Understanding Catecholamine Synthesis Pathway

Welcome back to Dirty Medicine's biochemistry series. In today's video, we're going to be talking about a very high yield topic. Specifically, we're going to be talking about catecholamine synthesis. Now when I say catecholamines, you should think dopamine, norepinephrine, and epinephrine. So if you've not made that association in your brain yet, well now's the time to begin. Catecholamine is a fancy way of saying neurotransmitter. Specifically, we're talking about three substances that act in the sympathetic or adrenergic sympathetic nervous system, dopamine, norepinephrine, and epinephrine. Now these molecules are synthesized in the chromophane cells of the adrenal medulla, but they're also produced in the postganglionic fibers of the sympathetic nervous system. If you've sort of been meandering your way through the first two years of medical school or whatever health organization slash school that you attend. You probably know that dopamine, norepinephrine, and epinephrine are used in the brain, but also throughout the hypothalamic pituitary adrenal axis as part of the sympathetic nervous system. So if you have a little bit of confusion as to where these catecholamines or these neurotransmitters, if you will, come into play, they're really used diffusely. And I would like you to take a step back and think that they are used not only in neurotransmission, but in the sympathetic transmission in the adrenal axis used throughout the body. to act on end targets such as the heart. Now today's video is going to specifically talk about where these are synthesized and pay special attention to the biochemical pathway that synthesizes them. I'm going to give you a really great mnemonic to help remember this pathway, but I want to sort of outline this video right now and tell you that we're going to start by talking about the pathway in conjunction with an awesome mnemonic that I'm going to give you. This will tie everything together and as we go We'll talk about some really, really high yield diseases that come about when certain points of the biochemical pathway get disrupted. Overall, this is a hugely important topic, and I'm going to spend a lot of time to make sure that you understand these concepts because they show up on exams all the time. Now, unfortunately, or maybe fortunately, today's mnemonic is a Game of Thrones mnemonic. So if you've never seen the show, then I'm sorry, you're going to have a little bit of difficulty with the mnemonic, but I'm still going to be able to teach you the scientific concepts of catecholamine synthesis. But if you're a Game of Thrones fan like me, then this is going to work out beautifully. Now, like all good biochemical pathways, we have to start with something. And when we talk about where these catecholamines get synthesized, they'll be downstream. But we have to start with an amino acid called phenylalanine. Phenylalanine gets converted into tyrosine by the enzyme phenylalanine hydroxylase. As you may have noticed in my other videos, I like to keep the big picture in mind. So if you look at the name of the enzyme, it's telling you that phenylalanine is being hydroxylased, which means to break off a certain part of it. So if you're not sure what the reactant in the product is, you can look at the enzyme name or vice versa. So in this case, phenylalanine goes to tyrosine. We know that phenylalanine must be the reactant because the enzyme is called phenylalanine hydroxylase. Now tyrosine will then go to DOPA and DOPA stands for dihydroxyphenylalanine and you don't need to know that. So just know it is DOPA, but the enzyme that categorizes... that catalyzes this conversion is tyrosine hydroxylase. Once again, look at the enzyme name, tyrosine hydroxylase. Therefore, you know that that enzyme has to be acting on tyrosine because of its name. Now, this is where my mnemonic comes into play. And today's mnemonic, I already told you, is a Game of Thrones mnemonic. And the Game of Thrones mnemonic is going to be based around Peter Dinklage, aka Tyrion Lannister, my favorite character in Game of Thrones. Again, Game of Thrones. And how are we going to remember that the mnemonic with Tyrion is the mnemonic for catecholamine synthesis? Well, what is a catecholamine, guys? It is used as a neurotransmitter. And where do neurotransmitters act? In the brain. Brain. Hmm. Who's the smartest character in Game of Thrones? That's right. It's Tyrion Lannister. So let's talk about how Tyrion Lannister is going to help us remember this pathway to understand how catecholamines get synthesized through this biochemical pathway. So far, we've talked that phenylalanine goes to tyrosine, goes to dopa. So how does tyrian lanister or peterdynklage come into play here? Well, here's the mnemonic. Peterdynklage, P for phenylalanine. Peterdynklage plays tyrian. Tyr in tyrian and tyr in tyrosine or tyrosine. So peterdynklage, the P for phenylalanine, plays tyrian. Tyr, T-Y-R, in both tyrian and tyrosine. Peterdynklage plays tyrian, who's a dope. character dope and dopa almost sound exactly the same So that's where we are so far. And I'm going to put the mnemonic on hold and we'll come back to this when we fill in the rest of the pathway. But let's get back to just the science part of this. So here's where we left off. Now, tyrian is such a dope character that the two chemicals in this case, tyrosine and dopa that correspond to tyrian and dope because tyrian is such a dope character. They can actually break off and branch sideways and make other products that aren't necessarily in the catecholamine synthesis pathway. So I'm pausing the catecholamine synthesis biochemical pathway, and what I'm showing you is that tyrosine can become something else, and dopa can become something else, and this sort of right and left arrow is pivoting off of the catecholamine synthesis pathway. So how you remember this in our mnemonic is that tyrian is such a dope character that the tyrian or tyrosine and the dope or dopa can actually become their own end products that are distinct from the catecholamines. tyrosine or tyrosine, if you will, becomes homogentistic acid. And the enzyme that does that conversion is not important, so don't worry about it. But what is important is to know that homogentistic acid can then become malyl acetoacetic acid, which can then become fumarate. And if you