The Science of Everything Podcast - Episode 138: Biochemistry and Metabolism

Episode Date: August 31, 2023

A discussion of the metabolic pathways involved in breaking down proteins, carbohydrates, and lipids into simple components, extracting their energy, and building back up into more complex components needed for bodily function. We cover glycolysis, the citric acid cycle, lipolysis, beta oxidation, amino acid deamination, gluconeogenesis, fatty acid synthesis, and amino acid synthesis. Our overall focus is on the central role of acetyl-CoA and how the different metabolic pathways interact and intersect. Recommended pre-listening is Episode 18: Biochemistry Basics and Episode 75: Cellular Respiration. If you enjoyed the podcast please consider supporting the show by making a PayPal donation or becoming a Patreon supporter. https://www.patreon.com/jamesfodor https://www.paypal.me/ScienceofEverything

you're listening to The Science of Everything podcast, episode 138, biochemistry and metabolism. I'm your host, James Fodor. So in this episode, we're going to discuss biochemistry and human metabolism. And as part of that, we're going to look at the three major macromolecules or types of nutrients that are metabolized in the human body, proteins, carbohydrates, and lipids. Recommended pre-listening for this episode is episode 18, biochemistry basics. as well as episode 75 on cellular respiration. We build on some of the material developed there, so I strongly recommend you check those out before listening to this one.

What we're going to talk about in this episode, as I've said, are the three major macronutrient molecules, and in particular we're going to discuss how each of them is broken down into smaller constituents, and then how each of them can be built up again to form new versions of proteins and carbohydrates and lipids that are needed throughout the body. So these two types of processes are known as catabolical,

and anabolic. So catabolic is breaking down and anabolic is building up. And we'll look at each of those processes for each of our three major types of macromolecules. So let's get started by first giving a quick introduction to what metabolism is before we go through all of the three different types of molecules. So metabolism is the set of chemical reactions that occurs in organisms that sustains life. So the three main functions of metabolism are converting energy from food into a form that's available to run cellular processes, converting food to building blocks for structural and functional components of the body, so those are proteins, lipids, and nucleic acids and so forth.

And finally, eliminating metabolic wastes. I'll talk about eliminating wastes in a different episode. When we get to the urinary system, we'll discuss that. In this episode, we're going to focus on the first two purposes of metabolism, converting energy from food into forms that are accessible to cells, and then using that energy to build new molecules that are needed for different aspects of cell structure and function and for sustaining the body. As I mentioned, we can categorize metabolic reactions into the breaking down ones, which is catabolic, and the building up ones, which is anabolic. So catabolic reactions typically release energy, so catabolic reactions you can think of as the process of breaking down complex molecules into simpler ones and releasing energy,

and anabolic reactions as the opposite, putting together simple molecules into more complicated forms, then consuming energy. And obviously there needs to be a balance between both of these for bodily functions. So we're going to go through each of these in turn. We'll start with catabolic reactions and move to anabolic processes. So first we'll do breaking down and then we'll do building up. And there are three major macronutrients that will go through and we'll start with carbohydrates, move to lipids, and then talk about proteins. Before we get into the details though, I just want to give a general overview of what we're going to be looking at here. The general idea is that for each of these three, proteins, carbohydrates, and lipids, there are a series of reactions which break down the initial form,

the initial complex form of the molecule, into its simple components. So for proteins, there's amino acids. For carbohydrates, this is glucose. And for lipids, these are mostly fatty acids. So once you've broken down these polymers or complex molecules into simpler components, monomers or other ingredients like the fatty acids, then those in turn can be. either broken down further and converted into energy or possibly modified to turn them into something else that's needed. So for example, one amino acid could be converted into a different type of amino acid. If one amino acid was in excess and the other was in a deficit, then you could convert one to the other. Likewise, different types of carbohydrates can be converted from one another.

There's also conversion between different types of lipids, depending on what the needs of the body are. But in addition to conversion within types of molecules, there's also conversion between the types of molecules, and that's where it gets quite interesting. And to understand this, we're going to introduce the key player in today's podcast, which is acetal coer. Now this we have talked about previously. We discussed it in episode 75 on cellular respiration because it is a key component of the citric acid cycle, or technically it's an input into the citric acid cycle. If you're not familiar with that, then I'd recommend going and listening to Episode 75. I will review it briefly, but I'm expecting that you've kind of heard of the citric acid cycle,

as well as glycolysis, which we will discuss as well. So these are both processes in the breakdown of glucose into energy. Acetylco is a very special molecule. It consists of two carbons bonded to an oxygen atom and a few hydrogens. At least that's the acetyl part to it. Then there's a bunch of other larger components that are bonded to it, which is the co-a part. So there's the acetyl and the co-opart. The acetyl group is very simple, just two carbons and oxygen and a few hydrogens. The co-a part is co-enzyme A. It's a co-enzyme A. It's a co-enzyme A

task. I won't describe the structure of co-enzyme A in detail, but it consists of a few acid residues and a modified adinocene group. So it's sort of large and complex, and it helps to carry around the acetyl group and incorporate it or facilitates its incorporation in different reactions. But the part we kind of want to focus on is the acetyl group because what we're going to do is try to understand how the energy as well as the carbon atoms, which are sort of the two key aspects, the carbon atoms and the energy that they carry around, how that's transmitted and transported through the different types of metabolic reactions that can occur. These reactions are tightly interconnected by many different processes.

