Amino Acid Oxidation 2: Study with Video Lessons, Practice Problems & Examples

The liver processes amino acids primarily through glutamine, synthesized from glutamate and ATP by glutamine synthetase. Glutamine is converted back to glutamate in the mitochondria, releasing ammonium for the urea cycle. The glucose-alanine cycle allows muscles to send alanine to the liver, where it is converted back to pyruvate for gluconeogenesis. The urea cycle is regulated by N-acetylglutamate, stimulated by arginine, which indicates nitrogen levels. Transaminases play a crucial role in amino group transfer and can indicate tissue damage, particularly in the liver and heart.

Amino Acid Oxidation 2

So how does the liver get amino acids to perform the urea cycle? Well, most amino acids are going to actually come in as glutamine. Basically all the tissues in your body are capable of delivering glutamine to the liver to get rid of that nitrogen. So glutamine synthetase is the enzyme that makes glutamine to send to the liver. And basically, it will take glutamate and ATP and a nitrogen group, and it will make glutamine and of course, you will be left with ADP and inorganic phosphate. And basically the reason for this is that it is very easy for the cell to convert amino acids into glutamine this way. So that's how it's going to transport the majority of amino acids to the liver and it also can get rid of this extra nitrogen group by doing so. So glutamine enters the mitochondria and will actually get broken down into glutamate. So kind of undoing what happened up here and it'll cleave off that, ammonium and this is carried out by an enzyme called glutaminase. Now, that glutamate will then be acted upon by glutamate dehydrogenase and it will be converted to alpha-ketoglutarate. Basically glutamate dehydrogenase just cuts off that, cuts off that amino group and it comes off as ammonium, and in the process, it's actually going to reduce NAD⁺ or NADP⁺ that's why the p is in parenthesis there. It's actually either or. And it's going to reduce that to NADH or NADPH. Now, these nitrogens that got cut off, those are going to be used to feed the urea cycle. Remember that the first step requires ammonium to form carbamoyl phosphate. It should be noted that some glutamate is actually used to add the ammonium instead of just cutting it and releasing it to the urea cycle. That ammonium is actually added to oxaloacetate and that forms aspartate. Now you might remember that during the urea cycle in step 3, we actually use aspartate. Guess what? That aspartate is this aspartate. So some glutamate is actually used to form the aspartate that is used during the urea cycle. And of course, the cell has to kind of regulate the amount of glutamate that it cleaves to provide ammonium and the amount it uses to form aspartate. And it's worth noting that this is going to happen in the mitochondria which should make sense because we have oxaloacetate. So then this aspartate has to actually be exported from the mitochondria into the cytosol for step 3 of the urea cycle. Now I said that most tissues or rather all tissues export glutamine but muscles, muscles actually can send alanine as well. This is called the glucose alanine cycle. And this again only occurs in the muscles and basically muscles will send alanine to the liver. And the way they do that is by converting pyruvate into alanine and to provide the amino group for this, they're going to cleave glutamate, glutamate, right. They're going to take the amino from glutamate. So glutamate is going to turn into alpha-ketoglutarate. Now that alanine gets transported through the blood to the liver and once in the liver, what happened in the muscle, what we just talked about up here, gets undone. That's a pattern in general that I hope you've started to notice and are going to notice later that a lot of processes are done and then undone after some transport. Anyhow, so alanine gets converted back into pyruvate by sending that amino group over to alpha-ketoglutarate which reforms glutamate and then that glutamate ammonium to the urea cycle or by being used to make aspartate. Now, what's going to happen to that pyruvate? Well, remember, this is the liver, the site of gluconeogenesis, right? So we are going to use pyruvate or we can use pyruvate I should say for gluconeogenesis which is going to make glucose, right, and then guess where a lot of that glucose is going? Right back to the muscles. Right? Now this is why this is called a cycle because that glucose goes back to the muscles, it gets broken down into pyruvate and then we can use that pyruvate to make alanine and repeat this picture And just zoom in on the liver for a second and show you what's going on here. So, we have alanine and glutamine being used to make glutamate to feed urea cycle. Of course, if you're using glutamine to make glutamate, you're going to cut off, a nitrogen from it which will be released as ammonium. And if you, use glutamate, you can use it to either provide ammonium or aspartate, right, to the urea cycle. Alright. So you may have noticed that fumarate also came off of the urea cycle. Well, the urea cycle is connected to the citric acid cycle, right? It's happening in part in the mitochondria So it's very easy for that fumarate to actually enter the citric acid cycle where it will be turned into malate and then oxaloacetate. And of course, that oxaloacetate as we previously discussed can be used to make aspartate, right? That is the aspartate that we saw right here. The aspartate that is used as part of the urea cycle. So in a sense, argininosuccinate is kind of the link between the citric acid cycle and the urea cycle. Of course here we have it says TCA cycle, which is the same thing as the citric acid cycle. All right. Last thing I want to talk about is transaminases. These are used throughout this process, right? Whenever we're moving an amino group from one molecule to another, we use transaminase. And these always go amino keto to amino keto. And what's interesting about these is they can actually be an indicator of tissue damage, a really easy indicator of internal tissue damage because if you have internal tissue damage, enzymes will be spilling out and you can assay for these transaminases to see where the tissue damage is depending on which transaminases you have. These transaminases right here GPT and G OT indicate liver damage and this S just means serum as in in the blood. And this, transaminase right here can be the indication of heart damage. So either, you know, imminent heart attack or heart attack or infection. Last thing I want to talk about before moving on is regulation of the urea cycle. So remember, step 1 is carried out by carbamoyl phosphate synthetase. This molecule N Acetylglutamate actually stimulates, that enzyme. So it can kick the urea cycle into gear. And the way that's going to happen is with this, basically it's like a regulatory enzyme sort of similar or kind of akin to what we saw with, phosphofructokinase 2. So N Acetylglutamate synthase will take Acetyl CoA and glutamate and make N Acetylglutamate. This enzyme that produces the molecule that stimulates the urea cycle is stimulated by arginine. I hope that this makes a lot of sense to you. Why would why do you think arginine would stimulate the urea cycle in essence? It's a few steps removed but basically arginine can stimulate the urea cycle is what we're seeing. Arginine has a lot of nitrogen, doesn't it? Well, hopefully you're putting 2 and 2 together and if you have a lot of nitrogen, you're going to want to kick that urea cycle into gear. Alright. Let's flip the page.