recall from our TCA cycle video, fumarate can enter the TCA cycle. So what is important and what do you need to know? Well, the conversion of homogentistic acid to malyl acetoacetic acid. is catalyzed by homogentisate oxidase. You need to memorize this enzyme. Now look at DOPA. Let's pause for a second. DOPA can go to melanin through the enzyme tyrosinase or tyrosinase. Now, why do you need to know homogentisate oxidase? Homogentisic acid will become malyl acetoacetic acid through the enzyme homogentisate oxidase. The reason that you need to know this is because this is the first disease that we're going to talk about. So if you knock out homogentisate oxidase, you get what's called alkaptonuria. Alkaptonuria is due to a knockout of homogentisate oxidase. Now, let's think about this for a second. Homogentisate oxidase catalyzes the conversion of homogentisic acid to malyl acetoacetic acid. So if we knock out this enzyme, that means we can't form the products and we have a buildup of the reactants. So I'm putting in little arrows here so you can see and reason through what you'll find with Alkaptonuria. So you can't form malyl acetoacetic acid and therefore you can't form fumarate. But if that can't form, then the homogentistic acid will build up because it cannot be converted into malyl acetoacetic acid. So in Alkaptonuria, the inheritance is autosomal recessive. And again, this is caused by a deficiency of the enzyme. homogentisate oxidase. I just copy and paste the enzyme so your brain can get used to seeing it this way. And we sort of already talked about this, but our findings are a buildup of homogentisic acid and a decrease in the products, malyl acetoacetic acid and a decrease in fumarate. Now, what kind of symptoms does this cause? Well, because homogentisic acid is actually pigment, that will cause pigmented changes all throughout the body. So this buildup of this molecule that actually is a pigment. is going to cause the deposition of bluish-blackish pigment in places like the ear, the hands, and the sclera. So these are the classic symptoms that you see. And in addition to these, you have things like dark urine, arthralgias, and discolored face. The discolored face is because of the pigment. The dark urine is because of the pigment. And the arthralgia is because the pigment actually gets deposited into joint spaces. And any molecule that gets put into a joint space that's not supposed to be there is going to cause... arthralgia. Makes sense. So big picture here, guys. Alkaptonuria is due to the enzyme homogentosate oxidase being knocked out. And when that happens, you're going to get a buildup of the reactant, homogentosate acid, and a decrease in the products because you simply can't form them. And in this case, because the reactant is a pigment, the symptoms that you see clinically are going to be pigmentation. So that pigment is going to build up and deposit in places like the sclera, the ear, the hands, the urine. and the joints. And that gives you the classic symptoms that you see on this slide. in addition to dark urine, arthralgias, and a discolored face. Now, that should make sense biochemically, and if you want to relate it to our mnemonic using Tyrion Lannister, you can look at this Game of Thrones flyer and see that he has dark sclera and a dark face, and it's bluish-blackish, which should remind you of this pigment deposition, which is blue-black. That is Alcaptanuria, okay? And another way to remember it is instead of Alcaptanuria, you can say Blackcaptanuria because BLK and ALK are very similar. And a lot of people write BLK as the shorthand for black. So here's where we've left off so far. Again, Peter Dinklage, P for Peter for phenylalanine, plays Tyrion, Tyrion for tyrosine, who is a dope character, dope for dopa. That is our catecholamine pathway, which is only half done at this point. But I wanted to point out that Tyrion is such a dope character that Tyrion or tyrosine and dopa or dope can become other things. Tyrion can become homogenetic acid and dope or dopa can become melanin. Now we've talked about Alkaptonuria, which is a knockout of homogentosate oxidase. But now let's talk about what happens if we knock out the other enzyme, tyrosinase. So I told you that DOPA can be converted into melanin. That enzyme that does that conversion is tyrosinase or tyrosinase, however you want to say it. But if we knock out that enzyme, we get albinism or, you know, some people incorrectly refer to it as albino. But albinism is due to a knockout of tyrosinase. So now let's talk about our second disease. albinism. So the inheritance here is autosomal recessive. Now this is a defect in pigmentation that's due to one of two things, either a decrease in the enzyme tyrosinase or a decrease in the ability to transport tyrosine. So I've put a little picture of part of our pathway right here so you can see what I'm talking about. So in the first case, we simply knock out the enzyme tyrosinase. And if you knock that out, then you're going to have a problem converting DOPA to melanin. And in the second option... in decreased tyrosine transport. If you can never transport tyrosine to DOPA, then you can never convert DOPA to melanin. So you have still a problem with melanin, but it's due to a more upstream problem. It's not DOPA or tyrosinase that's the problem. It's the inability to transport tyrosine to later be converted to DOPA to later be converted to melanin. So these are the two different genetic causes of albinism. What's very high yield, and I'm going to pause and put this in huge letters so you'd never forget this because this shows up on exams all the time, is that albinism is due to a normal number of melanocytes, but a decreased production of melanin. So oftentimes they'll ask you about this and people will get so tripped up and they'll click the answer that says decreased melanocytes, but it's not the cell itself. It's not the melanocyte itself. It's the actual melanin within the cell that's not being produced. So it's the decreased production of melanin, not a decreased number of melanin producing cells. I hope that that distinction makes sense because it's extremely high yield. So rewind the video if you need to hear that one more time. But again, albinism, normal melanocytes, but decreased melanin. Now, symptoms of albinism you're probably a little bit familiar with. Things like white