DIP Episode 15 - Metabolism Review B

Welcome to the 15th episode of the Divine Intervention Podcasts. My name is Divine, I'm a fourth-year medical student and in today's podcast we're going to continue our story relating to metabolism. Okay, so let's jump right in. So the first light talks about the central dogma of metabolism. Basically, I mean this is not an actual central dogma, but it's just something you want to keep in mind to help you remember how insulin and glycogon affect metabolic pathways. So insulin, think of insulin as a default for a leader and think of glycogon as a phosphorylator. If you can get the central principle into your head, it will make it very easy for you to remember many things. So insulin is a default for a leader, glycogon is a phosphorylator. So if insulin activates an enzyme, it activates it by default for a relation, if glycogon activates an enzyme, it activates it by phosphorylation. So next slide. So how is fructose absorbed in interocytes? Well, that's with the Glute 5 transporter. Okay, and how can glucose be converted to fructose? Well, the thing is there is a pathway where glucose can be converted to something known as sorbitol. Okay, with an enzyme known as all those reducties. All those reducties reduces all those sugars like glucose. And then there is another enzyme known as sorbitol dehydrogenase that converts sorbitol to fructose. Okay, and the thing is, sorbitol dehydrogenase is highly expressed in certain tissues like like like seminal vesicles and stuff like that.

But in other tissues, it's not necessarily expressed or if it's expressed it expressed in very minute quantities. For example, like the lens of the eye or shuan cells and stuff like that, right? Or even the cells that line the nephra. So if you think about it, if you have limited expression of sorbitol dehydrogenase or no expression, you will basically stop at the conversion of glucose to sorbitol. And sorbitol is automatically activated in poor water into cells and it can cause osmotic damage. Okay, that's why that's one potential mechanism behind the nephropathy and the neuropathy and the retinopathy that you get in diabetes. So what is the general pathophysiology behind lactase deficiency? In general, the order you get, at least in certain populations of individuals, especially Asians, it gets much harder to metabolize lactose. Okay, so they have like reduced levels over time of lactase. Okay, that's the general pathophysiology. There are very few people that have like absolutely no lactase from birth. Okay, and remember it's a brush border enzyme deficiency. That's another with the constipation. We can test that concept on step one. Okay, next slide. So galactose metabolism, right? So you may see met 21. I'm just referring to some students at my at my med school, but basically let's assume you're a milk lover. Okay, you consume milk and milk contains lactose. Okay, and lactose is a bisacharide. Right?

So it's broken down by the brushbritter enzyme lactase to glucose and galactose. Okay, and remember glucose and galactose are both all those sugars. As you see later, fructose is not an all those sugar. It's a keto sugar. Okay, so glucose and galactose, but in this case, we're dealing with galactose metabolism. So let's just keep going with the pathway. Galactose can be acted on by by galactokines to form galactose one phosphate. Okay, and then galactose one phosphate uradil transfer is can help us go from galactose one phosphate to glucose one phosphate. You basically take the galactose and put it on UDP glucose. You take the glucose from UDP glucose and make glucose one phosphate. Okay, there's like some epimaries that exist that keeps that cycle going, but that's not relevant for for word exams. Okay, so if I'm glucose one phosphate, that glucose one phosphate by some magic by some isomerase enzyme, you make glucose six phosphate and then you can go into glycolysis. So there's a lot of pathology associated with this slide that I think is high yield to no force step one. Okay, the first thing is as we've talked about on the preceding slide, if you have a lactase deficiency, that's a brush border enzyme deficiency. Okay, pretty common in Asians. So that's the demographic you may see on exams. And if you have a lactase deficiency, lactose can build up in the lumen of your GI tract that can osmoticly draw water. Okay, so you can get an osmotic diarrhea.

Okay, that's one pathology. Another pathology, we already talked about this with glucose being acted on by aldeus reductives to form sorbidol. Okay, galactose can also be acted on by aldeus reductives to form galactetol. Okay, and these two things again are osmoticly active. That's why if you see in galactose metabolism disorders, there's almost always cataracts. Okay, because the galactetol builds up in the lens attracts water that will pacifies the lens and you get cataracts. Okay, but you don't get that in a fructose metabolism disorder as you'll see on the on the next slide. Now, one high yield thing you want to know, if a person has a classy galactoseemia, I'm going to talk about that. I guess let me just talk about that next and then I'll jump down to the green stuff at the bottom. Okay, so galactokines deficiency. It's a deficiency of galactokines, that's pretty obvious. And basically, the thing that happens is if you have that deficiency, you have a lot of galactose in your blood, okay, but it's not very severe. Okay, but the big thing you want to watch out for on that with that deficiency is that those people tend to have cataracts again for the galactetol reasons that I explained. That's one because even if galactokines cannot act on galactose, all those reducties can almost certainly act on galactose, okay, so you can get the cataracts with that. But the reason this is not very severe is that hexocaine is can also actually act on galactose.

So the phenotype is pretty mild, other than the cataracts, you don't get very significant liver symptoms or anything of that sort. But if you have a second enzyme deficiency in galactose metabolism, that's a galt deficiency of galtonephosphoridio transferries, you have much more severe problems, right, because the thing is in galactokines, deficiency are not necessarily trapping galactose one phosphate in cells. In galt deficiency, you are in fact trapping galactose one phosphate in cells. And galonephosph is very osmoticly active, so that phosphate trapping can pull water that like sugar, like phosphorylithic sugar. It's trapped in the liver, for example, it can bring in water and it can destroy the hepatocytes. And you also get many other problems, right, so you get cataracts, like we said for galactokines deficiency, you get a lot of vomiting, okay, you get a lot of mentor, you those kids classically have a mentor retarditions, actually a pretty nasty disease. So those people in general, they want to avoid lactose or galactose containing items in the diet, because they cannot metabolize galactose, okay. Now, if you have a galt deficiency, it's known as essential galactocemia. One high yield tidbit, you certainly want to know for step one, and even for step two and like shelf exams, is that people that have a galt deficiency, they have a very high risk of death from sepsis with equal life.