Here’s what students ask on this topic:

How does the liver obtain amino acids for the urea cycle?

The liver primarily obtains amino acids for the urea cycle through glutamine. Glutamine is synthesized from glutamate and ATP by the enzyme glutamine synthetase. This process occurs in various tissues, which then transport glutamine to the liver. In the liver's mitochondria, glutamine is converted back to glutamate by glutaminase, releasing ammonium. This ammonium is then used in the urea cycle to form carbamoyl phosphate, the first step in the cycle. Additionally, muscles can send alanine to the liver via the glucose-alanine cycle, where alanine is converted back to pyruvate and then used for gluconeogenesis.

What is the role of transaminases in amino acid metabolism?

Transaminases, also known as aminotransferases, play a crucial role in amino acid metabolism by transferring amino groups from one molecule to another. This process is essential for the synthesis and degradation of amino acids. Transaminases always transfer amino groups between amino acids and keto acids. For example, alanine transaminase (ALT) transfers an amino group from alanine to α-ketoglutarate, forming pyruvate and glutamate. These enzymes are also important clinical markers; elevated levels in the blood can indicate tissue damage, such as liver damage (ALT and AST) or heart damage (AST).

How is the urea cycle regulated?

The urea cycle is regulated primarily by the enzyme carbamoyl phosphate synthetase I, which catalyzes the first step of the cycle. This enzyme is activated by N-acetylglutamate, which is synthesized from acetyl-CoA and glutamate by N-acetylglutamate synthase. The production of N-acetylglutamate is stimulated by arginine, an amino acid rich in nitrogen. High levels of arginine indicate an excess of nitrogen, thereby signaling the need to activate the urea cycle to dispose of the excess nitrogen. This regulatory mechanism ensures that the urea cycle operates efficiently in response to the body's nitrogen levels.

What is the glucose-alanine cycle and its significance?

The glucose-alanine cycle is a metabolic pathway that occurs between muscles and the liver. In this cycle, muscles convert pyruvate to alanine by transferring an amino group from glutamate. Alanine is then transported to the liver, where it is converted back to pyruvate, releasing the amino group to form glutamate. The pyruvate can then be used for gluconeogenesis to produce glucose, which is sent back to the muscles. This cycle is significant because it helps transport nitrogen from muscles to the liver for disposal via the urea cycle and provides a means for muscles to obtain glucose for energy.

What is the connection between the urea cycle and the citric acid cycle?

The urea cycle and the citric acid cycle (TCA cycle) are interconnected through shared intermediates. One key link is fumarate, which is produced during the urea cycle when argininosuccinate is cleaved into arginine and fumarate. Fumarate can enter the citric acid cycle, where it is converted to malate and then to oxaloacetate. Oxaloacetate can be used to form aspartate, which is required in the urea cycle. This interconnection allows for efficient utilization of intermediates and energy production, integrating nitrogen metabolism with cellular respiration.