skin, white hair, blue eyes. The other symptoms that you may or may not have heard before is decreased visual acuity and increased risk of skin cancer. This is also associated with Chediak-Higashi syndrome. So albinism is one of the hallmark features of Chediak-Higashi. But know, in addition to the white skin, you know, the fair skin, fair hair, blue eyes, is that they actually do have trouble seeing and that they have an increased risk of skin cancer. Of course, know the association with Chediak-Higashi syndrome. But again, all of this is packaged within albinism. Now, coming back to our Game of Thrones mnemonic using Tyrion Lannister, if you need a little mnemonic to remember the symptoms of albinism, just look at this picture of Tyrion Lannister. Very fair skin, very fair hair. They said, you know, in season one, it was supposed to be blonde, but it was so blonde that it was almost kind of whitish, if you will. I know that's kind of stupid in terms of mnemonics, but just another way to tie this back into what we're talking about today. Game of Thrones with Tyrion Lannister, again, because Tyrion is the smartest character in Game of Thrones. And that reminds us of catecholamines, which are used as neurotransmitters in the brain. Brain, smart. Tyrion, smart. See the connection. Anyway, here's where we are so far. We've talked about two diseases so far. We've talked about albinism, shown under the enzyme tyrosinase. And we've talked about alkaptonuria, shown under the enzyme homogentosate oxidase. Again, both of those diseases will manifest if you knock out either one of those respective enzymes. But these are just side options in this pathway. In terms of catecholamine synthesis, we've only talked about three things so far, phenylalanine, tyrosine, and DOPA. We got to keep going down this pathway because we haven't even produced. any of our catecholamines yet. Remember, the catecholamines are dopamine, norepinephrine, and epinephrine. So in the second half of this pathway, we're going to see where those are actually produced. And at the end, we'll wrap up by talking about our third and final disease. I know I'm moving sort of quickly here, but I hope that this is making sense. I think that I'm doing a pretty good job of explaining. So now let's go back to DOPA. So DOPA can be converted into dopamine through the enzyme DOPA decarboxylase. Once again, it's going to sound like I'm beating a dead horse here. Look at the name of the enzyme. It's dopa decarboxylase. So we know that it acts on dopa. It acts on dopa and it forms dopamine. So this is the first time we're seeing a catecholamine actually get produced in this pathway. Now dopamine can be converted to norepinephrine through dopamine beta hydroxylase. Again, ladies and gentlemen, look at the enzyme name. It's dopamine beta hydroxylase. Therefore, it's acting on dopamine. So dopamine goes to norepinephrine. And then norepinephrine goes to epinephrine, it just drops the nor, through a very long-winded enzyme, which is called phenol, ethanolamine, and methyltransferase. So it's very important to notice something here, guys and girls. Dopamine is produced first, which then goes to norepinephrine. Norepinephrine is produced second, which then goes to epinephrine, which is produced third and last in this chain. So in the order of catecholamine synthesis. You can make dopamine first, norepinephrine from dopamine, and epinephrine from norepinephrine. That is a very, very high yield fact to keep in mind. But you watched this video today because you wanted to know the biochemistry of catecholamine synthesis. So we got to go back to our Tyrion Lannister mnemonic in order to finish this pathway. So here's where we left off. We said that Peter Dinklage plays Tyrion, who's a dope character. The P in Peter told us that phenylalanine comes first. The Tyr in Tyrion told us about the Tyr in tyrosine. which told us that that came second. And then Peter Dinklage plays Tyrion, who is a dope character, dope for dopa. So dope was the third sentence of this mnemonic and dopa is the third product in this catecholamine biochemistry pathway. So let's keep going. So I told you that dopa goes to dopamine. So here's where our mnemonic is. Peter Dinklage plays Tyrion, who is a dope character. And without him, Game of Thrones could do, do for dopamine. No, no for no repinephrine. Episodes. Epi and episodes for epi and epinephrine. So Peter Dinklage plays Tyrion, who is a dope character, and without him, Game of Thrones could do no episodes. Without Tyrion Lannister or without Peter Dinklage, Game of Thrones could really do no episodes because the episodes would all be crap because he's the best character. So this is my mnemonic for remembering catecholamine synthesis, and I'm going to explain it to you one more time so you can really nail it and imb- embed it into your brain and see it on test day like I always saw it over the past few years. So Peter Dinklage plays Tyrion Lannister, who is a dope character. And without him, Game of Thrones could do no episodes. Do for dopamine, no for norepinephrine and episodes for epinephrine. Now, how do we connect Tyrion Lannister to catecholamine synthesis? I mean, how do you remember that this mnemonic is for catecholamines? Well, catecholamines dope. dopamine, norepinephrine, and epinephrine are used as neurotransmitters in the brain. The brain reminds me that I'm talking about the smartest character in Game of Thrones. And who's the smartest character in Game of Thrones? Tyrion Lannister. So that's the mnemonic. And this is everything that I've explained so far. Now, before we wrap up by talking about our third and highest yield disease due to a problem in this pathway, I first need to draw in some of the cofactors of the catecholamine synthesis pathway. So they're shown here in blue text. When you go from phenylalanine to tyrosine, the cofactor is BH4. When you go from tyrosine to DOPA, same cofactor, BH4. When you go from DOPA to dopamine, the cofactor is B6. When you go from dopamine to norepinephrine, the cofactor is vitamin C. And when you go from norepinephrine to epinephrine, when we drop the nor, the cofactor is SAM. Now these are... you know, sort of important to know, but the one that you should absolutely know is what I've shown in bold lettering with the little star next to it, the BH4 cofactor when you go from phenylalanine to tyrosine. And