DIP Episode 13 - Metabolism Review A

Well, on that Indian note, welcome to the 13th episode of the Divine Intervention Podcasts. My name is Divine. I am a fourth year medical student. Some friends of mine. I have an appreciation for Indian music and I've been trying to learn one song. So I was discussing with some friends of mine yesterday about trying to learn this specific song. That was just a teaser release for my new album just kidding. But hopefully I can learn that song at some point in the future. Okay, so today we're going to be talking about metabolism. I'm going to break this up in parts. Metabolism is something that's probably a little too big to discuss in one podcast. So I'll discuss it over a series of podcasts and by the end hopefully you should have a very good review going into step one. So let's go ahead and jump right in. So the big things I'm going to say I'm going to talk about today. I'll talk about nucleotide synthesis and I will also talk about some problems with proteins and drawing a lot of like pharmacology and other biochemistry and pathology and all that crap. So let's go ahead and start. So summary of nucleotide synthesis. Remember that nucleotides include DNA and RNA. Right. So to make DNA and RNA you're doing fuck need nucleotides. And nucleotides basically contain sugar and nitrogen based on a phosphate group. Okay, sugar, nitrogen based and a phosphate group. So that nucleotide the precursor to a nucleotide is a nucleoside. A nucleoside is just the sugar and the nitrogen base.

You haven't added a phosphate group just yet. Okay, but those nucleosides need to come from a nitrogen base. Okay, and those nitrogen bases can be one of two kinds. It can be a purine or it can be a pyramidine. Okay, so you start with the nitrogen base. If you add a sugar you form a nucleoside. If you form a phosphate you form a nucleotide. Okay, and those nitrogen bases like I said they can be one of two kinds. They can be a two-ringed nitrogen base. They are called the purine nitrogen bases. Those include adenine and guanine. Okay, and the way you differentiate between adenine and guanine is adenine has an amino group at a like the topmost position like the 12 o'clock position. Guanine has a ketone, right? So it has like a carbonyl group, carbon double bondate to an oxygen. The pyramidine nitrogen bases. They're one base. They're one ring nitrogen bases. Okay, and there's three kinds. There is cytosine. There's uracil and there's thymine. There's a classic numonic called the pi that can help you remember those three. And one nice thing about them that I think is actually kind of helpful is that order also shows you how those nucleoside nitrogen bases are made, right? So cytosine, if you deaminate cytosine with cytosine deaminase, you make uracil. You see a pharmacology time with that in a bit. And if you methylate your uracil, you actually form thymine. Okay, so you see a pharmacology time with the first step shortly.

And this sugar that joins up with a nitrogen base to form a nucleoside. Where does this sugar come from? The thing is the sugar actually comes from the hexos monofosophyte shunt, which is also known as the pentosphosphate pathway. So that pathway makes ribosophyte phosphates. That ribosophyte phosphate can join up with a pyrophosphate group from ATP, right? So two phosphates to make something called phosphoribosyl pyrophosphate. And the enzyme that makes that happen is PRPP Synthethase. Okay, so that's a summary of nucleoside synthesis. So now we know how to actually synthesize nucleothides. Let's then go into a little bit more detail. But first let's talk about Pyramidines. As you can see on the second slide, I say that Pyramidines to make them you make the nitrogen base first and then you add the sugar. But for the purines, you make the sugar first and then you add the nitrogenous base. So let's talk about Pyramidines. Let's make the nitrogen base first and then we add the sugar. So to make the base first, all of this actually happens in the cytosol or nucleothide synthesis in general happens in the cytosol. So the first thing that happens is that you condense glutamine and carbon dioxide with some other stuff. Okay, and you make something called carbamol phosphate. And the enzyme that makes this happen is CPS2 carbamol phosphate synthethase too. Okay, and again, this is a cytosolic enzyme. There's a CPS2. You should probably know that there's a CPS1.

Okay, remember the one in CPS1 as being like an eye to help you remember that CPS1 works in the mitochondria. Okay, works in the mitochondria of the urea cycle. Talk about that in a later slide. Okay, so you make carbamol phosphate and then that carbamol phosphate is then made into a radic acid by some magic that we don't are not really interested in for the purposes of board exams. And then that radic acid is the nitrogen base. So we've accomplished our first objective. Okay, now we want to make a nucleotide. Okay, so we are adding a sugar and we're adding phosphate. Right, and that's done by an enzyme known as UMP synthase. UMP synthase sticks that force for riboseal pyrophosphate. I talked about on the previous slide. Okay, and helps us make your radine monophosphate. I'll talk about pathology associated with that in a bit. And then that UMP is made into UDP. Don't care much about that, but that UDP is a ribonucleothide. Okay, UDP is a ribonucleothide. The thing is we have RNA and DNA. If you want to go down the DNA pathway, you need to convert your ribonucleothides to a deoxyribonucleothide. Ribonucleothides in general have hydroxy groups at the 2 prime and the 3 prime carbons of the sugar structure. Okay, but a deoxyribonucleothide does not have that 2 prime hydroxy group. It only has that 3 prime hydroxy group that uses to form those force for dyster bonds with a 5 prime phosphate.

