Ammonia and the Urea Cycle Flashcards
NH3 (ammonia) is transported from peripheral tissues using what AA
Glutamine (incorporation of ammonia to Glu)
Alanine (transport of NH3 from muscle)
What is the fate of alanine once it gets to the liver from the muscle?
alanine is broken back down to pyruvate (goes into gluconeogenesis) and NH3 (urea cycle)
fate of urea after formation
it is transferred from liver to kidney where it is excreted (75%)
or it goes to the colon (25%)
when does intestinal formation of NH3 become a problem
in normal conditions, it is sent to the liver to form urea but problems arise with patients with liver cirrhosis.
liver can’t carry out normal functions so ammonia increases in the system which leads to neurotoxicity, coma, and death
where in the liver does the urea cycle occur
partially in mito and partially in the cytosol
where does the N atoms in urea come from
one from ammonia (GDH and glutaminase) and one from aspartate
some molecules released from the urea cycle
fumarate and NADH
what is the rate limiting step of urea cycle
CPS I
what is the activator of the rate limiting enzyme of urea cycle
N-acetyl glutamate (NAG)
what stimulates the urea cycle?
increased formation of NAG and presence of arginine
all urea cycle disorders are characterized by what
increased blood NH3 level (hyperammoniaemia) and blood glutamine levels
also decreased urea formation
symptoms of urea cycle disorders
early symptoms: lethargy, irritability, and feeding difficulties
untreated: neurological manifestation, seizures, and mental retardation
hyperammoniaemia type I is a deficiency of what
CPS-I (first enzyme)
why is CPS I deficiency toxic for the brain?
glutamate dehydrogenase and glutamine synthetase deplete the brain of the neurotrasmitters glutamate and GABA
and high glu levels in brain cells leads to cerebral edema
treatment of CPS I deficiency
L arginine supplementation (stimulates formation of NAG), high levels of NAG,
methods of managing hyperammoniaemia that bypass urea cycle
1) use benzoic acid (drug) that combines with gly and form hippuric acid and excretes one N atom
2) use phenylbutyrate (prodrug) that combines with Gln to form phenylacetylgluatmine and gets rid of two N atoms
what is deficient in hyperammoniaemia type II
OTC deficiency (ornithine transcarbamoylase) which is X linked
manifestation of OTC deficiency
hyperammoniaemia, decreased BUN (blood urea nitrogen), high blood gln levels, orotic aciduria, cerebral edema, lethargy, convulsions, coma, death
what enzyme deficient in citrullinaemia
argininosuccinate synthetase
manifestation of argininosuccinate sythetase deficiency
hyperammoniaemia, high levels of serum citrulline, citrulline in urine
treatments of citrullinaemia
arginine administration
what is deficient in argininosuccinic aciduria
argininosuccinate lyase
manifestation of argininosuccinic aciduria
elevated plasma and cerebral spinal fluid argininosuccinate, moderately high levels of citrulline, argininosuccinate detected in urine
treatment of argininosuccinic aciduria
surplus arginine so as to allow urinary excretion of argininosuccinate
what is deficient in hyperargininaemia
arginase
manifestations of hyperagininaemia
increased serum arginine and ammonia
in comparison to the rest of the urea disorders, hyperammoniaemia not as bad because arginine would stimulate the urea cycle reducing the amount of ammonia
treatments of hyperagininaemia
diet of essential AA except arginine
what other way can one have hyperammonaemia without a deficiency in the urea cycle?
excessive drinking (alcohol cirrhosis) and viral or drug induced hepatitis
mechanisms of ammonia neurotoxicity
energy and osmotic effect and neurotransmitter effect
describe the energy and osmotic effect of ammonia neurotoxicity
alpha ketoglutarate is converted to glutamate using glu DH. The use of alpha ketoglutarate takes an intermediate away from the TCA cycle meaning less ATP being formed which is needed by the brain. So, Na+/K+ ATPase activity being reduced so change in osmotic pressure and eventually neuronal cell death
describe the neurotransmitter effect of ammonia neurotoxicity
Glu converted to Gln using Gln sythetase so less Glu which is needed for formation of GABA. GABA is a neurotransmitter so less GABA would affect the brain
treatment of acquired hyperammonemia (alcohol cirrhosis or drug hepatitis)
low protein/high carb diet, lactulose, neomycin
these basically reduce the absorption of urea in the gut