the reason that you have to know that one is because it's involved in our third and final disease, which also happens to be our highest yield disease when you get a problem in this pathway. So if you knock out phenylalanine hydroxylase, you get what's called phenylketonuria, also known as PKU. The reason that you need to know that BH4 is a cofactor is because you can also get PKU from not knocking out phenylalanine hydroxylase, but actually from knocking out the cofactor BH4. So phenylketonuria, also known as PKU, is an autosomal recessive disease that causes an elevation of phenylalanine. due to a problem with either, one, a deficiency of phenylalanine hydroxylase, or two, a deficiency of the cofactor BH4. Now, I've put in that little gray square a little part of our pathway that you should keep in mind as we have this discussion about phenylketonuria. So, notice that phenylalanine is converted to tyrosine through phenylalanine hydroxylase, but the cofactor is BH4. So, if either one of those things, the enzyme or the cofactor, is knocked out or deficient, you're going to get PKU. And if you can't convert phenylalanine to tyrosine, then the problem with this disease is that you're going to have a buildup of phenylalanine and a decrease in tyrosine. So tyrosine actually becomes what's called essential. You can't create it, so you have to get it through the diet. So you have too much phenylalanine and too little tyrosine. Now, clinically, this will explain the symptoms that we see. So when you have too much phenylalanine, you actually get too much of... what is known as phenyl ketones in the urine. So phenylalanine gets converted into a phenyl ketone and that gets excreted out into the urine. Now, not only does that cause symptoms when it's in the urine, but it causes symptoms when it's floating around in the body. And those symptoms are shown here. You get what's referred to as a musty odor. You have growth restriction or low height. You get a dermatitis, specifically you get eczema. epilepsy, so seizures. Now, the buzzword here that you should keep in mind is musty or musty odor. If you see musty on an exam, they're telling you that it's PKU. So, it's going to be a question about phenylketonuria. It's probably going to ask you either about the enzyme that gets knocked out or the cofactor that gets knocked out or the accumulation of phenylalanine, which leads to phenylketones or the decrease in tyrosine. So, keep that in mind if you see the buzzword musty. It's very, very high yield. So, how do you remember these symptoms? Now, you probably know about the musty odor, but if a test writer really wants to go after this, they might not give you that buzzword. They might ask you to know things like low height, eczema, or epilepsy. So what's the mnemonic here? Well, because everybody knows musty, we're going to pick a mnemonic that sort of is a synonym for the word musty. So I remember PKU by saying moldy, M-O-L-D-E. M for musty, O for odor, L for low height, aka growth restriction, D for dermatitis, aka eczema, and E for eczema. E for epilepsy. So, phenylketonuria moldy. I think of that moldy, musty smell. Moldy, musty odor, low height, dermatitis, epilepsy. Those are your symptoms of PKU. Now, very, very high yield is the treatment of PKU. So, obviously, if you have a decrease in tyrosine, you need to get it in the diet. So, you're going to want to eat or increase your tyrosine intake. You're going to want to decrease your phenylalanine because, face it, you're getting a buildup of phenylalanine, which is causing those phenylketones to... cause the clinical symptoms or the damage throughout the body. So you want to limit your phenylalanine. Now, this is very important and it shows up on exam. So I'm going to take a minute here. You cannot eat aspartame. If you have PKU, you cannot have aspartame. Aspartame is an artificial sweetener that has phenylalanine in it. So you can't eat it. If you have ever looked on a label before, on a nutrition label, there's always a little spot on it that says in bold letters, like you see here in this picture, hey, phenylketonurics. this has phenylalanine in it, or hey, phenylketonurics, this has aspartame in it. So if you look at the ingredient list and you see the artificial sweetener aspartame, there's going to be big, bold letters that say, yo, PKU people, don't eat this. It's got phenylalanine in it, aka it's got aspartame in it. Aspartame is an artificial sweetener that's commonly put in a lot of sodas, diet sodas especially, because in lieu of the sugar, since it's a diet soda or a diet drink. They load it with artificial sweeteners. So it still gives your brain that same sort of high feeling. But know that high yield, just know that people with PKU cannot eat aspartame because they need to decrease their phenylalanine intake. So that is very, very high yield. And that's why PKU is the highest yield disease in this discussion. So in summary, here's everything that we've talked about in this lesson on catecholamine synthesis. Remember the order, phenylalanine, tyrosine, DOPA, dopamine, norepinephrine, epinephrine. That pathway going straight down is technically the catecholamine synthesis pathway. But it's also important to keep in mind that tyrosine and DOPA kind of branch off and can become other pigmented molecules. In the case of tyrosine, it can become homogentistic acid, which leads us to our first disease that we talked about, alkaptonuria, if homogentisate oxidase is knocked out. DOPA can spin off to the side and become melanin. And if we knock out the enzyme that does that conversion, tyrosinase, you get albinism. And then of course, our highest yield fact today was PKU or phenylketonuria. If you knock out either phenylalanine hydroxylase or its cofactor. And of course, remember the order, phenylalanine, tyrosine, dopa, dopamine, norepinephrine, epinephrine, using our Tyrion Lannister mnemonic because Peter Dinklage plays Tyrion, who's a dope character, and without him, Game of Thrones could do no episodes. I know that I went through this video probably a little quickly, but it's very high yield and I think that I've done a good job explaining it. I don't want you to waste too much brain space on this, but know the diseases, know their symptoms. know what enzymes get knocked out to cause those diseases, and know the pathway or the order of catecholamine synthesis.