No one really knows why that's the case, but it's something you definitely, definitely, definitely want to know, going forward. It's a very high yield concept. Not many people know that stuff, but it's something you definitely want to know for tests. So let's jump onto the next slide. Fructose metabolism, right? Fructose metabolism is a little simpler, okay. So you consume like fruits, right, like oranges, right? That contains sucrose. Suprose is also a dysacharine, okay, it's acted on by sucrose, okay, which is a brush powder enzyme. Remember, you can only reabsorb monosaccharides, you have no ability to reabsorb dysacharides. So that sucrose breaks up sucrose to glucose and fructose, we already talked about how fructose enters enterocytes with the glute 5 transporter, okay. That transporter is also very heavily expressed in spermato sites, because sperm actually uses fructose as its source of energy, okay. So fructose is then converted to fructose 1 phosphate by fructokines, okay. If you have a deficiency of fructokines, that's something called essential fructoseuria. You just have a ton of fructose in your blood, a ton of fructose in your urine, not a big deal, okay. It's a pretty big night again, because hexokines also has the ability to act on fructose in a minor path work. Now, fructose 1 phosphate is then cleaved by all the least B, not all the least A, all the least B. Remember all the least B is in fructose metabolism, all the least A is in glycolysis, okay.

All the least B cleaves fructose 1 phosphate to DHAP, dihydroxy acetone phosphate and glycerol to hide, okay. If you have a deficiency of all the least B, a second enzyme problem, okay. You have more severe issues, okay. Again, because the fructose 1 phosphate is trapped in cells, because once the sugar is phosphorylithet, it has a very hard time getting out of a cell. So that fructose 1 phosphate automatically draws water into tissues and you can get very, very serious problems with that. In fact, that all the least B deficiency is known as fructose intolerance. So the principle I want you to establish here is that the first enzyme deficiency galactose or fructose metabolism is bad but not very severe, but the second enzyme deficiency is almost always pretty devastating, okay. So that's one thing you certainly want to keep in mind, okay. And these kids tend to have like a lot of hypo glycemia again because the liver is not working right. Remember the liver is the primary organ of gluconeogenesis. They have like increased levels of bilirubin because again, remember that's the liver takes care of like bilirubin metabolism sorry the error with the urethyl cool and all that stuff. But actually these people actually tend to have a hypo ammonemia because they're going to liver failure relatively rapidly, okay. And then the type 2 RTA business I'll talk about it in a little podcast. I have to give like a big explanation to highlight that concept and I'll talk about it later.

But just remember that a type 2 RTA is associated with Aldo-Lis B deficiency which is fructose intolerance, just something to keep in mind. Now fructose like I said is not an Aldo sugar is a keto sugar, okay. And as far as I know there is no such thing as keto reductase, okay. So you do not get you do not get the cataracts that you're classically observing galactose, galactose metabolic disorders, okay. So if you see cataracts on your exam think of a problem with galactose metabolism. If you see no cataracts, think more about a problem with fructose metabolism. And if you go to the next slide, you also sort of want to like think of your temporal associations, right. Breast meal contains a lot of lactose. So galactose problems, galactose metabolism problems tend to show up like in the first few days of life versus fructose metabolism problems that tend to show up after like six months when fructose has slowly introduced into the diet, okay. And again I already talked about how the second enzyme deficiency is more severe, okay. So next slide. So discussion of microb destruction in lysosomes of macrophages after phagocyteosis by the respiratory burst, right. So basically I'm referring to the respiratory burst pathway that operates in neutrophils in macrophages and in a lot of our white blood cells, right. So when you phagocyteose something, you get it to the lysosome to destroy it, okay. And you use something known as the oxidative burst to make that happen.

So the first step of the oxidative burst is an enzyme known as NADPH oxidase, okay. NADPH oxidase takes molecular oxygen and helps you convert it to superoxide radicals, okay. And then superoxide dismutance helps you convert those superoxide radicals to hydrogen peroxide, I mean, yeah hydrogen peroxide each tool to and then myeloperoxidase converts the hydrogen peroxide to hypochlorosacid which is basically bleach, okay. And if you have a deficiency of the first enzyme in that pathway, NADPH oxidase deficiency, you'll have something known as chronic granulomatous disease, right. So in chronic granulomatous disease, those people have an NADPH oxidase deficiency, they basically cannot make hydrogen peroxide. So those people have to depend on the production of hydrogen peroxide from bacteria, okay. Those people that co-ops the hydrogen peroxide from bacteria, uh, aceton it with myeloperoxidase, make bleach and kill that bacteria. But if that bacteria has an enzyme known as catalyst, which has the ability to break up hydrogen peroxide to oxygen, I mean to basically metabolize it to, uh, water and oxygen, then those people would have an increased risk of infection with those kinds of organisms, right. So catalyst positive organisms like staphoreus, like E. coli, like aspergillus, okay. So that's something I definitely want to keep in mind.

