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Overview of Amino Acid Metabolism

Video transcript
- [Instructor] In this video, I wanna provide you with a crash course overview of amino acid metabolism. And, specifically, I wanna focus on the catabolism of amino acids and how that catabolism allows us to produce ATP inside of ourselves. Now, compared to carbohydrate catabolism and fatty acid catabolism, recall the pathways of glycolysis and fatty acid oxidation. Compared to those pathways, amino acid metabolism only accounts for about 10 to 15% of ourselves total energy production. So that's why I think that amino acid metabolism doesn't usually get its fair share of airtime, compared to processes like glycolysis and fatty acid oxidation. And to do that, let's go ahead and follow what happens to amino acids in the fed, as well as the fasted states of our body. Now, fed refers to our body's state right after, immediately after eating a meal. And, remember, that in terms of hormones, the hormone that's going to be elevated is going to be insulin, which is elevated in response to higher blood glucose levels, immediately following a meal, and levels of the hormone glucagon are going to be decreased. Now, of course, this is going to be opposite several hours after a meal, which we called the fasted state, in which the levels of insulin will be decreased and, of course, in response to low blood glucose levels, the levels of glucagon in our body will start to rise along with a couple of other hormones as well. But these are the two, or two at least, big hormones that regulate the bulk of metabolism in our body. Now, starting with the fed state, let's start at the beginning of this story. Recall that we ingest proteins from our food and those proteins are broken down into amino acids inside of our small intestine. And just as a side note, you might hear the terms essential and non-essential amino acids used, especially in medical literature. And what this simply refers to is that essential amino acids are those amino acids, of the 20 that we know of, that our body cannot synthesize and so we must, somehow, get these in our diet. Whereas non-essential amino acids can be actually synthesized in our body and we don't need them as part of our diet. But, getting back to these amino acids, once they're broken down in the small intestine, they travel via the blood stream directly to the liver, just like glucose. Now, once the amino acids have made it to the liver, several things can happen. The liver can use these amino acids directly for protein synthesis. But it can also use any excess amino acids and convert these into glucose and/or fatty acids. And, of course, recall that the storage, the ultimate storage forms of these two molecules are gonna be glycogen, in the case of glucose, which is stored in the liver mainly, and, for fatty acids, we store these as triacylglycerides in our adipose tissue. So how did this conversion from amino acids to glucose and fatty acids happen, you might ask? Well, remember that the precursor for glucose, or I should say precursors, can be pyruvate as well as oxaloacetate. And, for fatty acids, the main precursor for fatty acid synthesis is the molecule acetyl-CoA. And, as a relevant side note, I wanna point out that acetyl-CoA happens to be in equilibrium with another molecule in the cell called acetoacetyl-CoA. And oxaloacetate if you remember is in equilibrium with a lot of the intermediates of the Krebs cycle. So I'm gonna abbreviate here as intermediates of Krebs cycle, and there are numerous molecules with numerous names that I won't mention here, but just so that you get the big picture. Now the key point here is that amino acids, specifically the carbon backbone of these amino acid molecules can be interconverted and metabolized directly into the molecules in the precursor molecules that I've listed here for fatty acids and glucose. So they can be converted directly into pyruvate, into oxaloacetate, as well as intermediates of the Krebs cycle, acetyl-CoA, as well as acetoacetyl-CoA. Now another classification that you might hear with regard to amino acids is whether an amino acid is so-called a ketogenic amino acid or whether it is a glucogenic amino acid, and that simply refers to whether the carbon backbone of these amino acid molecules feeds into the precursor molecules for glucose synthesis or whether it feeds into the precursor molecules for fatty acid synthesis. So in this case, ketogenic amino acids are converted to acetyl-CoA or acetoacetyl-CoA and ultimately fatty acids, whereas glucogenic amino acids feed into pyruvate, oxaloacetate, or intermediates of the Krebs cycle. Now just as a fun fact, it turns out that there are two amino acids that are exclusively ketogenic and those are lysine and leucine. So anytime you ingest lysine or leucine, you will definitely be making fatty acids from those amino acids if they're ingested in excess. Of course, other amino acids can actually contribute to glucogenic pathways, and some might even contribute to both, but that's just kind of a fun fact. Now going back to the journey of our amino acids here, remember that it enters the liver and the liver can either use it for protein synthesis or convert it into other energy storage forms. But it can also send it off, and it can send it off to other tissues such as the muscle, for example, where the muscle can use it for its own protein synthesis. So other cells will also receive amino acids that are digested that they can use for protein synthesis as well. Now moving on to the fasted state, I'm also gonna put the liver here at kind of the center of our diagram because, remember, the liver is quite a centerpiece when it comes to metabolism. A lot of things are