Ammonia and the Urea Cycle

Question 1

NH3 (ammonia) is transported from peripheral tissues using what AA

Answer 1

Glutamine (incorporation of ammonia to Glu)

Alanine (transport of NH3 from muscle)

Question 2

What is the fate of alanine once it gets to the liver from the muscle?

Answer 2

alanine is broken back down to pyruvate (goes into gluconeogenesis) and NH3 (urea cycle)

Question 3

fate of urea after formation

Answer 3

it is transferred from liver to kidney where it is excreted (75%)

or it goes to the colon (25%)

Question 4

when does intestinal formation of NH3 become a problem

Answer 4

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

Question 5

where in the liver does the urea cycle occur

Answer 5

partially in mito and partially in the cytosol

Question 6

where does the N atoms in urea come from

Answer 6

one from ammonia (GDH and glutaminase) and one from aspartate

Question 7

some molecules released from the urea cycle

Answer 7

fumarate and NADH

Question 8

what is the rate limiting step of urea cycle

Answer 8

CPS I

Question 9

what is the activator of the rate limiting enzyme of urea cycle

Answer 9

N-acetyl glutamate (NAG)

Question 10

what stimulates the urea cycle?

Answer 10

increased formation of NAG and presence of arginine

Question 11

all urea cycle disorders are characterized by what

Answer 11

increased blood NH3 level (hyperammoniaemia) and blood glutamine levels

also decreased urea formation

Question 12

symptoms of urea cycle disorders

Answer 12

early symptoms: lethargy, irritability, and feeding difficulties

untreated: neurological manifestation, seizures, and mental retardation

Question 13

hyperammoniaemia type I is a deficiency of what

Answer 13

CPS-I (first enzyme)

Question 14

why is CPS I deficiency toxic for the brain?

Answer 14

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

Question 15

treatment of CPS I deficiency

Answer 15

L arginine supplementation (stimulates formation of NAG), high levels of NAG,

Question 16

methods of managing hyperammoniaemia that bypass urea cycle

Answer 16

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

Question 17

what is deficient in hyperammoniaemia type II

Answer 17

OTC deficiency (ornithine transcarbamoylase)
which is X linked

Question 18

manifestation of OTC deficiency

Answer 18

hyperammoniaemia, decreased BUN (blood urea nitrogen), high blood gln levels, orotic aciduria, cerebral edema, lethargy, convulsions, coma, death

Question 19

what enzyme deficient in citrullinaemia

Answer 19

argininosuccinate synthetase

Question 20

manifestation of argininosuccinate sythetase deficiency

Answer 20

hyperammoniaemia, high levels of serum citrulline, citrulline in urine

Question 21

treatments of citrullinaemia

Answer 21

arginine administration

Question 22

what is deficient in argininosuccinic aciduria

Answer 22

argininosuccinate lyase

Question 23

manifestation of argininosuccinic aciduria

Answer 23

elevated plasma and cerebral spinal fluid argininosuccinate, moderately high levels of citrulline, argininosuccinate detected in urine

Question 24

treatment of argininosuccinic aciduria

Answer 24

surplus arginine so as to allow urinary excretion of argininosuccinate

Question 25

what is deficient in hyperargininaemia

Answer 25

arginase

Question 26

manifestations of hyperagininaemia

Answer 26

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

Question 27

treatments of hyperagininaemia

Answer 27

diet of essential AA except arginine

Question 28

what other way can one have hyperammonaemia without a deficiency in the urea cycle?

Answer 28

excessive drinking (alcohol cirrhosis) and viral or drug induced hepatitis

Question 29

mechanisms of ammonia neurotoxicity

Answer 29

energy and osmotic effect and neurotransmitter effect

Question 30

describe the energy and osmotic effect of ammonia neurotoxicity

Answer 30

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

Question 31

describe the neurotransmitter effect of ammonia neurotoxicity

Answer 31

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

Question 32

treatment of acquired hyperammonemia (alcohol cirrhosis or drug hepatitis)

Answer 32

low protein/high carb diet, lactulose, neomycin

these basically reduce the absorption of urea in the gut