So to remove that 2 prime hydroxy group, we need an enzyme known as ribonucleothide reductase. I'll talk about some pathologies related to that. So that UMP, DUDP, you can clip off a phosphate made DUNP and then that DUNP can then be converted to DTMP. And if you remember, I say that the difference between your cell and thymine is a methyl group. Okay, so this reaction clearly needs a methyl donor. Okay, and one high-yield methyl donor that exists in the body is the methylated form of tetrahydrofolate. The methylated form of tetrahydrofolate can give a methyl group to DUNP and then we make deoxythymidine monophosphate from that. And then that cycle needs to keep going and I'll talk about some pathologies related to that shortly. So what are those pathologies? If you go to the very top of the slide, I top right, I guess. I talk about how having a UMP synthase deficiency is a sociotheral or radicaciduria. The thing is if you have a deficiency of the enzyme that metabolizes or radicacet, obviously your levels of radicacet in the serum will go up. You see how this is related to another disorder that I'll talk about in a later slide. Okay, now ribonucleothide reductase helps you go from RNA land to DNA land. The thing is you can actually inhibit that enzyme with an anti-cancer drug known as hydroxyurea.

Hydroxyurea, yes, it's an anti-cancer drug and it is in fact used for some hematologic malignancies, but the thing is hydroxyurea is primarily used in the real world for the treatment of sickle cell disease. Okay, because by some non-mechanism it increases the synthesis of hemoglobin F, which is alpha-2 gamma-2. Now if you then jump down to 5-dilate synthase, 5-dilate synthase, which helps us go from DUMP to DTMP, that enzyme can be inhibited by a drug known as 5-fluory or cell. Okay, 5-fluory or cell. So 5-fluory or cell is an anti-cancer drug. The thing is you can, if you look for the upstream, there is an arrow going from 5 F-C to 5 F-U. The 5 F-C actually stands for 5-fluous cytosine. If you remember this is an anti-fongal that is used to treat cryptococcal and your formants and meningitis in 8 patients. Okay, the way 5-fluous cytosine actually works is that it is deaminated by cytosine deaminase. So remember that principle I talked about on the preceding slide. Scydosine deaminase converts the 5-fluous cytosine to 5-fluory or cell. That 5-fluory or cell inhibits thymidylates in phase, you make less thymidine monofosate and then you basically treat the cryptococcal meningitis. Okay, so that's a very nice time there. Now I also said that for thymidylates synthase to work. Okay, you need a methyl, methyl group, okay, coming from methylintetrahydrofolate. So when methylintetrahydrofolate gives that methyl group to thymidylates synthase to make the TMP.

Okay, dihydrofolate is made as a byproduct of that reaction. If you want to keep thymidylates synthase doing it to job, okay, that dihydrofolate has to be reconverted back to tetrahhydrofolate by an enzyme known as dihydrofoli reductase. Okay, this enzyme is inhibited by methyl tri-methyl-traxate, trimethyl-prim and pyramethamine. Methyl-traxate remember it causes pulmonary fibrosis as a side effect and it can also cause a liver dysfunction. And remember that methyl-traxate can be used to treat a hydratidiform mole, right? So like monopreglances. Remember the snowstorm appearance on an ultrasound of the pelvis. Trimethyl-prim, it's usually combined with SMX, right? So trimethyl-prim, so from ethoxazole to tri-thernomocistis gerovetsinomonia, you can also use it to profile acts against the PCP when the CD4 count drops below 200. And remember that trimethyl-prim, TMP SMX, back trim, right? It can also be used to treat UT Is, it can also be used to treat a nocardia. Okay, remember as a review from previous podcasts, remember that nocardia is an aerobic organism. It's a gram-positive branching filamentous rod and it's also weakly acid-fast, right? So it's the ins positive with a zil-nil synth state. And then pyramethamine combined with sulfur diazine can actually be used to treat the toxoplasmosis, right? So classically, if you think about an AIDS patient that has ring-enhancing lesions on an MR, on a MR magnetic resonance imaging, you think about to toxoplasmosis.

Okay, so that's what I'm going to say about this, about this slide. So let's jump onto the next one. So an interesting comparison of two cycles, right? So these two cycles, they are not just in train, I mean, intellectually stimulating to compare these two cycles, but these two cycles actually, what USMLE relevant, okay? So these two cycles include the urea cycle and the synthesis of pyramidines. I just said that to make pyramidines, you do that in the cytosome. But the thing is, the urea cycle actually appreciates two spots in the body, I mean in a cell, okay? The first two steps actually work in the mitochondria and then the final steps work in the cytosome, okay? You may ask yourself, divine, this is too low you to know, well, think again, it's actually high you to know these double localization details for step one. So in the urea cycle, stuff including ammonia is acted on by Kaboomol phosphates into these one to make Kaboomol phosphate, okay? That's the first step of that cycle. And then that Kaboomol phosphate can be converted to citrullin by an enzyme known as anything trans-Crabamolase, okay? So anything trans-Crabamolase converts Kaboomol phosphate to citrullin, okay? And that citrullin can then go into the cytosome to complete the remaining steps of the urea cycle, right? So it condenses with asperate and all that fun stuff. Now, so that is the urea cycle, okay?