Now the ALS relationship is, I'm just trying to refer to the second enzyme in the pathway, I remember that a superoxide dismutee's mutation is associated with, um, uh, familial, uh, amyotrophic lateral sclerosis. So that's just one factor you want to know. And, uh, the AML relationship is that remember that myeloid cells, uh, have myeloperoxidase as, uh, as a marker, okay. So remember if my, if you have a hematologic malignancy and it's myeloperoxidase positive, M. P. O. positive, you know it's of myeloid origin, as against being of lymphoid origin. And another thing you can actually think of, those are our rods that you see in the M3 kind of AML, acute pro myelocytic leukemia, those are our rods actually made of myeloperoxidase. Remember that if those are rods spill into circulation, they can cause a DIC and death. Now, glutathione is an agent that really helps us deal with oxidative stress, okay. And the thing is, uh, it's actually a pretty essential pathway to reducing, to providing, uh, reducing power for ourselves, right. So, if for example you're subjected to high stress with hydrogen peroxide, uh, that hydrogen peroxide is converted to water and oxygen with an enzyme known as glutathione peroxidase. Glutathione peroxidase, oxidizes glutathione, but remember it's a redox reaction, so as something has been oxidized, the other thing is being reduced.

As glutathione is oxidized from its reduced form to its oxidized form, hydrogen peroxide is converted from its oxidized form to its reduced form, which is water and oxygen, which is much safer. But if you want to keep that cycle going, you need to reconvert the oxidized glutathione back to reduced glutathione. You do that with an enzyme known as glutathione reductase, okay. And that enzyme depends on any DPH as a cofactor. That's why you can see that if you have a G6 PD deficiency, where you're not making any DPH, okay. Because remember, uh, the pentals phosphate pathway, one of its byproducts is any DPH. They have a G6 PD deficiency, they're not making any DPH. You're not making a cofactor for the regeneration of reduced glutathione, to keep that glutathione cycle going. And one thing I will bring into play here is that there is a drug that actually works like, it's basically a glutathione analog because it has a lot of soft hydro groups. The drug I'm referring to is enacidocestine, okay. Enacidocestine is a pretty ubiquitous drug. It, uh, you can use it to treat acetaminophen toxicity because remember acetaminophen can be metabolized to an agent known as NAPQI, okay. And that NAPQI is a very powerful oxidizing agent. So if you give reducing power in the form of enacidocestine, okay. You could dumb down the, the oxidative damage that you get with acetaminophen toxicity and you could potentially stave off, uh, liver damage, okay.

So that's one thing enacidocestine can do for you, okay. Enacidocestine can do many other things, right. So you can cleave disulfide bonds, okay. In mucus plugs, so you can use that to treat the cystic fibrosis to sort of break up the nasty guppy stuff that clogs up their airways. You can actually use enacidocestine as well to prevent contrast in using an apathy, okay. Because one of the thoughts is that contrast creates a lot of free radicals that damage the kidney and cause kind of intra-renol, uh, cuter-renol failure, okay. So you can give, uh, enacidocestine prophylaxically to sort of prevent that. Another thing you can use enacidocestine for is you can actually use it to, to prophylax against the, uh, bladder toxicity, right. The hemorrhagic is tightest that you get with cyclophosphamide. Remember cyclophosphamide makes, uh, metabolite known as acroling and that acroling is toxic to the bladder. Uh, you're classically thought that you could use mesenophilite, that a mesen- uh, does in fact work better, but you could get an unusual step one question where enacidocestine is actually the right answer, okay. You can actually use enacidocestine to prophylax against the hemorrhagic cystitis that goes with cyclophosphamide. Now, CGD already talked about how CGD is treated in the previous podcast. I said because it's a microfage problem, you can try to give something that spursus of microfage function like interferon gamma, okay. Next slide.

So how does isoniasid cause seizures? How does isoniasid cause seizures? The mechanism behind is, isoniasid cause incisions is that isoniasid depletio vitamin B6 and it so happens that vitamin B6 is the cofactor for an enzyme known as glutamid decarboxylase. Glutamid decarboxylase helps you go from glutamate to GABA, okay. And glutamate is sort of an excitatory neurotransmitter. GABA is an inhibitory neurotransmitter, okay. So if you depleted your B6, you have no cofactor for glutamid decarboxylase, your glutamate levels build up, okay. You can get seizures with that, okay. So that's one potential mechanism behind INH causing seizures. And I want to draw you attention to the facts that autoantibodies against glutamid decarboxylase associated with type 1 diabetes, okay. And this is another like off-putting question, how does the urea cycle relate to nitric oxide synthesis? Remember that one of the byproducts of the urea cycle is arginine, okay. And arginine can be added on by nitric oxide synthesis to make nitric oxide. Remember nitric oxide is a powerful viso dilator, so it decreases after load. Now, next question says patient with recurrent episodes of bronchospasm, flushing and diarrhea, okay. Presents with new onset memory loss and the diffuse body rash. Opolosis, stolic murmur is heard at the left lowest turnal order, okay. So if you see a person having bronchospasm, they have flushing, they have diarrhea, okay.

I really hope you are thinking about carcinoid syndrome, okay. There's a very nice numani for carcinoid syndrome. It's called BFDR, okay. The B stands for bronchospasm, the F stands for flushing, the D stands for diarrhea, and the R stands for right-sided heart lesions. The reason you get right-sided heart lesions is that the serotonin that's secreted by the carcinoid tumor can be metabolized by the lungs, okay. So the serotonin will basically like scrub the right side of your heart, but the long end of the philium has the ability to metabolize that serotonin, okay. So it doesn't make its way to the left side of your heart, so you do not get left-sided heart problems, okay. And in general, you get symptoms with carcinoid syndrome when you have met to the liver. The most common location of carcinoid tumor is in the appendix, okay. So the liver has the ability just like the lungs to metabolize the serotonin, but once you have met from the appendix to the liver, then the serotonin can then move all over the body and begin to cause these systemic symptoms, okay. So why does this person have this new and hopefully remember a pulocystolic murmur, left-low sternal border? I really hope you're thinking about a tricospidarygurge, okay. In general, in carcinoid syndrome, you either get tricospidarygurge or pulmonic stenosis. For a cospidarygurge, a pulmonic stenosis, okay. There is a nice and monic for that. It's called tips, okay. Try cospidiancy, pomonic stenosis.