Catecholamine is a fancy way of saying neurotransmitter. Specifically, we're talking about three substances that act in the sympathetic or adrenergic sympathetic nervous system, dopamine, norepinephrine, and epinephrine. Now these molecules are synthesized in the chromophane cells of the adrenal medulla, but they're also produced in the postganglionic fibers of the sympathetic nervous system. If you've sort of been meandering your way through the first two years of medical school or whatever health organization slash school that you attend. You probably know that dopamine, norepinephrine, and epinephrine are used in the brain, but also throughout the hypothalamic pituitary adrenal axis as part of the sympathetic nervous system.

So if you have a little bit of confusion as to where these catecholamines or these neurotransmitters, if you will, come into play, they're really used diffusely. And I would like you to take a step back and think that they are used not only in neurotransmission, but in the sympathetic transmission in the adrenal axis used throughout the body. to act on end targets such as the heart.

Now today's video is going to specifically talk about where these are synthesized and pay special attention to the biochemical pathway that synthesizes them. I'm going to give you a really great mnemonic to help remember this pathway, but I want to sort of outline this video right now and tell you that we're going to start by talking about the pathway in conjunction with an awesome mnemonic that I'm going to give you. This will tie everything together and as we go We'll talk about some really, really high yield diseases that come about when certain points of the biochemical pathway get disrupted. Overall, this is a hugely important topic, and I'm going to spend a lot of time to make sure that you understand these concepts because they show up on exams all the time. Now, unfortunately, or maybe fortunately, today's mnemonic is a Game of Thrones mnemonic.

So if you've never seen the show, then I'm sorry, you're going to have a little bit of difficulty with the mnemonic, but I'm still going to be able to teach you the scientific concepts of catecholamine synthesis. But if you're a Game of Thrones fan like me, then this is going to work out beautifully. Now, like all good biochemical pathways, we have to start with something.

And when we talk about where these catecholamines get synthesized, they'll be downstream. But we have to start with an amino acid called phenylalanine. Phenylalanine gets converted into tyrosine by the enzyme phenylalanine hydroxylase.

As you may have noticed in my other videos, I like to keep the big picture in mind. So if you look at the name of the enzyme, it's telling you that phenylalanine is being hydroxylased, which means to break off a certain part of it. So if you're not sure what the reactant in the product is, you can look at the enzyme name or vice versa.

So in this case, phenylalanine goes to tyrosine. We know that phenylalanine must be the reactant because the enzyme is called phenylalanine hydroxylase. Now tyrosine will then go to DOPA and DOPA stands for dihydroxyphenylalanine and you don't need to know that. So just know it is DOPA, but the enzyme that categorizes...

that catalyzes this conversion is tyrosine hydroxylase. Once again, look at the enzyme name, tyrosine hydroxylase. Therefore, you know that that enzyme has to be acting on tyrosine because of its name. Now, this is where my mnemonic comes into play.

And today's mnemonic, I already told you, is a Game of Thrones mnemonic. And the Game of Thrones mnemonic is going to be based around Peter Dinklage, aka Tyrion Lannister, my favorite character in Game of Thrones. Again, Game of Thrones.

And how are we going to remember that the mnemonic with Tyrion is the mnemonic for catecholamine synthesis? Well, what is a catecholamine, guys? It is used as a neurotransmitter.

And where do neurotransmitters act? In the brain. Brain.

Hmm. Who's the smartest character in Game of Thrones? That's right. It's Tyrion Lannister.

So let's talk about how Tyrion Lannister is going to help us remember this pathway to understand how catecholamines get synthesized through this biochemical pathway. So far, we've talked that phenylalanine goes to tyrosine, goes to dopa. So how does tyrian lanister or peterdynklage come into play here? Well, here's the mnemonic.

Peterdynklage, P for phenylalanine. Peterdynklage plays tyrian. Tyr in tyrian and tyr in tyrosine or tyrosine. So peterdynklage, the P for phenylalanine, plays tyrian. Tyr, T-Y-R, in both tyrian and tyrosine.

Peterdynklage plays tyrian, who's a dope. character dope and dopa almost sound exactly the same So that's where we are so far. And I'm going to put the mnemonic on hold and we'll come back to this when we fill in the rest of the pathway.

But let's get back to just the science part of this. So here's where we left off. Now, tyrian is such a dope character that the two chemicals in this case, tyrosine and dopa that correspond to tyrian and dope because tyrian is such a dope character.

They can actually break off and branch sideways and make other products that aren't necessarily in the catecholamine synthesis pathway. So I'm pausing the catecholamine synthesis biochemical pathway, and what I'm showing you is that tyrosine can become something else, and dopa can become something else, and this sort of right and left arrow is pivoting off of the catecholamine synthesis pathway. So how you remember this in our mnemonic is that tyrian is such a dope character that the tyrian or tyrosine and the dope or dopa can actually become their own end products that are distinct from the catecholamines. tyrosine or tyrosine, if you will, becomes homogentistic acid. And the enzyme that does that conversion is not important, so don't worry about it.

But what is important is to know that homogentistic acid can then become malyl acetoacetic acid, which can then become fumarate. And if you recall from our TCA cycle video, fumarate can enter the TCA cycle. So what is important and what do you need to know? Well, the conversion of homogentistic acid to malyl acetoacetic acid. is catalyzed by homogentisate oxidase.

You need to memorize this enzyme. Now look at DOPA. Let's pause for a second. DOPA can go to melanin through the enzyme tyrosinase or tyrosinase.