But the thing is, if you contrast that with pyramidines synthesis, pyramidines synthesis, I said that instead of using CPS1, you actually use CPS2, okay? CPS2, Kaboomol phosphate synthesis, two works in the cytosome, okay? It converts glutamine and CO2 with some other stuff to Kaboomol phosphate. And then that Kaboomol phosphate by some magic becomes a radic acid. And then that radic acid, okay, is converted to urea monofosphate by an enzyme known as urea monofosphate synthase, or UNP synthase, okay? So if you notice, I put two red star excess in those two pathways, right? So first we've contrasted those pathways by location, right? So like mitochondria for the first two steps of the urea cycle, cytosol for all the steps of pyramidines synthesis. But the thing is, you can have two enzyme deficiencies in both pathways that can create an erotic acidemia if you may, okay? That erotic acidemia, right? It's like similar phenotype, but they're different, they are some extra findings that can tell you that, oh, it's this enzyme deficiency that's in operation versus this other enzyme deficiency, right? So if you have an OTC deficiency and only think trans-cabamolese deficiency, you have a very big buildup of Kaboomol phosphate, okay? And if you're thinking with regards to Loshakli's principle from college chemistry, as Kaboomol phosphate builds up, okay? It can spill into the cytosol, okay? It can spill into the cytosol, that's one fit.

Another thing that can happen is, as Kaboomol phosphate builds up, the upstream contributor to the synthesis of Kaboomol phosphating the mitochondria also builds up, okay? So ammonia in this case, so you can get a hyperamonemia with OTC deficiency. But this Kaboomol phosphate that spills in from the mitochondria into the cytosol, it can actually just basically join into the pyramidine synthesis game, okay? That Kaboomol phosphate can be covered at a erotic acid and you can get an erotic acid acidemia on that those circumstances, okay? Now, if we go to the pyramidine synthesis side of things, okay? If we have a UMP synthesis deficiency, we have a disease known as erotic aciduria, okay? So if you have a deficiency of UMP synthesis, erotic acid builds up, okay? But because this is part of the pyramidine synthesis path, we are not the urea cycle, okay? You don't have any elevations in your ammonia, so that is how you tell the urea cycle deficit, only thing Kaboomol is deficiency apart from the pyramidine synthesis deficit, okay? UMP synthesis deficiency. And then in the middle, I put as an aside, if they wanted to make this a more nifty step one question, they could talk about, oh, a person has hyperamonemia, so already have like the encephalopathy you get with too much ammonia dancing around in your blood, but these people have no already aciduria, okay? And maybe like, hmm, how that happened, right?

So that's one very nice way you can test your knowledge of the urea cycle, okay? If you have a CPS1 deficiency, your ammonia will build up, but because Kaboomol phosphate is downstream of that, you have decreased levels or normal levels of Kaboomol phosphate, okay? So that's how you can compare these three enzyme deficiencies. In fact, I try to do that on the next slide. If you have a CPS deficiency, it's a urea cycle problem, so your ammonia levels are up, when your Kaboomol phosphate and already acid levels are down, okay? If you have another urea cycle deficiency, that's a little more downstream, okay? Only thing trans Kaboomol is deficiency, your ammonia levels go up, okay? Because again, it's a urea cycle problem, your Kaboomol phosphate levels also go up, because only thing trans Kaboomol is converts Kaboomol phosphate to citrary, and then your already acid levels also go up, because that Kaboomol phosphate spills into the circulation, I mean spills into the cytosol, and that's joins in Pyramidine synthesis so you make more already acid, okay? But contrast that with the Pyramidine synthesis deficit, like a UMP synthesis deficiency where your levels of ammonia are normal, okay?

Because it's not a urea cycle problem, but your Kaboomol phosphate and your already acid levels are elevated, because again, these two things come upstream of UMP synthesis, and really the way you treat UMP synthesis deficiency is just to give back what is deficient, you give back your reading in the diet, and you can largely relieve the sequely of UMP synthesis deficiency, but if you have a CPS1 or OTC deficiency, it's really bad, because that ammonia can build up in the brain and cause a lot of problems for the infant, okay? So those kids usually don't leave super long, unfortunately. So, next slide, right? So we've talked about Pyramidines, now let's talk about purines, okay? So let's talk about how you make purines, and let's talk about how you break purines, okay? So to make purines, right? We said that you start with the sugar first, and then you add the nitrogenous base, okay? So we made the sugar first, I've talked about how the sugar is made with PRPP synthesis in a previous slide, okay? So you make PRPP, and then you make something known as 5-forceful ribosilamine, with an enzyme known as PRPP amythotransferase. The reason I mentioned in PRPP amythotransferase is that it's actually the reclimiting enzyme of purine synthesis, so you definitely want to know that for step one. So you make forceful, 5-forceful ribosilamine, and then you have some magic happen, and then you make anosimmonophosphate, okay?