Those are the lesions you tend to get with carcinoid syndrome. Now, why does this person have neon-set memory loss and a diffused body rash? Well, carcinoid is a tumor that oversecrates serotonin. Where does serotonin come from? I mean, if I'll give you a clue. Serotonin is also known as 5-HT or 5-hydroxy tryptophan, okay. So that should tell you that it comes from triptophan, okay. It so happens that triptophan is also a precursor to the formation of niacin, vitamin B3, okay. So if you're diverting all the triptophan that you have in your body towards the synthesis of serotonin, because a person has carcinoid syndrome, they don't make as much niacin as they could make, okay. And they can get pelagra from that, okay. Remember the four days of pelagra, okay. Diarya, okay. Dermatitis, right. So that's the skin rash dementia, right. So that's the memory loss and death, which is not ideal. So that's something you want to keep in mind, okay. And I've talked about the valve elitians. And the real quick thing, I'll just say about hydroxylation reactions. It's not always true. But I'll see that tetrahhydrobiobythrin, BH4, appears to be a pretty common co-factor for many hydroxylation reactions in the body. Take, for example, the conversion of phenylalanine to tyrosine with phenylalanine hydroxylase. Remember, that's the enzyme that's deficient in a PKU, okay. But basically, that's a hydroxylation reaction. It depends on BH4, okay.

There is at least like four or five biochem reactions in a tested on step one that also have BH4 as a co-factor. So just take that concept away. Tetrahhydrobiobythrin, BH4, co-factor for hydroxylation reactions in the body, especially with amino acids. Okay, so next slide. Location of fatty acid synthesis, right. So where does fatty acid synthesis happen? Fatty acid synthesis happens in the cytosol, okay. That's an easy question. The feedstock for fatty acid synthesis is acetylchoyne, okay. You basically join up a bunch of acetylchoyne monomers to make a fatty acid, okay. And how does this feedstock leave the mitochondria? Well, the thing is acetylchoyne cannot leave the mitochondria on its own, okay. The way acetylcholine leaves, I mean sorry, acetylchoyne, leaves the mitochondria is that it's converted to citrate, okay. So acetylchoyne is two carbons. It pairs up with oxaloacetylchoyne for carbons to make citrate, okay. There's a citrate transporter in the mitochondrial membrane, so that citrate goes out the mitochondria, okay. And then that citrate, it's split back or split right back into oxaloacetyl, so this is now in the cytosol. It's split right back into oxaloacetylchoyne and acetylchoyne. The acetylchoyne continues its destiny for fatty acid synthesis. The oxaloacetylchoyne continues its destiny for a pathway I'm going to talk about in a few minutes, okay. So that's how the acetylchoyne gets out of the mitochondria. And you may ask yourself, come on, divine.

Can't the acetylchoyne just do the TCA cycle in the mitochondria and be done for the day? Well, the thing is if the TCA cycle keeps running, you'll make a ton of ATP, you'll make a ton of NADH. That ATP and NADH are very powerful inhibitors of the retlymitting enzyme of the TCA cycle, isocetrate dehydrogenings, okay. So when the inhibit that enzyme, everything proximal to that enzyme begins to build up like acetylchoyne, okay. That's the inducement for fatty acid synthesis to begin. Now, the retlymitting enzyme of fatty acid synthesis is acetylchoyne carboxylase, okay. Basically helps you convert acetylchoyne to malano-coe, and then you do some magic and you ultimately make a fatty acid, okay. Now, acetylchoyne carboxylase, has carboxylase in the name. Any enzyme that is a carboxylase enzyme always uses three things, okay. It uses ATP in that reaction, that's an A. It uses biotene in that reaction, that's a B, that's vitamin B7, okay. And then it uses CO2 in that reaction as well, because it's a carboxylase enzyme, right. So it should make sense that it uses carbon dioxide, okay. So all carboxylase enzymes are ABC enzymes, they use ATP, biotene of vitamin B7, and CO2. And remember that you can get a biotene deficiency if you consume a ton of egg whites, okay. Because egg whites contain Avidin, and Avidin is a very powerful vitamin B7 binder. Okay. Now, how is fatty acid synthesis regulated?

Well, fatty acid synthesis is regulated by three primary mechanisms you want to know, primarily in the context of acetylchoyne carboxylase, okay. So think about it, will insulin or glucagon promote the storage of fat? Well, I hope you're thinking insulin, and how does insulin work? Is insulin of phosphorylator or dephosphorylator? I said this in the beginning, it's a dephosphorylator, okay. So that means the dephosphorylated form of acetylchoyne carboxylase is the active form, okay. While the phosphorylated form of acetylchoyne carboxylase is the inactive form, okay. So when acetylchoyne carboxylase is not phosphorylated, it's active, that's what insulin wants. When acetylchoyne carboxylase is phosphorylated, it is not active, that is what glucagon wants. Okay. Remember, glucagon works through a G-protein computer receptor, okay. Now, in terms of feed-forward activation, citrate is a powerful feed-forward activator of acetylchoyne carboxylase, okay. But the product of fatty acid synthesis, parmital cohe, it's like a 16-carbon fatty acid is a very powerful feedback inhibitor of acetylchoyne carboxylase. So that's the way acetylchoyne carboxylase is mentioned in general. And citrate, feed-forward acts. If feed-forward activates an acetylchoyne carboxylase, just reminds me to tell you that if you go back to glycolysis, right. The last enzyme of glycolysis, pyruvate kinase, okay. It's actually recolipated by feed-forward activation, okay.