going on in the liver, and, specifically, in the fasted state, you might recall that fatty acids are being released from adipose tissue and being sent to the liver where they're being oxidized, and all of that ATP is fueling the synthesis of glucose. And if the person is in a very severe state of starvation, let's say they haven't had a meal for two or three days, we might even be producing ketones as well. Now even though we think of fatty acids as being the main fuel that's being sent to the liver in times of fasting, we can't forget about amino acids, which are released from our tissues, mostly our muscles really, and they're sent via the bloodstream also to the liver. Now once amino acids have arrived at the liver, the factory house, so to say, for energy production in times of fasting, remember that they can enter a diverse array of metabolic pathways. So I want to remind you in our fed discussion, we talked about glucogenic and ketogenic amino acids. So in times of fasting, potentially these glucogenic amino acids can contribute to these precursors of gluconeogenesis and help support the production of glucose in times of fasting. Now those that become intermediates of the Krebs cycle might potentially also contribute to the production of some ATP in the cell, but I want to remind you of the big picture, that only about 10 to 15% of our total energy production is supplied by amino acids, so we really still think about fatty acids comprising the bulk of ATP production inside of our body, but these amino acids are clearly important for providing those carbon backbones to support glucose synthesis. And of course, these ketogenic amino acids could also potentially contribute to the synthesis of acetyl-CoA and subsequently ketones, but remember that the whole purpose of ketone synthesis was to try and preserve the degradation of protein in our muscles so that we could switch to a more kind of sustainable fuel based on the immense influx of fatty acids that we were getting into the liver. So really this acetyl-CoA that contributes to ketone synthesis, we think about as largely coming from these fatty acids, so I'll go ahead and kind of write this double arrow in to remind us of that fact. Now I want to go ahead and scroll down and actually mention one unique thing about the catabolism of amino acids. Recall the basic structure of an amino acid, and I'll go ahead and draw the structure of an amino acid at physiological pH. So at physiological pH, we know that we have this carboxylate anion, and we have this carbon here attached to an amino group that's protonated. And we also have some type of functional group which we usually abbreviate as R, which makes the identity of all these amino acids unique, and then we can't forget this extra hydrogen here. So that's the basic structure of an amino acid, and the point that I want to highlight here is that something's that unique to the breakdown of proteins that we haven't run into in the breakdown of fatty acids or glucose is the presence of this nitrogen in this amine group right here. Now, notably, I did not mention that this amine group was contributing in any way to these precursor molecules that we talked above with regard to the breakdown of amino acids, and, specifically, if you remember, I used the term carbon backbone of amino acids to refer to this part right here that was being converted to all of these precursor molecules. And indeed generally the first step involved in the catabolism of amino acids or the breakdown of amino acids is something called a transamination step, in which the amine group on this amino acid is transferred to another molecule for eventual excretion by the body, and that, of course, frees up the carbon backbone to contribute to the rest of these metabolic pathways. And so ultimately, this becomes something called an alpha-keto acid, and it's called an alpha-keto acid because of what its structure looks like, so it ends up looking something like this. It obtains a ketone group here and, of course, is still attached to its R group. So it's alpha because it refers to this alpha carbon relative to this carboxylate ion, and it's a keto because it's a ketone, and it's an acid because it's attached to this carboxylic acid functional group here. So alpha-keto acid and this is the carbon backbone that can contribute to all of those metabolic pathways. And now even though I'm only gonna touch the surface of this, there's one last thing I do want to mention, that the common acceptor for this amine group, the common molecule that accepts this amine group from amino acids is a molecule called alpha-ketoglutarate. And this might ring a bell because it is an intermediate in the Krebs cycle, and when it accepts this amine group, it becomes a molecule of the amino acid glutamate. And then finally what the glutamate does is that once it reaches the liver because the liver happens to have the right types of enzymes for this next process, it can donate this amine group in the form of ammonia, which is NH3, and I'll remind you that this, of course, is in equilibrium with ammonium, NH4 plus. It will donate this as ammonia, and this will enter something called the urea cycle inside of the liver, where this ammonia is converted to a molecule of urea. And, of course, this urea is then excreted in your urine, so that's how our body is able to effectively use the carbon backbone of these amino acids and also essentially detoxify our body of this nitrogen-containing amine compound. And the reason I should mention why it's so important to you is eventually excrete this compound from our bodies because ammonia is toxic at very high levels to our bodies. So we need some way to effectively rid it from our body, and this is how our body does it.