Now the anosimmonophosphate can either be converted to anosimmonophosphate or anosimmonophosphate, and the enzyme that helps you go from anosimmonophosphate to anosimmonophosphate is anosimmonophosphate behindrogenase. Now why do I mention the enzyme? I mentioned the enzyme because it's inhibited by certain drugs, okay? So one drug that inhibits the enzyme is myocopenolipmofatil, okay? It's an immunosuppresent, it's used after transplants, okay? Ribovarine, which is used to treat the RSV and also like Hepsi, on the certain circumstances, also works by inhibiting anosimmonophosphate behindrogenase. And the reclimiting enzyme, PRPP amythotransferase, if you notice, I put like 5 red thins by PRPP amythotransferase. I put AMP, GMP, IMP to help you remember the regulation of PRPP amythotransferase, those products of that enzyme go back and feed back and inhibit the enzyme. And then alopurinol and 6-microthelpurin actually go back and also inhibit PRPP amythotransferase. So you may be like, hmm, it's fine. How is that relevant to our discussion? You'll see why when we're don't talking about a purine breakdown, I'll talk about some integration with that. So let's break down our purines, right? So again, remember nucleotide, nucleoside nitrogen base, okay? So the nucleotide, AMP, GMP, you pull out a phosphate, you make the nucleoside, you pull out the sugar, you make the nitrogenous base, okay? Anitrogenous basis, hypoxanthin or guanine, okay?

And then those nitrogenous basis, they can be converted by xanthin oxidase, okay? In two sequential steps to uric acid, to uric acid, okay? And then that uric acid is actually poorly soluble, right? So if you have too much uric acid in your blood, you could get gout or you could get nephrolithiasis from uric acid stones. Remember, uric acid stones are radio loosened so you don't see them on an x-ray, we can see them on a CT scan, okay? And then in birds, in birds, the uric acid could actually be converted by an enzyme known as uricase to alantoin. Alantoin is water soluble, okay? It's much more soluble than uric acid, okay? So now that we understand this, we can then begin to bring in some integration and then I'll go back to that PRPP Amideotransfer history that I was fleshing out a few minutes ago. So one thing we could do is if a person has gout, right? Or they have tumor lysis syndrome where they have some kind of hematologic malignancy and the person's white cells or whatever are dying and they're dumping a lot of purines into the serum and making a lot of uric acid that's clogging up the kidneys and also causing gout. You could try to solubilize that uric acid by giving pharmacological agent that replicates the activity of uricase, okay? That's where drugs like big lotty case and raspberry case coming, okay?

Big lotty case and raspberry case, the uricase analogs that help you dissolve uric acid and nicely by converting it to something that's a little more water soluble. Now another thing you could do to prevent tumor lysis syndrome, right? It's to say, okay, you know what? Let me go ahead and inhibit the enzyme that breaks, that helps us make uric acid in the first place, Zanthin oxidase, right? So that's how drugs like alopurinol and phyboxyl start work, okay? They inhibit Zanthin oxidase so you don't make uric acid. Now the thing is Zanthin oxidase, in addition to making help in us make uric acid, it actually has another high-yield USML euro, okay? One thing it does is that it breaks down six-megaphthopurin to inactive metabolites, okay? So if you think about it, if you give a Zanthin oxidase inhibitor, like alopurinol of a boxo start, you decrease the breakdown of six-megaphthopurin and that can do one of two things. One is that it could do a bad thing to you, right? It could increase the toxicity of six-megaphthopurin. Alternatively, if you're wise pharmacologist of physician, you can actually give alopurinol with a spot of the drug cocktail. For a person that's being treated, we came with therapy that includes six-megaphthopurin to decrease the dose of six-megaphthopurin that you have to administer, okay? So that's a very nice time there.

Now the thing is if you want to take this mitrogenous base that you got from breaking down the purin and like remaking, if you want that to say, okay, you know what? Why don't I conserve my purins instead of wasting them in the urine? Why don't I conserve them by converting the mitrogen base back to nucleotide? You do that in a path known as the purin salvage pathway, okay? And the one big enzyme you need to know for that pathway is HGPRT, okay? HGPRT stands for hypoxanthin guanine, phosphorybosol transferase, okay? It's the enzyme that takes hypoxanthin and guanine and adds a sugar and a phosphate back, right? So phosphorybosol, okay? It transfers a sugar and a phosphate back to hypoxanthin and guanine and remakes the nucleotide, okay? So why is it important to know this enzyme? It's important for certain reasons. One is that you have... One is that it's the enzyme that helps us in the purin salvage pathway. The other thing is this is the enzyme that's deficient in Lyschnihen syndrome, okay? Lyschnihen syndrome, I was actually discovered at my at my med school by a med student, GoFeeder, and some physician. You can look that up in your free time. So Lyschnihen syndrome, it's a HGPRT deficiency and the thing is if you think about it, if HGPRT is deficient, you basically kill the pathway that helps us deal with a nitrogen basis, okay? Because these nitrogen basis, we can deal with them in one of two ways, at least on this slide.