With substrate known as fructose-16bisphosphate. Fructose-16bisphosphate is actually a feed-forward activator of pyruvate kinase, okay. Feed-forward activation is not very common in metabolism. So whenever it pops up, it's usually high, for example. The two high-year essential fatty acids, there's alphalynolenec acid and linoleic acid. That's just something you want to memorize. It's commonly tested on exams. And then the two sources of NADPH for fatty acid synthesis. I'll say the big thing you want to remember here is that G6bD, glucose 6-phosphid dehydrogenase from the oxidative fees of the pentose phosphate pathway, makes NADPH as a byproduct. So that's one source of NADPH. But there is another high yield source of NADPH that I'm going to talk about now. So this is where I'm going back to that citrate story that I sort of dropped for a bit, right. So we say that in the mitochondria acetylquic cannot make its way out. So it combines with oxaloacety to form citrate. That citrate goes through a citrate transporter, okay. And then that citrate is cleaved by an enzyme known as ATP-C-trytlyase into acetylquic that continues its destiny as a part of fatty acids synthesis. And then that oxaloacety is actually reconverted back to malit, okay, in the cytosol, by an enzyme known as malibihydrogenase. Okay, malibihydrogenase does in fact also exist in the mitochondria, but there is another isophone that also exists in the cytosol, okay.

So malibihydrogenase converts oxaloacety to malit. And then that malit can be converted back to pyruvate by an enzyme known as NADPH dependent malic enzyme, okay. Malic enzyme converts malit to pyruvate, but it actually forms NADPH as a byproduct. And then that pyruvate can be recycled back into the mitochondria to go back to the TCA cycle or to keep the cycle of fatty acid synthesis going, okay. Because it can undergo the pyruvate hydrogenase complex, make acetylquic, that acetylquic and parapet with oxaloacetyl again, form c-try, get out of the cell and then do what I just described, okay. So those are the two high yield sources of NADPH, malic enzyme and glucose 6-phosphate hydrogenase. So next slide. Now we're jumping into glycolysis, okay. Like colicis, you don't need to know the enzymes in the pathway, but I'll say there are certain high yield enzymes you generally want to know and I'm going to emphasize them. And while I'm concurrently discussing the pathway, I'll also discuss the regulation, okay. So the first step of glycolysis is that you want to trap glucose in a cell. You trap glucose in cells by phosphorylating glucose, okay. So how do you phosphorylite glucose? You use a kinase, kinase is enzymes that phosphorylite thins. So hexokinase, right. Hexosix carbons, glucose is a 6-carbon sugar, it's a 6-carbon auto sugar. So hexokinase converts glucose to glucose 6-phosphate. Okay. Remember that in general you find hexokinase everywhere in the body, okay.

But the enzyme that does that scene reaction in the liver, in the beta cells of the pancreas, in the kidneys, for example, is glucose kinase. Okay. Glucokinase helps us convert glucose to glucose 6-phosphate. Okay. And remember that if you wanted to reverse that reaction in glucose neogenesis, for example, that would be with the use of glucose 6-phosphate. So remember that enzyme is highly expressed in the endoplasmic reticulum, okay. And if you have a deficiency of glucose 6-phosphate, you have glycogeant storage disease type 1, okay. That's one-gear disease. Now, there are certain different, higher differences between hexokinase and glucose kinase, okay. Hexokinase is feedback inhibited by glucose 6-phosphate, which is its product, okay. But glucose kinase is not, okay. Glucokinase, like I said, it's more liver specific. It's not feedback inhibited by glucose 6-phosphate. It's actually feedback inhibited by glucose 6-phosphate. And I'll talk about the mechanism behind that in our not-common slide, okay. And unlike hexokinase, where insulin does not necessarily increase its genetic expression, insulin does increase the genetic expression of glucose kinase. So that's another high-ealth thing you want to keep in mind, okay. And again, this first step is to phosphorylate the glucose so you can trap the glucose in the cell. Now, next slide, okay. So key differences between hexokinase and glucose kinase. Hexokinase has a low KM, so it has a very high affinity for glucose, okay.

And it has a very low V-max, okay. So it has a, it gets to its maximum rate of reaction very quickly. Why does this make any sense? If it makes sense because hexokinase is expressed in many tissues of the body, like the brain, for example, your brain always depends on glucose. So even if your blood glucose levels are low, okay. Hexokinase will be working at max capacity, which is a good thing, okay, because you want to supply glucose to your organs. Well, glucose kinase is different. Glucocinase, think of it as a glucose sensor enzyme, okay. It has a high KM and it has a high V-max, because the thing is, by having a high KM and a high V-max, that means there's a very wide range over blood glucose concentrations over which glucose kinase can work. That's why it works as a very good sensor. Okay. And the thing is, when you hit blood glucose levels of like 15 millimolar, for example, right. Hexokinase is already a prisoner of like max, max, max speed, okay. Glucocinase is beginning to get going and that helps you again bring more glucose into the liver so that you can store it as glycogen, for example, okay. So glucose kinase has a high KM, so it has a lower affinity for glucose and it has a high V-max. And because it has a high KM and it has low affinity, if you have a mutation in glucose kinase, okay. You won't be able to sense blood glucose levels very well, okay. So you will be hyperglycemic for longer periods of time and that can create a kind of diabetes.