Now, why do you need to know homogentisate oxidase? Homogentisic acid will become malyl acetoacetic acid through the enzyme homogentisate oxidase. The reason that you need to know this is because this is the first disease that we're going to talk about. So if you knock out homogentisate oxidase, you get what's called alkaptonuria.

Alkaptonuria is due to a knockout of homogentisate oxidase. Now, let's think about this for a second. Homogentisate oxidase catalyzes the conversion of homogentisic acid to malyl acetoacetic acid. So if we knock out this enzyme, that means we can't form the products and we have a buildup of the reactants. So I'm putting in little arrows here so you can see and reason through what you'll find with Alkaptonuria.

So you can't form malyl acetoacetic acid and therefore you can't form fumarate. But if that can't form, then the homogentistic acid will build up because it cannot be converted into malyl acetoacetic acid. So in Alkaptonuria, the inheritance is autosomal recessive.

And again, this is caused by a deficiency of the enzyme. homogentisate oxidase. I just copy and paste the enzyme so your brain can get used to seeing it this way. And we sort of already talked about this, but our findings are a buildup of homogentisic acid and a decrease in the products, malyl acetoacetic acid and a decrease in fumarate.

Now, what kind of symptoms does this cause? Well, because homogentisic acid is actually pigment, that will cause pigmented changes all throughout the body. So this buildup of this molecule that actually is a pigment. is going to cause the deposition of bluish-blackish pigment in places like the ear, the hands, and the sclera.

So these are the classic symptoms that you see. And in addition to these, you have things like dark urine, arthralgias, and discolored face. The discolored face is because of the pigment.

The dark urine is because of the pigment. And the arthralgia is because the pigment actually gets deposited into joint spaces. And any molecule that gets put into a joint space that's not supposed to be there is going to cause...

arthralgia. Makes sense. So big picture here, guys. Alkaptonuria is due to the enzyme homogentosate oxidase being knocked out. And when that happens, you're going to get a buildup of the reactant, homogentosate acid, and a decrease in the products because you simply can't form them.

And in this case, because the reactant is a pigment, the symptoms that you see clinically are going to be pigmentation. So that pigment is going to build up and deposit in places like the sclera, the ear, the hands, the urine. and the joints. And that gives you the classic symptoms that you see on this slide. in addition to dark urine, arthralgias, and a discolored face.

Now, that should make sense biochemically, and if you want to relate it to our mnemonic using Tyrion Lannister, you can look at this Game of Thrones flyer and see that he has dark sclera and a dark face, and it's bluish-blackish, which should remind you of this pigment deposition, which is blue-black. That is Alcaptanuria, okay? And another way to remember it is instead of Alcaptanuria, you can say Blackcaptanuria because BLK and ALK are very similar.

And a lot of people write BLK as the shorthand for black. So here's where we've left off so far. Again, Peter Dinklage, P for Peter for phenylalanine, plays Tyrion, Tyrion for tyrosine, who is a dope character, dope for dopa.

That is our catecholamine pathway, which is only half done at this point. But I wanted to point out that Tyrion is such a dope character that Tyrion or tyrosine and dopa or dope can become other things. Tyrion can become homogenetic acid and dope or dopa can become melanin.

Now we've talked about Alkaptonuria, which is a knockout of homogentosate oxidase. But now let's talk about what happens if we knock out the other enzyme, tyrosinase. So I told you that DOPA can be converted into melanin. That enzyme that does that conversion is tyrosinase or tyrosinase, however you want to say it.

But if we knock out that enzyme, we get albinism or, you know, some people incorrectly refer to it as albino. But albinism is due to a knockout of tyrosinase. So now let's talk about our second disease.

albinism. So the inheritance here is autosomal recessive. Now this is a defect in pigmentation that's due to one of two things, either a decrease in the enzyme tyrosinase or a decrease in the ability to transport tyrosine.

So I've put a little picture of part of our pathway right here so you can see what I'm talking about. So in the first case, we simply knock out the enzyme tyrosinase. And if you knock that out, then you're going to have a problem converting DOPA to melanin. And in the second option... in decreased tyrosine transport.

If you can never transport tyrosine to DOPA, then you can never convert DOPA to melanin. So you have still a problem with melanin, but it's due to a more upstream problem. It's not DOPA or tyrosinase that's the problem.

It's the inability to transport tyrosine to later be converted to DOPA to later be converted to melanin. So these are the two different genetic causes of albinism. What's very high yield, and I'm going to pause and put this in huge letters so you'd never forget this because this shows up on exams all the time, is that albinism is due to a normal number of melanocytes, but a decreased production of melanin.

So oftentimes they'll ask you about this and people will get so tripped up and they'll click the answer that says decreased melanocytes, but it's not the cell itself. It's not the melanocyte itself. It's the actual melanin within the cell that's not being produced. So it's the decreased production of melanin, not a decreased number of melanin producing cells. I hope that that distinction makes sense because it's extremely high yield.

So rewind the video if you need to hear that one more time. But again, albinism, normal melanocytes, but decreased melanin. Now, symptoms of albinism you're probably a little bit familiar with.

Things like white skin, white hair, blue eyes. The other symptoms that you may or may not have heard before is decreased visual acuity and increased risk of skin cancer. This is also associated with Chediak-Higashi syndrome.

So albinism is one of the hallmark features of Chediak-Higashi. But know, in addition to the white skin, you know, the fair skin, fair hair, blue eyes, is that they actually do have trouble seeing and that they have an increased risk of skin cancer. Of course, know the association with Chediak-Higashi syndrome. But again, all of this is packaged within albinism.