You can deal with them with HGPRT, which is what happens more than 85% of the time, or you can deal with them with Zanthinoxidase, okay? So if the 85% tau plus pathway is gone, then this other pathway then becomes the 100% pathway, okay? So make a ton of uric acid. So Gout is a classic finding in Lyschnihen syndrome, although you also tend to get self-mutilation and all that stuff in Lyschnihen syndrome. So one treatment for Lyschnihen syndrome is that you can give a Zanthinoxidase inhibitor to sort of prevent the gaudy sequely that you get with the disease. Although the self-mutilation and the neurological problems, those are unfortunately not very treatable. Now the thing is, if you notice, another red I put by HGPRT is a thyloprene. So the thing is, is a thyloprene is an anti-cancer drug that is a precursor to another drug known as six-mecaptopurin, okay? So the way is a thyloprene works is that it's converted to a purine analogue, okay? By the action of HGPRT, HGPRT helps us activate is a thyloprene, helps us convert it to six-mecaptopurin, okay? Six-mecaptopurin has purine in the name. That should help you remember that it's a purine analogue, okay? So six-mecaptopurin goes and inhibits PRPP amydotransferies, okay? And by inhibiting PRPP amydotransferies, you basically shut down the synthesis of purines. It also so happens that six-mecaptopurin can also inhibit HGPRT, okay?

So overall, you decrease purine synthesis and that's how is a thyloprene slash six-MP work as anti-cancer agents. So that's what I'm going to say on this slide, okay? And let me just talk about one last option of the purine salvage pathway, right? So again, you start with a nucleotide, you break it down to a nucleoside, and then that nucleoside is broken down to an nitrogenous base, okay? So AM Ps and nucleotide is broken down to a denocene, okay? That's a nucleoside, and then you pull off the sugar with... Actually, you don't pull off a sugar just yet, you deaminate the adenosine to make another nucleoside known as anosene, and the enzyme that makes that happen is adenosine deaminase, okay? And then you make anosene, anosene, you then pull off the sugar, okay? And then you're left with an nitrogenous base hypoxanthene, okay? So the thing is, if you notice, I put ADA adenosine deaminase between adenosine and an anosene, okay? The thing is, if you have a deficiency of adenosine deaminase, it's an autosomal recessive disease, you'll have a build-up of adenosine, okay? And again, if you're walking backwards with the Lochacli principle, as your adenosine levels go up, your AMP levels go up, if your AMP levels go up, your deoxy ATP levels go up, okay? And that your higher levels of ATP, that ATP can combine with methionine, okay? To make SAM, right? We'll talk about SAM in a different podcast. As you come to know, SAM is a very good methyl carrier in the body.

It works like in the Adrenaline Medulla, for example, to help you convert noripinephrine to epinephrine. But that's a difference to refer another podcast. So SAM, if you pull off a methyl group from SAM, you can actually make something called esadenosyl homocysteine, okay? Esadenosyl homocysteine. The thing is esadenosyl homocysteine is actually toxic to be antilimphoblasts, okay? So if you kill your be antilimphoblasts, you do not make B or T cells. So you get something called a severe combined immunodeficiency, okay? So that's the path physiology behind adenosine diamines deficiency, being one cause of autosomorescensive skin. Now, another thing that could also happen is that AMP that's building up, right? Because it's not being, because of a buildup of adenosine, that AMP that builds up, okay? Remember, if you remember, your negative feedback, that inhibits PR or PPM idol transfers, which as we said, is the retlymitting enzyme of purine synthesis, okay? So you also have decreased purine synthesis under those conditions. That's why you're getting to a lot of trouble with adenosine diamines deficiency. So next slide, right? So protein metabolism, protein metabolism, basically, for the rest of this podcast, I'm just going to talk about how you deal with proteins, okay? So let's assume you you eat some protein containing dish like meat or chicken or turkey, whatever, okay?

So you go through it down your throat and as it goes down your self-aggress, it gets to the stomach, okay? The stomach, remember, there's parietal cells that make acid, okay? Through hydrogen potassium antiporter, okay? It is an antiporter, it's an AT Pase, right? So you make a ton of acid that has the nature of the protein, okay? And then that protein pepsin in the stomach begins to digest the protein, okay? Remember, pepsin is the active form of pepsinogen. Pepsinogen actually comes from chief cells, okay? Chief cells, another cell type you find in the stomach. To actually go from pepsinogen to pepsin, you actually need the acidity of the stomach to make that happen as well. So that's a nice GI tide there, okay? Now that protein then makes its way to the to the small intestine, okay? And the pancreas releases certain enzymes like tripsin, chemotripsin, carboxypeptidase, whatever, they also help with digestion in the protein. Although remember that enterocainis is what kicks that's this process, right? So enterocainis converts tripsinogen to tripsin and then tripsin can then go and break down the zymogen forms of chymotripsin and carboxypeptidase to the more active forms, okay? So you break down those proteins to amino acids, okay? Amino acids are like the monomers that build up proteins, but another thing that would happen is instead of breaking the protein down completely to the amino acid, you can break it down to like a dipeptide or a tripeptide, okay?