That's known as moody. Maturity onset of diabetes of the yoke, okay. It's classically like the fit diabetic. Like you see these people, they're diabetic, but they're super fit. They're like, I mean, I'm not saying they're ripped or anything, but they're not obese like you observe in many diabetics, okay. So let's jump to the next slide and talk about how hexokinase is regular, I mean, glucokinase is regular. So glucose kinase is regular by your protein known as glucokinase regulatory protein, okay. The way this protein works is that it binds to glucose kinase and sends it to the nucleus. Glucokinase is useless in the nucleus, okay. But the thing is, glucokinase regulatory protein has the ability to bind fructosex phosphate or glucose, okay. When it's bound by glucose, it has a lower affinity for glucose kinase. So glucose kinase can then come out of the nucleus, come to the cytosol and do its job. But if glucose kinase regulatory protein is bound by fructosex phosphate, it actually makes it have a higher affinity for glucose kinase. When it has a higher affinity for glucose kinase, it takes it to the nucleus and glucose kinase cannot do its job, okay. So this is how fructosex phosphate negatively regulates the activity of glucose kinase. So next step of glycolysis, right. So it's where you go from fructosex phosphate to fructose-1-6bisphosphate. The enzyme that helps you go from glucose, 6-phosphate to fructosex phosphate is not relevant, for example.

But fructosex phosphate is converted to fructose-1-6bisphosphate by the reglimitin enzyme of glycolysis known as PFK-1. First, four fructose kinase-1, okay. And first, four fructose kinase-1, right. Because it's the reglimitin enzyme of glycolysis, it has a lot of regulation, okay. It has a lot of regulation. And if you think about it, if glycolysis helps you make energetic intermediate, it should thus make sense that anything that speaks high energy should inhibit PFK-1. Anything that screams low energy should activate PFK-1. Because if you have low energy, you want glycolysis to happen so you can make ATP to power the cell. So, low energy substrate like AMP, adenosine monofosphate, actually activates PFK-1, but high energy indicators like ATP and citrate actually inhibit PFK-1, okay. But there is something else that also activates PFK-1, and this is fructose-2-6bisphosphate. Think of fructose-2-6bisphosphate as the conduit that enables humans to homonally regulate the activity of PFK-1, okay. So, just like fructose-1-6bisphosphate is made by PFK-1, fructose-2-6bisphosphate is made by PFK-2, okay. That's no way the story ends. It so happens that PFK-2 is part of a bifunctional enzyme complex, okay. The bifunctional enzyme complex includes PFK-2, which converts fructose-6bisphosphate to fructose-2-6bisphosphate, and fructose-2-6bisphosphate, which reverses that reaction converts fructose-2-6bisphosphate to fructose-6bisphosphate, okay.

So, the thing is, I just told you that fructose-2-6bisphosphate is an activator of PFK-1, okay. And we know that insulin is proglycolicis. So, it should make sense that the formation of fructose-2-6bisphosphate is encouraged by insulin. And if we know that PFK-2 helps us make fructose-2-6bisphosphate, and you know that insulin is proglycolicis and fructose-2-6bisphosphate is an activator of PFK-1, that should help you remember that the defaults-4-releted form of PFK-2 is its active form, okay. So, when you defaults-4-releted PFK-2, right, you make, you activate PFK-2, you make more fructose-2-6bisphosphate, okay. And then that fructose-2-6bisphosphate can then go and activate PFK-1, okay. I'm not going to talk about the reverse reaction because it's just something you have to take the opposite off, okay. And you will get that regulation down, okay. This is not something really need to memorize. If you just remember the central dog-move metabolism I talked about earlier, and you talk about how oh, insulin is a defaults-4-releted, and how it's proglycolicis, you can basically recreate all this from memory. So, next slide. So, fructose-2-6bisphosphate broken down by all the least A, not all the least B, remember all the least B is enzyme that's deficient in hair-diffre fructose intolerance, okay. But all the least A converts fructose-1, 6bisphosphate to DHAP, that hydroxy acetone-phosphate, and glycerol-outa-hyde-3-phosphate, okay.

And that glycerol-outa-hyde-3-phosphate, okay, can be converted by glycerol-outa-hyde-3-phosphid dehydrogenase to one-three bisphosphoglycerate, okay. Because this enzyme, glycerol-outa-hyde-3-phosphid dehydrogenase has dehydrogenase in the name, you should know that you're either using up or making any DHAP, FADH tour, any DPH in this reaction. In this reaction, we're actually making any DHAP, okay. This NADH can actually have multiple fates, okay. It can actually go to the electron transport chain to complex one, okay, to supply power for the synthesis of ATP. Another thing that the red cells actually use this NADH for is that they use it to convert methemoglobin, which is hemoglobin that has iron in the three-plus state, the ferric form, to regular hemoglobin, which has iron in the two-plus state, okay. Remember, two-plus iron is the iron that can carry oxygen, three-plus iron actually cannot carry oxygen, okay. So methemoglobin reductase uses any DHAP as a cofactor to convert methemoglobin to hemoglobin in a red cell, because a red cell's job is to carry oxygen, okay. But another thing you want to keep in mind is that methemoglobin actually has a very good ability to bind cyanide, okay. So the person actually is poisoned with cyanide. One treatment is to actually induce a methemoglobinema, methemoglobinemia with a drug known as immunitrade. It's a powerful oxidizing agent. Remember, oxidation is an increase in oxidation number.