Now, coming back to our Game of Thrones mnemonic using Tyrion Lannister, if you need a little mnemonic to remember the symptoms of albinism, just look at this picture of Tyrion Lannister. Very fair skin, very fair hair. They said, you know, in season one, it was supposed to be blonde, but it was so blonde that it was almost kind of whitish, if you will.

I know that's kind of stupid in terms of mnemonics, but just another way to tie this back into what we're talking about today. Game of Thrones with Tyrion Lannister, again, because Tyrion is the smartest character in Game of Thrones. And that reminds us of catecholamines, which are used as neurotransmitters in the brain. Brain, smart.

Tyrion, smart. See the connection. Anyway, here's where we are so far.

We've talked about two diseases so far. We've talked about albinism, shown under the enzyme tyrosinase. And we've talked about alkaptonuria, shown under the enzyme homogentosate oxidase.

Again, both of those diseases will manifest if you knock out either one of those respective enzymes. But these are just side options in this pathway. In terms of catecholamine synthesis, we've only talked about three things so far, phenylalanine, tyrosine, and DOPA.

We got to keep going down this pathway because we haven't even produced. any of our catecholamines yet. Remember, the catecholamines are dopamine, norepinephrine, and epinephrine.

So in the second half of this pathway, we're going to see where those are actually produced. And at the end, we'll wrap up by talking about our third and final disease. I know I'm moving sort of quickly here, but I hope that this is making sense.

I think that I'm doing a pretty good job of explaining. So now let's go back to DOPA. So DOPA can be converted into dopamine through the enzyme DOPA decarboxylase. Once again, it's going to sound like I'm beating a dead horse here. Look at the name of the enzyme.

It's dopa decarboxylase. So we know that it acts on dopa. It acts on dopa and it forms dopamine.

So this is the first time we're seeing a catecholamine actually get produced in this pathway. Now dopamine can be converted to norepinephrine through dopamine beta hydroxylase. Again, ladies and gentlemen, look at the enzyme name. It's dopamine beta hydroxylase. Therefore, it's acting on dopamine.

So dopamine goes to norepinephrine. And then norepinephrine goes to epinephrine, it just drops the nor, through a very long-winded enzyme, which is called phenol, ethanolamine, and methyltransferase. So it's very important to notice something here, guys and girls. Dopamine is produced first, which then goes to norepinephrine.

Norepinephrine is produced second, which then goes to epinephrine, which is produced third and last in this chain. So in the order of catecholamine synthesis. You can make dopamine first, norepinephrine from dopamine, and epinephrine from norepinephrine.

That is a very, very high yield fact to keep in mind. But you watched this video today because you wanted to know the biochemistry of catecholamine synthesis. So we got to go back to our Tyrion Lannister mnemonic in order to finish this pathway. So here's where we left off.

We said that Peter Dinklage plays Tyrion, who's a dope character. The P in Peter told us that phenylalanine comes first. The Tyr in Tyrion told us about the Tyr in tyrosine.

which told us that that came second. And then Peter Dinklage plays Tyrion, who is a dope character, dope for dopa. So dope was the third sentence of this mnemonic and dopa is the third product in this catecholamine biochemistry pathway.

So let's keep going. So I told you that dopa goes to dopamine. So here's where our mnemonic is.

Peter Dinklage plays Tyrion, who is a dope character. And without him, Game of Thrones could do, do for dopamine. No, no for no repinephrine.

Episodes. Epi and episodes for epi and epinephrine. So Peter Dinklage plays Tyrion, who is a dope character, and without him, Game of Thrones could do no episodes. Without Tyrion Lannister or without Peter Dinklage, Game of Thrones could really do no episodes because the episodes would all be crap because he's the best character.

So this is my mnemonic for remembering catecholamine synthesis, and I'm going to explain it to you one more time so you can really nail it and imb- embed it into your brain and see it on test day like I always saw it over the past few years. So Peter Dinklage plays Tyrion Lannister, who is a dope character. And without him, Game of Thrones could do no episodes.

Do for dopamine, no for norepinephrine and episodes for epinephrine. Now, how do we connect Tyrion Lannister to catecholamine synthesis? I mean, how do you remember that this mnemonic is for catecholamines?

Well, catecholamines dope. dopamine, norepinephrine, and epinephrine are used as neurotransmitters in the brain. The brain reminds me that I'm talking about the smartest character in Game of Thrones.

And who's the smartest character in Game of Thrones? Tyrion Lannister. So that's the mnemonic. And this is everything that I've explained so far.

Now, before we wrap up by talking about our third and highest yield disease due to a problem in this pathway, I first need to draw in some of the cofactors of the catecholamine synthesis pathway. So they're shown here in blue text. When you go from phenylalanine to tyrosine, the cofactor is BH4. When you go from tyrosine to DOPA, same cofactor, BH4.