And then the dipeptide or tripeptide or monopeptide, which is an amino acid, we can all go, they can be pumped into an interro site in the small intestine by sodium glucose, a linked transporter, okay? Sorry, not sodium glucose, sodium amino acid linked transporter, okay? So remember sodium is primarily an extracellular ion because of the activity of the sodium potassium ETP is pumped. So as that sodium goes down its gradient into the interro site, you have the active transport, I guess not pumping, active transport of amino acids, okay? Or dipeptides or tripeptides? And if you notice in the slide I see that over those glucose, I just want to remind you that you cannot transport die-saccharides or trisaccharides across an interro site membrane with sodium linked transportation, okay? Contrast that with your amino acids where O, you could take like a diamino acid, okay? A dipeptide or a tripeptide and bring it into the interro site with a sodium-align transporter, okay? Now if you have a problem, some kind of mutation in those transporters from amino acids, you can have two high-eo diseases for step one, okay? You can have something known as heart-nub disease or you can have something known as a cystinuria, okay? And the thing is these transporters did not just work in the, in the small intestine, they actually also work in the proximal convoluted tubule, okay? They actually work in the kidney as well. In fact, I'll just tell you this as a general principle.

Most transporters you'll find in the small intestine are also found in the proximal tubule. Why does that make any sense? The thing is both parts of the body, okay, have involved in reabsorption, right? So if they are both involved in reabsorption, it should make sense that they have similar transporters. If you even want that a very nice time here, if you remember, like the sodium glucose linked transporter, right? So we have SGLT transporters in the kidney, like SGLT2, but in the interro site in the small intestine, we actually have SGLT1, right? So remember your SGLT2 inhibitors like canagly flusin and the pagly flusin that basically help you pee out a sugar in your urine. So these are sodium amino acid linked transporters. They you find them in the in the GI tract in the small intestine and also in the proximal tubule. In fact, if you also think about both parts of the body being involved in reabsorption, you can see why there's microv lie in the small intestine and there's also microv lie in the proximal convoluted tubule, okay? So just some nice times between those two parts of the body. So heart-nub disease is basically a problem with neutral amino acid transporter, okay? And again, this transporter is found in the small intestine and the kidneys, right? So if you have a mutation in this transporter, you do not reabsorb. You do not reabsorb a neutral amino acids, either in the gut or in the urinary tract. And if you have that, you won't reabsorb triptophan.

Triptophan is a high-yield neutral amino acid. The thing is, triptophan can be used to make things like serotonin, right? Serotonin is 5 HT, 5 HD, triptophan. But triptophan can also be converted to niacin, okay? So if you have a triptophan deficiency, you can also get a niacin deficiency, okay? With heart-nub disease. A niacin deficiency remember the four Ds, okay? So like dermatitis, dementia, diarrhea, okay, and death. Death is the fourth D, because that's not very ideal, okay? So you can get a pelaigra presentation if you have a heart-nub disease. Now, cystinuria is a mutation in another amino acid transporter. Well, this transporter, it's classically known as the cola transporter because it transports cystine or nithen, lysine, and arginine, okay? Which are all basic amino acids, okay? So the thing is, again, if you have a mutation in this transporter and like I said, that this transporter operates in the GI tract and in the urinary tract, cystine can begin to show up in your urine, okay? And the thing is the cystine can pair up with a body, another cystine body, and you make a cystine, and that cystine can form kidney stones, okay? Because it's not very soluble in the urine, okay? So you can form kidney stones, remember those cystine stones are like 16 stones, right? So they're shaped like hexagons, like benzene rings, so that can cause a nephrolithiasis, okay? So that can be a presentation of cystinuria, okay?

And the thing is those cystine stones, you can actually solubilize them under basic conditions, okay? So you can actually give us an azulamide, a treatment for cystinuria, it helps you solubilize the cystine stones. Now, the thing is we like protein, right? But the thing is protein actually does some bath things to the body, okay? I mean, it's not necessarily bad, if you have a good organ to deal with it, in this case, the liver and your kidneys to a limited extent, okay? So the thing is to deal with a protein problem, we need, we also need to deal with the ammonia that we get from proteins, okay? So to deal with that ammonia, we have something known as the urea cycle, but before I can talk about the urea cycle, let me just give some preamble, relating to amino acids. Now, the thing is amino acids, they have two lives, okay? So one life is as being an alpha-kidro-acet, the second life is as being a amino acids, okay? Now, the thing is to basically interconvert between alpha-kidro-acet and amino acid, you either lose an amino group or gain an amino group. If you lose an amino group, you go from an amino acid to an alpha-kidro-acet, if you gain an amino group, you go from an alpha-kidro-acet to an amino acid, okay? So to make those interconversions, you need enzymes known as amino transferases, okay? Amino transferases, you could also know them as transaminesis, just one of the same name for the same kind of enzyme, okay?