If you have oxidation numbers becoming more positive, your oxidizing a substance, okay. So you go from Fe2 plus to Fe3 plus. Fe3 plus has a very high affinity for cyanide. You bind up that cyanide and then you give thiosolthase to help you from thiosyanide and then you put or pee out the cyanide safely, okay. So that's one application of this pathway, okay. And after the site, you'll see glycerol-3-phosphate listed as coming from dihydroxyacetone-phosphate under the action of the enzyme glycerol-3-phosphate dehydrogenase. Please don't confuse glycerol-3-phosphate dehydrogenase with glycerol-the-high-3-phosphate dehydrogenase, okay. glycerol-3-phosphate dehydrogenase helps you make glycerol-3-phosphate, okay. glycerol-3-phosphate is used for triglyceride synthesis. I'll talk about that in a little podcast. Next slide. So, one-three-bisphosphoglyceric can be converted to three-phosphoglyceric, okay. So this is the first step where you make ATP in glycolysis, okay. This is substrate-level phosphorylation. So you're converting ADP directly to ATP, okay. And then by some magic, you go from three-phosphoglyceric to phosphoenol-pyroviqt, and then you have the last step of glycolysis, okay. The last step here is that phosphoenol-pyrović is converted to pyroviqt, my name's I know that pyroviq kinase. I already talked about how pyroviq kinase is feed-forward activated by fructose-1-6-bisphosphate, okay. What's the only enzyme I mentioned that is also feed-forward activated?

Acetylquicarboxylic. So I'll give you a member. That's feed-forward activated by citrate. So pyroviq kinase converts phosphorylationol-pyroviq to pyroviq, okay. In addition to being activated by fructose-1-6-bisphosphate, anything, again, that screams high energy in hybrids pyroviq kinase, okay. So ATP is an inhibitor of pyroviq kinase. Alamine is also an inhibitor of pyroviq kinase, and that should sort of make sense. If you have high levels of alamine, it's kind of indicative potentially of a high energy state because pyroviq can be converted by ALT to alamine, okay. Pyroviq is like the alpha-kilo acid of alamine, okay. So it should sort of make sense that alamine is an inhibitor of pyroviq kinase. And remember that a pyroviq kinase deficiency is actually one of the most common causes, one of the is one of the most common likeolytic enzyme deficiencies that perpetuates a hemolytic anemia. I'll talk about the mechanism behind that in a different podcast. So this pyroviq kinase step also makes ATP, okay. And again, this is another example of substrate level phosphorylation. Now, on the left of this slide, you see one 3 BPG being converted to 2, 3 BPG, okay. There's an enzyme known as BPG mutase that does that. It's actually a pretty heavily expressed enzyme in red cells, and you may ask yourself, hmm, why does this make any sense? Well, remember that 2, 3 BPG, okay, binds to the beta subunit of hemoglobin.

Remember, hemoglobin has two alphas and two betas, okay, at least a hemoglobin A. So that beta subunit can be bound by 2, 3 BPG, and that shifts the oxyhemoglobin dissociation curve to the right, okay. So that it can inhibit red cells to release more oxygen, okay. But contrast that with theta-hemoglobin that is 2 alpha, 2 gamma has no beta subunits, okay. You need those beta subunits to bind to 3 BPG, okay. So because phenylhemoglobin does not have that beta subunit, it can not bind to 3 BPG, that's why hemoglobin F is left shifted, and that makes sense because it creates a gradient of oxygen flow from maternal hemoglobin, which should be hemoglobin A, to the phenylhemoglobin, which is hemoglobin F, because hemoglobin F has a higher affinity for oxygen compared to hemoglobin A. Okay, so next slide. Some other important stuff, pyruvate kinase, you can almost predict what I'm going to see here, right. It's regulated by phosphorylation and dephosphorylation, right. And we already established that insulin is proglycolicis, okay. So that means that the dephosphorylated form of pyruvate kinase is the active form, okay. So hopefully with this, you're seeing that regulation in metabolism is actually very easy to remember, okay. You just need to put certain principles together and you don't need to memorize much, okay. And in glycolysis, you make 280 P's, okay. Net, 2 net AT Ps, you make 2 net NEDH's and 2 pyruvate, okay.

Remember, you're getting 2 pyruvate because glucose 6 carbon is split into 2 pyruvate, okay. And pyruvate has many things, okay. You can form lactate under the action of lactate dehydrogenase. Basically, the point of this step is it helps regenerate NED so that the glycerol, the high 3, 4 speed dehydrogenase step can keep working, okay. Alternatively, pyruvate can go into the mitochondria and be acted on by the pyruvate dehydrogenase complex. I'll talk about that in a different podcast to make acetylchoye, okay. Another thing that would happen is that pyruvate can be acted on by pyruvate carboxylates, okay, which uses acetylchoye as a cofactor, okay. Acetylchoye is a very powerful, anosteric, in fact, I'll say it's an obligated activator of pyruvate carboxylates, okay. You can form OA from that and again, because it's a carboxylates enzyme, it's adding an extra CO2, okay. That's why you're going from 3 carbon pyruvate to 4 carbon acetylchoye. And that acetylchoye can make its way up the glycolysis chain because remember, many of those reactions are reversible to ultimately form glucose in gluconeogenesis, okay. And remember that because pyruvate carboxylates, again, is a carboxylates enzyme, it's ABC, so it uses ATP, it uses bio-tin and it uses carbon dioxide, okay. So next slide. Glute transporters, so this is what I'm going to end with today.

