Bioc Lecture 4

Created by finson 

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Where is urea made?

The liver

Describe urea:

Keeps nitrogen in non-toxic, soluble form. Is released into the circulation, gets filtered by kidneys, then goes into urine to be excreted. Carries 2N, so for every molecule of urea excreted, 2N are excreted.

Urea carries 2N. Where do these come from?

1 from aspartate, the other 1 from carbamoyl phosphate. Both these molecules introduce 1N each into the urea cycle.

How is carbamoyl phosphate made?

When a CO2 joins to a FREE NH4+ (that would've been released after a glutamate dehydrogenase reaction). This reaction is catalysed by CARBAMOYL PHOSPHATE SYNTHETASE enzyme and requires 2 ATP (in the mitochondria).

How is aspartate made?

Transamination. Glutamate gives an NH4 to oxaloacetate, forming aspartate.

What are the TWO ways that glutamate in the liver can put NH4's into the urea cycle?

1) Glutamate dehydrogenase reaction...as glutamate --> alpha ketoglutarate, NH4 is released and is free. This NH4 combines with CO2 to form carbamoyl phosphate and enters the urea cycle this way.

2) Transamination reaction. Glutamate gives NH4 to oxaloacetate, forming aspartate. Then aspartate enters the urea cycle.
Both ways make a-ketoglutarate which is used for CAC or gluconeogenesis.

What part of the Urea Cycle occurs in the mitochondria?

The part where carbamoyl phosphate joins to ornithine to make citrulline (energy for this comes from cleaving phosphate off carbamoyl phosphate). This part occurs here because carbamoyl phosphate is made in the mitochondria (there is lots of ATP there).

What goes in and out of the mitochondria during the urea cycle?

Ornithine (basic scaffold) goes in, and Citrulline (carbamoyl + ornithine) comes out.

Describe the Urea Cycle:

IN MITOCHONDRIA: 1N from carbamoyl phosphate gets added to basic scaffold (ornithine). The citrulline produced leaves the mitochondria. IN CYTOSOL: Whack whole aspartate onto citrulline to add 2nd 1N. Rest of aspartate cut off (leaves as fumarate). Forms arginine. Hydrolyse urea off arginine (use arginase) and you're left with ornithine scaffold again.

What happens to fumarate after it leaves the urea cycle?

It is recycled. Fumarate-->Malate-->Oxaloacetate (by redox). This oxaloacetate accepts a NH4 from glutamate and becomes aspartate, which can feed into the urea cycle again.

How much ATP in needed to make 1 Urea molecule?

Energy demanding : Total cost is 4 ATP even though only 3 ATP are used. It takes 2 ATP-->2ADP to join CO2 and NH3 together to make carbamoyl phosphate and 1 ATP-->1AMP to join whole aspartate onto citrulline.

What are the two ways of regulating the Urea Cycle?

1) Alter the concentration of urea cycle enzymes (incr. concentration gives more flux through). You get increased [enzymes] with high protein diet, OR if starving.
2) Through carbamoyl phosphate synthetase activity. CPS is allosterically regulated by N-acetyl glutamate. N-acetyl glutamate amount is regulated by amount of arginine --> positive feedback loop!

What happens if you give an intense amount of protein (eg a steak) to a starving person?

Their urea cycle enzymes will be amped up lots because they're used to starving. If they eat a steak, all the nitrogen will be liberated by these enzymes and will result in toxic N levels.

Describe the positive/negative feedback loop that regulates the Urea Cycle.

Increased arginine stimulates n-acetyl glutamate synthase to make more N-acetyl glutamate. Increased N-acetyl glutamate stimulates carbamoyl phosphate synthetase to make more carbamoyl phosphate. More carbamoyl phosphate gives means more substrate for the urea cycle, to more arginine...
If arginine amount decreases, negative feedback starts in this same loop.

What happens when you have urea cycle enzyme disorders?

You get elevated levels of NH4 which can be toxic (may deplete intermediates of the CAC etc). Many different phenotypes, but all have common theme of brain damage (because too much ammonia is toxic to the brain). Treated early on by dietary modification and supplementation. Tested for by NEWBORN SCREENING (stops brain damage accumulating early).

A baby is found to have a urea cycle enzyme disorder. It must change its diet to limit Nitrogen consumption. How would it make sure it gets enough amino acids?

Give carbon skeletons (ketoacids) in the diet. Then exploit transamination so that these ketoacids are turned into amino acids in the body.

What are the FOUR nitrogen compounds in urine?

Urea,
NH4+ (this stuff made though glutaminase reaction in the KIDNEY. Neutralises pH there),
Uric Acid (is break-down product of purines),
Creatinine (independent of diet, proportional to muscle mass)

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