And these enzymes, they all use vitamin B6 as a cofactor, okay? Pyrodoxyl phosphate. Hopefully you remember your B vitamins, right? So vitamin B1, right? That's thymine, okay? Vitamin B2 is riboflavin, B3 is myocene, there's no B4, B5 is biotene, okay? B6 is pyrodoxyl phosphate, hang on, vitamin B5, B5, B5, wait, B1 is thymine, B3 is riboflavin, B3 is myocene, vitamin B5, wow, I'm actually ashamed I forgot this, I actually kind of like biocam, vitamin B5, what is B5? Panthotenic acid, oops, sorry, so it's panthotenic acid, B6 is pyrodoxyl phosphate, B7 is biotene, okay? B9 is folic acid, B12 is cobalamine, right? So vitamin B12, okay? So just a quick review there, and we'll talk about what you use different vitamins for in a little podcast. So back to this, so B6 is a cofactor for the amino transferases, okay? It also happens that B6 is a cofactor for ALA synthase, okay, which is the reclimiting enzyme of hym synthesis, and B6 is also a cofactor for glutamate decarboxylase, which helps us convert glutamate to GABA, okay? So hopefully with these other reactions I mentioned, you can see why a person taking isoniasid can get acetyloblastic anemia because they can, I remember, I in each depletes vitamin B6, so by having a B6 deficiency, ALA synthase doesn't work so you can get acetyloblastic anemia because you're not making him alternatively, if you have a B6 deficiency, you have a buildup of glutamate and a down regulation of GABA synthesis, okay?

I remember glutamate is an excitatory neurotransmitter, so you can get seizures with that. So this alpha-kiloacid aminoacid pairing, there's some that I will say are relatively high to no for step one, that's for example like pyruvate and alamine or alpha-kilo-glutamate and glutamate or oxaloacity then as partite, okay? Pyruvate for example is the alpha-kiloacid of alamine. So to deal with our protein problem, we need to also deal with the ammonia that comes as a byproduct of proteins, right? So the thing is one way we can deal with this ammonia problem is to simply just pair it up with a hydrogen ion, okay? You make ammonium and then you pee out ammonium in the kidney, this is the primary way the kidney deals with ammonia problems for us, but that's a very minor pathway, it doesn't do much, okay? To really really get rid of ammonia, you want to condense it with a carbonyl group and another ammonia, okay, into something known as urea, okay? So you make urea and then urea, controlling the blood nicely, it doesn't cause any problems, doesn't change the heat of the blood, doesn't need any kind of carrier in the blood, so you move safely in the blood and then we just pee it out in the urea, okay? So urea is a great molecule, we actually have to make that urea and it so happens that that urea is made in the liver, okay? That's why if you have liver problems, you can get a hyper ammonium because your urea cycle doesn't work anymore, okay?

So the urea cycle is a very complex cycle but to be honest, there is not much you really need to know for step one, there are just very few things that you sort of need to take away, okay? So the thing is urea contains two amino groups, okay? And those two amino groups come from glutamate and aspartate, okay? Glutamate and aspartate. So the glutamate and aspartate take ammonia because remember glutamate is an amino acid, aspartate is an amino acid as well, so it should stand to reason that these two amino acids were previously alpha-kidro acids at some point in the distant past, okay? So those alpha-kidro acid forms of glutamate and aspartate receive ammonia, okay? And they are made into glutamate and aspartate which then do need the amino groups to the urea cycle to help us make urea, okay? And the thing is for those, because I mean think about it, ammonia is not made only in the liver, ammonia is made in many different parts of the body, it's made in muscle, it's made in spleen, it's made in many, many, many organs, okay? The thing is the ammonia from those many, many, many, many organs have to find a way to get to the liver to participate in the urea cycle, okay? So the thing is ammonia itself should probably not be traveling in blood, right? Because it's a basic molecule, it will raise the blood pH and you could like die, okay?

So the body puts that ammonia within an amino acid format and then those amino acids, they travel safely in the blood, get to the liver and in the liver they dump those amino groups, okay? Into oxaloacety to make uspartate and into alpha-kidro glutamate to make glutamate and then you're good to go, okay? And those ammonia carriers in the blood, okay? There's glutamine and there's alany, okay? And the alany in primarily comes from muscle and again, that should also make sense. The body was actually created in a pretty, pretty nice way, okay? Because the thing is that alany is the amino acid that comes from the alpha-kidro acid pyruvate, okay? And if skeletal muscle is running low on glucose, okay? One thing you can do is to say, okay, you know what pyruvate come here, okay? Let's take the muscle breakdown ammonia, pair it up with pyruvate, you make alany, that alany makes its way to the liver, okay? And then in the liver, that alany dumps the amino group with alpha-kidro glutamate to make glutamate or with oxaloacety to make uspartate and then you reform pyruvate and then that pyruvate can be acted on by pyruvate carboxylaves to make oxaloacety, that oxaloacety can then be acted on by phosphorynopyrovic carboxykinics to make phosphorynopyrovite and then you work your way up and remake glucose that can then be shipped right back to skeletal muscle, okay? Basically all I describe right now is the alany in cycle, okay?

