 3+4)
Morbidity
75% mental retardation (mean IQ 50), Seizure disorders, Visual
deficits (proportional to extent of NH4 ), Protein intolerance
Brain: NH4 causes increased permeability and TRP
serotonin behavior abnormalities
quinolininc acid neuronal injury
Also with type V block Arg but ~ NH4+ severely retarded
Treatment (contd)
1. Compounds to Conjugate AA:( urea load) (see
Diagram)
Benzoate: combines with GLY to generate hippurate
urine
Phenylacetate: +GLN to produce phenylacetyl GLN
urine
2. NAG Permeable Analog:
N carbamoyl glutamate enters mitochondrial.
3. Hemodialysis used to remove both AA & NH4 during
hyperammonemia coma
Treatment:
Stimulate Alternate Pathways
Future
(i) Enzyme Replacement Therapy
(Liver Transplant) but expensive and lack donors
virus vector is
(iii) Diagnosis
Molecular Diagnostics (RFLP) can reveal genetic defects by prenatal
diagnosis when indicated.
Direct enzyme determination in amniocytes or chorionic vilus
biopsy to determine presence/absence enzyme
Reactive or anticipatory treatment if defect suspected
Case #3 Discussion
A 6-month-old infant began to vomit occasionally and
ceased to gain weight. At age 8 months he was readmitted to
the hospital. Routine examination and laboratory tests were
normal, but after 1 week he became habitually drowsy, his
temperature rose to 39.4oC, his pulse was elevated, and his
liver was enlarged. The electroencephalogram was grossly
abnormal.
Since the infant could not retain milk given by gavage
feeding, intravenous glucose was administered. He improved
rapidly and came out of the coma in 24 hours. Analysis of his
urine showed abnormally high amounts of glutamine, uracil &
orotic acid but urea, which suggested a high blood ammonium
concentration. This was confirmed by the laboratory.
Discussion:
1. Hereditary hyperammonemia can result from defects in
genes for urea cycle enzymes. Which enzymes might be
affected?
2. Considering the data ( uracil & orotic acid) which enzyme
may be defective in this patient?
3. Why was the urine glutamine concentration elevated?
1. Hyperammonemia is characteristic of all steps
(including NAG synthase) Most frequent OTC
2. N BUN ( blood urea N), ALSO uracil (& orotic
acid) due to carbamoyl phosphate which leaks from
mito cyto increased pyrimidine synthesis.
Unusual: clinical symptoms slow (6 months old)
3 Why? Exceeds kidneys ability GLN GLU + NH4+
Contd
4. Offer a genetic explanation for the observation that this disease
is usually lethal in males but not in affected females.
5. This patient was treated using procedures available at the time.
He was given a daily diet of 1.5 g of protein/kg body weight. After 2 years
on this diet, his height and weight were judged to be normal for his age.
What is the effect of diet on a growing child in terms of nitrogen balance?
6. How would you treat a similar patient today?