L16: Urea Cycle & Averting NH3 toxicity

Question 1

Fish are ___?

Answer 1

Ammonotelic (NH3-excreting)

Question 2

Birds are___?

Answer 2

Uricotelic (Uric Acid-excreting)

Question 3

Mammals are___?

Answer 3

Ureotelic (Urea-excreting)

Question 4

Problem of making too much urea?

Answer 4

Gout

Question 5

What is the principal site of NH3 detoxification?

Answer 5

The Liver; since high levels of ammonia in the blood are toxic, nitrogen is transported between organs in organic forms such as alanine, glutamate, glutamine, and urea.

Question 6

Where are the enzymes located that the Urea cycle uses?

Answer 6

In both cytosolic and mitochondrial compartments

Question 7

Overall stoichiometry for urea synthesis?

Answer 7

HCO3- + NH4+ + 3ATP + Aspartate + H2O -> UREA + 2ADP + 2Pi + AMP + PPi + Fumarate + 5H+

Question 8

what does the urea cycle help do?

Answer 8

it helps to control body pH

Question 9

Ornithine Transcarbamoylase rxn

Answer 9

Ornithine + Carrrbamoyl-P ->CITRULLINE

Question 10

Argininosuccinate Synthase rxn

Answer 10

CITRULLINE + aspatate + ATP ->ARGININOSUCCINATE

Question 11

Argininosuccinate lyase rxn

Answer 11

ARGININOSUCCINATE -> ARGININE + fumarate

Question 12

Arginase rxn

Answer 12

ARGININE -> ORNITHINE + Urea

Question 13

What stimulates the biosynthesis of all 5 urea cycle enzymes after a protein meal?

Answer 13

Glucagon

Question 14

what amino acid is highly effective in stimulating glucagon release?

Answer 14

casein (milk protein)

Question 15

What is the 1st committed step of the urea cycle?

Answer 15

CPS-1; it is allosterically activated by N-Acetylglutamate

Question 16

When amino acid catabolism increases, glutamate levels rise and so does N-acetyl-glutamate. How?

Answer 16

N-Acetyl-glutamate synthase (NAGS)

Question 17

NAGS rxn

Answer 17

Glutamate + Acetyl-CoA -> N-Acetyl-Glutamate + CoA

Question 18

What is NAG?

Answer 18

it is the allosteric activator of CPS-1; it is needed to start the Urea Cycle

Question 19

What are indicators of high AA content?

Answer 19

Glutamate and Arginine
Glu: substrate for NAG synthase
Arg: activates NAGS allosterically

Question 20

What does NAG synthase deficiency result in?

Answer 20

Hyperammonemia

Question 21

What is primary hyperammonemia?

Answer 21

it occurs when there is a mutation in the NAGS gene

Question 22

What is secondary hyperammonemia?

Answer 22

it occurs when there are mitochondrial changes interfering with NAGS function

Question 23

What can improve hyperammonemia?

Answer 23

the NAG analogue Carbamoylglutamate restores and improves Urea-Cycle function

Question 24

What is the most common inherited urea cycle disorder?

Answer 24

Ornithine transcarbamoylase deficiency

Question 25

OTC deficiency characteristics?

Answer 25

Clinical phenotype in affected males and heterozygous females ranges from neonatal hyperammonemic coma to asymptomatic results. In severely affected individuals, ammonia concentrations increase rapidly causing ATAXIA, lethargy, and death w/o rapid intervention

Question 26

What causes episodic hyperammonemia?

Answer 26

arginine deficiency

Question 27

Why aren’t children affected by arginine deficiency?

Answer 27

Because growth always requires arginine so it will be in abundance at the early growing stages of life.

Question 28

What is an ammonia trap?

Answer 28

Liver Acinus

Question 29

endothelial lining within the liver is ____?

Answer 29

fenestrated (full of openings exposing hepatocytes to blood)

Question 30

What doe the fenestration in the lining within the liver do?

Answer 30

It permits rapid metabolite exchange between the liver and blood

Question 31

What does the liver acinus prevent?

Answer 31

It prevents ammonia re-entry into circulation through differential utilization of ammonia

Question 32

Periportal hepatocytes include ___?

Answer 32

glutaminase and urea cycle enzymes which have a LOW AFFINITY for NH3 (high capacity)

Question 33

Perivenous scavenger cells include ___?

Answer 33

glutamine synthetase that has 40x HIGHER AFFINITY for NH3 (low capacity). GLN synthetase mope up NH3 that gets past the 1st segment (periportal hepatocytes)