So that's why it makes sense that alany comes from comes from muscle, okay? Because again, if you think about it, the alany brings a breakdown amino acid, breakdown ammonia from muscles but it also brings carbon which can be used as feed stocking gluconeogenesis so that the liver can replenish muscle glucose stores. Okay, so the ureth cycle again, it's a cycle that helps us deal with ammonia, okay? So the thing is that ammonia is usually packaged like in glutamate for example, okay? And that glutamate is condensed with carbon dioxide and some other stuff, okay? By an enzyme known as CPS1, which already talked about before, to make carbon monophosphate, okay? And then carbon monophosphate is converted to citrullin with an enzyme known as an only-thin transcarbon monolids, okay? And the thing is that's literally those twins' enzymes you need to know from the ureth cycle CPS1 and only-thin transcarbon monolids, okay? And remember that these twins' enzymes work just in the mitochondria, okay? And the regular-metallin enzyme of the ureth cycle is actually CPS1, okay? And the regulation is actually pretty easy, okay? You have a substance known as anacetyl glutamate, it's an obligate activator of CPS1 and when it activates CPS1, you have more flux through the ureth cycle, okay? And you may ask yourself, define this is kind of like out of thin air, how does anacetyl glutamate make any sense, right? Well, if you think about it, anacetyl glutamate, glutamate is an amino acid, okay?

You get amino acids from protein, okay? So it should make sense that if you're consuming a ton of protein, right? You're about to build up this nasty ammonia problem for your body, okay? So, a high protein meal should logically, right? Increase the production of anacetyl glutamate, which logically should activate CPS1, which logically should help you deal with that incoming ammonia load, okay? Now, so the ureth cycle, it's a high opath, it helps us make urea, but in the ureth cycle, one thing I just want to throw in here is that as an offshoot to make arginine, okay? And arginine is kind of important, okay? You can use it to make histones, remember histones, right? They have positively charged or basic amino acids in them, like lysine or arginine, okay? And remember that arginine is also used for nitric oxide synthesis, okay? Remember nitric oxide is a viso-dialiter. And if you're really thinking about this, you'll be like, hmm, arginine positively charged, binds DNA negatively charged, basic amino acids. Again, if you have a cola-transporter deficit, right? So cysteineuria, okay? Remember, it's a deficit deficit of a basic amino acid transporter, right? So cysteine, arginine, lysine and argin, okay? Lysine and argin are not made, okay? So you could potentially imagine that, oh, this per- your step one exam could work a question that says, oh, this person may potentially have problems with, like, DNA expression, for example, because they have an arginine deficit if you may.

And if you have that arginine deficit because they're not reabsorbing it from the diet or from the urinary tract, okay? You could imagine that you have decreased histone synthesis, although as far as I know, that having an arginine deficit does not really cause many problems for humans. Okay? And if a person has hepatic and cephalopathy, I just put that as an aside. In general, you give lactolose for that, right? So remember, lactolose is converted to lactic acid that can acidify ammonia, okay? Convert it to ammonia. Ammonium is not very reabsorbable, so you basically put it out, okay? So that's where I'm going to stop today and I will pick up from here in a different podcast. I just want to make sure you guys have a solid grounding for metabolism. So just keep going with this and other topics. If you have any questions or you spot any errors, feel free to post a comment or send me an email, okay? Divine intervention podcasts at gmail.com. I wish you a wonderful day and God bless. Thank you.

The first two steps occur in the mitochondria, while the final steps occur in the cytosol.

PRPP amidotransferase.

Hydroxyurea.

Alanine (via the alanine cycle).

CPS1 deficiency leads to high ammonia but normal/low carbamoyl phosphate. OTC deficiency causes a buildup of carbamoyl phosphate and citrulline precursors.

Kidney stones formed by basic amino acids; they are often hexagonal crystals.

Adenine has an amino group ($\text{-NH}_2$) at the 12 o'clock position, while Guanine has a ketone (carbonyl group, $\text{C=O}$).

Ribonucleotide reductase.

It impairs the purine salvage pathway, leading to massive overproduction of uric acid and subsequent gout/Lesch-Nyhan syndrome.

Vitamin B6 (Pyridoxal Phosphate).

Glutamine and Alanine.

5-Fluorouracil (or its metabolites).

Adenine has an amino group ($\text{-NH}_2$) at the 12 o'clock position, while Guanine has a ketone (carbonyl group, $\text{C=O}$).

Ribonucleotide reductase.

It impairs the purine salvage pathway, leading to massive overproduction of uric acid and subsequent gout/Lesch-Nyhan syndrome.

Vitamin B6 (Pyridoxal Phosphate).

Glutamine and Alanine.

5-Fluorouracil (or its metabolites).