The Urea Cycle

Front 1

Dietary protein is broken down in the GI tract, and excess amino groups can be transferred to __________ to form the amino acid __________.

Back 1

Amine groups can be transferred to pyruvate to make alanine.

Front 2

In most tissue, excess NH4+ is incorporated into ____________ to form __________ which carries it to the _________ through the blood stream.

Back 2

Amine groups are incorporated into glutamate to form glutamine which carries it to the liver.

Front 3

What are transaminations, what enzymes catalyse them, and what cofactor do they use?

Back 3

The transfer of an amine group from one compound to another, e.g. aKG to glutamate and the amine group comes from an amino acid which is converted to a keto acid. Aminotransferases required PLP - pyridoxal phosphate. The reaction is freely reversible.

Front 4

In the first step of amino acid catabolism, the amine group is given to __________ to form ____________. Thus storing many amine groups in its R group.

Back 4

It's given to a-ketoglutarate to form glutamate which is aKG + NH3. Freely reversible.

Front 5

How is ammonia released into the liver by glutamate?

Back 5

Glutamate DH, which can use NAD+ or NADP+, oxidatively deaminates glutamate back to aKG.

Front 6

What molecule negatively modulates glutamate DH activity? Therefore, what can happen if it is mutated? (Hint: 2 molecules accumulate).

Back 6

GTP - guanosine triphosphate. No regulation so too much ammonia is produced - hyperammonaemia - and too much aKG - hyperinsulinaemia.

Front 7

Excess NH4 in tissue is incorporated into __________ to form _________ via the intermediate ___________, catalysed by ___________. This is broken down in the liver by _____________.

Back 7

Into glutamate to form glutamine via y-glutamyl phosphate, catalysed by glutamine synthetase. Glutaminase releases the NH4 in the liver mitochondria.

Front 8

Why is urea a good compound for nitrogen excretion?

Back 8

It's energetically inexpensive, it has a high nitrogen content, it's non-toxic and it's water-soluble.

Front 9

Ammonia, in the protonated form, is incorporated into __________ in hepatocyte mitochondria. This is catalysed by ______________.

Back 9

Into carbamoyl phosphate via carbamoyl phosphate synthetase 1. This requires 2 ATP and HCO3.

Front 10

Nitrogen also enters the urea cycle in the form of ______________ which is the aminiated version of __________ from Krebs. This is catalysed by ____________ which also converts ______________ back to ____________.

Back 10

Aspartate - made from oxaloacetate. This is catalysed by aspartate aminotransferase which converts glutamate to aKG as it takes its NH3 and gives it to oxaloacetate. This step also takes 2 ATP.

Front 11

Name the 4 enzymes of the urea cycle, and the compounds formed.

Back 11

1) Ornithine in the matrix is converted to citrulline via ornithine transcarbamoylase.

2) Citrulline is converted to arginosuccinate via arginosuccinate synthetase. This is done via a citrullyl AMP intermediate and also requires aspartate - the 2nd N-gaining step.

3) Arginosuccinate is converted to arginine, releasing fumerate.

4) Arginine is converted back to ornithine and urea is released. This is catalysed by arginase.

Front 12

Name the 2 N-gaining reactions in the hepatocytes. Both reactions require ______.

Back 12

1) The incorporation of protonated ammonia into carbamoyl phosphate via CMPS1.

2) The incorporation of aspartate into citrulline via arginosuccinate synthetase.

Both require ATP.

Front 13

What is the link between Krebs and the urea cycle?

Back 13

Oxalo from Krebs is converted to aspartate and ultimately to fumerate (arginosuccinase) which can be used in Krebs - converted to malate which is then oxidized to yield NADH. This is the aspartate-arginosuccinate shunt. This reduces the overall energetic cost.

Front 14

How is the urea cycle regulated? Short vs longer term.

Back 14

Short-term = N-acetylglutamate allosterically activates CMPS1.

Long-term = high protein or starvation causes the transcription of the enzymes of the cycle to be increased.

Front 15

Name some defects that can result from accumulations of urea cycle metabolites.

Back 15

1) OTCD - orotic acid in urine (from carbamoyl P breakdown).

2) Arginase deficiency - build up of arginine in plasma.

3) Arginosuccinate synthetase deficiency - build up of citrulline in plasma.

Front 16

How do you manage/treat urea cycle defects? (4 things)

Back 16

1) Limit protein intake.

2) Increase renal excretion of ammonia.

3) Use biochemical tricks such as administer glycine synthase (requires NH4) or benzoate.

4) Specific therapies for enzyme deficiencies.

Front 17

The loss of N-acetylglutamate synthase causes what? How can you treat it?

Back 17

Loss of N-acetylglutamate synthase = loss of N-acetylglutamate = loss of allosteric activation of CPS1, so NH4+ accumulates. Treat with carbamoyl glutamate which is an analogue for N-acetylglutamate. Arginine supplements are a good idea for deficiencies of ornithine transcarbamoylase, arginosuccinate synthetase or arginosuccinase.