When you go from DOPA to dopamine, the cofactor is B6. When you go from dopamine to norepinephrine, the cofactor is vitamin C. And when you go from norepinephrine to epinephrine, when we drop the nor, the cofactor is SAM. Now these are...

you know, sort of important to know, but the one that you should absolutely know is what I've shown in bold lettering with the little star next to it, the BH4 cofactor when you go from phenylalanine to tyrosine. And the reason that you have to know that one is because it's involved in our third and final disease, which also happens to be our highest yield disease when you get a problem in this pathway. So if you knock out phenylalanine hydroxylase, you get what's called phenylketonuria, also known as PKU. The reason that you need to know that BH4 is a cofactor is because you can also get PKU from not knocking out phenylalanine hydroxylase, but actually from knocking out the cofactor BH4. So phenylketonuria, also known as PKU, is an autosomal recessive disease that causes an elevation of phenylalanine.

due to a problem with either, one, a deficiency of phenylalanine hydroxylase, or two, a deficiency of the cofactor BH4. Now, I've put in that little gray square a little part of our pathway that you should keep in mind as we have this discussion about phenylketonuria. So, notice that phenylalanine is converted to tyrosine through phenylalanine hydroxylase, but the cofactor is BH4. So, if either one of those things, the enzyme or the cofactor, is knocked out or deficient, you're going to get PKU.

And if you can't convert phenylalanine to tyrosine, then the problem with this disease is that you're going to have a buildup of phenylalanine and a decrease in tyrosine. So tyrosine actually becomes what's called essential. You can't create it, so you have to get it through the diet. So you have too much phenylalanine and too little tyrosine.

Now, clinically, this will explain the symptoms that we see. So when you have too much phenylalanine, you actually get too much of... what is known as phenyl ketones in the urine. So phenylalanine gets converted into a phenyl ketone and that gets excreted out into the urine. Now, not only does that cause symptoms when it's in the urine, but it causes symptoms when it's floating around in the body.

And those symptoms are shown here. You get what's referred to as a musty odor. You have growth restriction or low height.

You get a dermatitis, specifically you get eczema. epilepsy, so seizures. Now, the buzzword here that you should keep in mind is musty or musty odor. If you see musty on an exam, they're telling you that it's PKU. So, it's going to be a question about phenylketonuria.

It's probably going to ask you either about the enzyme that gets knocked out or the cofactor that gets knocked out or the accumulation of phenylalanine, which leads to phenylketones or the decrease in tyrosine. So, keep that in mind if you see the buzzword musty. It's very, very high yield. So, how do you remember these symptoms? Now, you probably know about the musty odor, but if a test writer really wants to go after this, they might not give you that buzzword.

They might ask you to know things like low height, eczema, or epilepsy. So what's the mnemonic here? Well, because everybody knows musty, we're going to pick a mnemonic that sort of is a synonym for the word musty.

So I remember PKU by saying moldy, M-O-L-D-E. M for musty, O for odor, L for low height, aka growth restriction, D for dermatitis, aka eczema, and E for eczema. E for epilepsy.

So, phenylketonuria moldy. I think of that moldy, musty smell. Moldy, musty odor, low height, dermatitis, epilepsy. Those are your symptoms of PKU. Now, very, very high yield is the treatment of PKU.

So, obviously, if you have a decrease in tyrosine, you need to get it in the diet. So, you're going to want to eat or increase your tyrosine intake. You're going to want to decrease your phenylalanine because, face it, you're getting a buildup of phenylalanine, which is causing those phenylketones to...

cause the clinical symptoms or the damage throughout the body. So you want to limit your phenylalanine. Now, this is very important and it shows up on exam.

So I'm going to take a minute here. You cannot eat aspartame. If you have PKU, you cannot have aspartame.

Aspartame is an artificial sweetener that has phenylalanine in it. So you can't eat it. If you have ever looked on a label before, on a nutrition label, there's always a little spot on it that says in bold letters, like you see here in this picture, hey, phenylketonurics.

this has phenylalanine in it, or hey, phenylketonurics, this has aspartame in it. So if you look at the ingredient list and you see the artificial sweetener aspartame, there's going to be big, bold letters that say, yo, PKU people, don't eat this. It's got phenylalanine in it, aka it's got aspartame in it. Aspartame is an artificial sweetener that's commonly put in a lot of sodas, diet sodas especially, because in lieu of the sugar, since it's a diet soda or a diet drink. They load it with artificial sweeteners.

So it still gives your brain that same sort of high feeling. But know that high yield, just know that people with PKU cannot eat aspartame because they need to decrease their phenylalanine intake. So that is very, very high yield.

And that's why PKU is the highest yield disease in this discussion. So in summary, here's everything that we've talked about in this lesson on catecholamine synthesis. Remember the order, phenylalanine, tyrosine, DOPA, dopamine, norepinephrine, epinephrine.

That pathway going straight down is technically the catecholamine synthesis pathway. But it's also important to keep in mind that tyrosine and DOPA kind of branch off and can become other pigmented molecules. In the case of tyrosine, it can become homogentistic acid, which leads us to our first disease that we talked about, alkaptonuria, if homogentisate oxidase is knocked out. DOPA can spin off to the side and become melanin. And if we knock out the enzyme that does that conversion, tyrosinase, you get albinism.

And then of course, our highest yield fact today was PKU or phenylketonuria. If you knock out either phenylalanine hydroxylase or its cofactor. And of course, remember the order, phenylalanine, tyrosine, dopa, dopamine, norepinephrine, epinephrine, using our Tyrion Lannister mnemonic because Peter Dinklage plays Tyrion, who's a dope character, and without him, Game of Thrones could do no episodes.

I know that I went through this video probably a little quickly, but it's very high yield and I think that I've done a good job explaining it. I don't want you to waste too much brain space on this, but know the diseases, know their symptoms. know what enzymes get knocked out to cause those diseases, and know the pathway or the order of catecholamine synthesis.

Transcript for:Understanding Catecholamine Synthesis Pathway

Transcript for:
Understanding Catecholamine Synthesis Pathway