Glute transporters, basically, you just want to know that they're heavily expressed in many in specific organs of the body and you want to know which organ expresses what, okay. So like, Glute One, Glute One is found in the brain and red cells. It has a low key, and again, because your brain and your red cells, they depend very heavily on glycolysis, okay. So because it has a low key, and it has a very high affinity for glucose, so that even if your blood glucose levels are super low, those transporters are still working super well, okay, to maintain your blood glucose levels. Now, Glute Two is found in the pancreas, okay. The beta cells of the pancreas and in the liver, okay. And Glute Two, the Glute Two transporter is bidirectional, and it should make sense because remember the liver participating glycolysis, but it also participating gluconeogenesis. So the liver, even if it brings glucose in through the Glute Two transporter, it can also export that glucose through the Glute Two transporter as well, okay. Because remember that the liver expresses glucose six phosphatese, so you can convert glucose six phosphate to glucose, okay. So if you're an organ that supplies glucose to other organs, you should have a bidirectional transporter that should kind of make sense, okay, because that glucose actually has to like leave the liver, for example, in some way, shape of form.

Now, Glute Three is expressed in many tissues, is also expressed in the brain, Glute Four is expressed in a dipocytes and in muscle, okay. I remember that with 4am, okay, so Glute Four at dipocytes and muscle, and one special thing to know about Glute Four is it's actually induced by insulin, okay. Not necessarily, you don't necessarily make more Glute Four with insulin, but insulin, one of the things it does is it causes you to place more Glute Four transporters on the cell membrane of an adipocyte or skeletal muscle, okay. And then Glute Five already talked about how that transports fructose, okay. And then glucose, remember when you consume glucose and is broken down by those brush border dysaccharidesis, of which lactase is an example, okay. You form those monosaccharides, those monosaccharides, they go in through secondary active transport into the entire site by using the SGLT transporters, the sodium glucose linked transporters. Remember that sodium is primarily an extracellular ion, okay. So as it goes down, it's gradient into the cell, it carries glucose alongside, okay, SGLT one. Don't forget SGLT two transporters that you find in the proximal convoluted tubule that are inhibited by drugs like a cannibal flossing, okay. That's an anti-diabetes, a medication, I'll talk about that drug in a different podcast. Okay, so the last slide, good one transporters, again they have a low KM, okay. So they basically bring in a constant amount of glucose per unit of time, okay.

Contrast out the Glute Two transporters that have a much higher KM lower affinity. So they bring in a more constant fraction of glucose per unit of time. And the thing is, again, think of your liver, your beta cells of the pancreas, let's say more beta cells of the pancreas, as having a glucose-sensin mechanism, okay. This is actually kind of coupled to the Glute Two transporter, okay. And I've talked about why the Glute Two transporters are bi-directional, and I've talked about how Glute Four transporters are insulin-dependent, although you begin to work out, your muscle needs glucose like crazy, okay. So there is actually an insulin-independent mechanism where you can put more Glute Four transporters on the surface of skeletal muscle in the setting of exercise, okay. That's why exercise is good for diabetes because you don't necessarily need insulin, but you're just putting Glute Four on the surface of skeletal muscle and skeletal muscle cells, so you're basically clearing the blood of glucose, okay. So that's where we're going to stop today. I'm going to pick up with another podcast. I hope you have a wonderful day. God bless you, and I'll see you next time. Thank you.

BFDR (Bronchospasm, Flushing, Diarrhea, Right-sided heart lesions).

Galactose metabolism disorders (specifically related to Aldose Reductase activity on galactose $\rightarrow$ galactitol).

They are bidirectional glucose transporters. The liver uses them for both taking up blood glucose (glycolysis) and releasing it into the bloodstream (gluconeogenesis).

GALT deficiency (Galactose-1-phosphate uridyl transferase deficiency), leading to essential galactosemia.

Insulin increases the genetic expression of glucokinase, but not necessarily hexokinase.

All carboxylase enzymes (e.g., Pyruvate carboxylase, Acetyl-CoA Carboxylase).

Insulin acts as a dephosphorylator, converting the inactive phosphorylated form of ACC back to its active dephosphorylated state.

Because these organs rely heavily on constant glucose supply (glycolysis) and require high affinity for glucose, even when blood levels are low ($K_M$ is low).

Serotonin (5-HT) derived from Tryptophan depletes the precursor needed for Niacin ($\text{B}_3$), leading to a secondary deficiency of Niacin and subsequent Pellagra.

Aldolase B (Note: This distinguishes it from aldolase A, which is involved in glycolysis).

1) Glucose-6-phosphate dehydrogenase (from PPP); 2) Malic enzyme (which converts malate to pyruvate and generates $\text{NADPH}$).

Lactose builds up, drawing water osmotically into the intestine, causing osmotic diarrhea.

Insulin acts as a dephosphorylator, converting the inactive phosphorylated form of ACC back to its active dephosphorylated state.

Because these organs rely heavily on constant glucose supply (glycolysis) and require high affinity for glucose, even when blood levels are low ($K_M$ is low).

Serotonin (5-HT) derived from Tryptophan depletes the precursor needed for Niacin ($\text{B}_3$), leading to a secondary deficiency of Niacin and subsequent Pellagra.

Aldolase B (Note: This distinguishes it from aldolase A, which is involved in glycolysis).

1) Glucose-6-phosphate dehydrogenase (from PPP); 2) Malic enzyme (which converts malate to pyruvate and generates $\text{NADPH}$).

Lactose builds up, drawing water osmotically into the intestine, causing osmotic diarrhea.