not like it's a highway where there's one way to get from one point to another point. It's more like the internet where there's a densely interconnected web of connections where there's many different ways you can convert one molecule to another molecule directly or more indirectly. And there's many different ways that you can enter or exit different metabolic processes by converting A to B to C to D and then to something else. So it's important to understand that we're not talking about purely linear processes, or talking about highly interconnected chain or web of biochemical interactions. But central to many of these is acetylcoa, and particularly these two carbon atoms and the single oxygen atom there. Now, the reason acetal coa is so important and so central is because all of the

major types of macromolecules, proteins, carbohydrates, and lipids can all be converted down to acetylcoa. When I say converted, that doesn't mean that every atom in them becomes part of Acetyl-Coa, but it means that the core carbons and much of their energy can be chopped up and converted down and become the carbons and the energy carried by Acetyl-Coa. So you can think of Acetal-Coa as sort of a universal energy-carrying molecule. You may recall ATP, which is another energy carrying molecule. ATP has a much lower amount of energy compared to acetyl-Coa. A single molecule of acetal-Coa can produce many molecules of ATP, and as such, Acetyl-Coa is not used directly to provide energy for reactions, but you can think of it more as a small-scale energy storage.

And as such, it forms an interface between many different types of metabolic processes. So proteins, carbohydrates, and lipids can all be broken down into acetal coa, which can then be used to produce energy through the citric acid cycle. So that was a brief introduction to acetylcoa and why it's so important. Hopefully, things will become clearer as we go through the different pathways and you see how Acidalkoa fits into all of them. So let's start with carbohydrate catabolism, so breaking down carbohydrate molecules, and I'll briefly, as I promised before, go through glycolysis and the citric acid cycle,

but I won't spend a lot of time on these because we discussed them in detail in episode 75. So glycolysis is a series of interactions which converts glucose, so that's a six-carbon sugar, into pyruvate, which is a three-carbon molecule. So it essentially splits the glucose into two pyruvate molecules, eventually it splits them into two. There's a series of 10 reactions that gets you from glucose to pyruvate. In most organisms, glycolysis occurs in the cytosol, and the process of breaking down glucose to pyruvate releases a large amount of energy, which can be used to form ATP, as well as NADH, which is another energy-carrying molecule. That's a fairly linear series of chemical reactions,

which go from, take you from six carbons down to two units of three carbons. We then have pyruvate, three carbon molecule. Pyruvate is transported into the mitochondria where it is further broken down into acetyl coa, so that's our friend Acetyl coa that we've seen appearing already, which is a two carbon molecule, so it loses one of its carbons. And then acetal coa is fed into the citric acid cycle, which occurs in the mitochondria. The citric acid cycle is a cyclical series of reaction, so glycolysis is linear. The citric acid cycle is a cycle, as the name indicates, the purpose of which essentially is to further break down acetal coa and release all of its energy. The energy in acetalcoa is effectively stored in the carbon-to-carbon bond. The way that

that energy is released by the body is by oxidizing that carbon. So if we remember, oxidation is the loss of electrons, and in this case, it refers to the loss of the electrons by the carbon to oxygen molecules. Oxygen has a very high electronegativity, which means that it has, it has a very strong pulling power for electrons. And so if it's a battle between carbon and oxygen, oxygen is going to win. And it's going to pull those electrons away from the carbon atoms.

Technically, they form bonds with them, but the oxygen has sort of the lion's share of the electrons, if you like. And so we still count it as oxidation. The point of that is that in order to oxidize the carbon atoms and remove their energy, what we do is we react them with oxygen. And so instead of carbon-to-carbon bonds, we break those carbon-to-carbon bonds and form carbon-oxygen bonds in their stead.

So ultimately, what happens? is that your two carbon and one oxygen atom molecule turns into two molecules of CO2. So one carbon and two oxygens and then another carbon and two oxygens. So we're effectively adding more oxygens in and breaking apart carbon-carbon bonds. And that's a general principle, by the way, in much of the catabolic interactions with carbohydrates and lipids and to a lesser extent proteins. When we're extracting energy, what we're doing is breaking carbon-carbon bonds and forming carbon-oxygen bonds in their stead.

Not always, but that's a general process that happens. And that's useful to understand because it helps us to see how the energy is transported in the system. So in terms of the citric acid acid coer enters the cycle and there's a series of conversions of different organic molecules, citrate, isocitrate, ketrogluterate, and so forth. I won't mention them all. But eventually the cycle terminates on the final molecule, which is called oxaloacetate. and then with the addition of a new acetal coa molecule, it regenerates citrate. So the cycle regenerates the same intermediates over and over again. The way it's able to do that is the continual addition of new acetal coa,

which is generated, as we've said, by glycolysis as well as we'll see later as other processes. So citric acid acid cycle extracts the energy from acetal coa, converting it to carbon dioxide, and high-energy intermediates like NADH. So that's the essential process of the citric acid acid acid cycle. And so we see immediately why acetal coa might be so important, because it's the core input ingredient in the citric acid cycle. There are other intermediates there that I mentioned, you know, citrate and succoranate and oxaloacetate and malinate and a whole bunch of others. Malate and a whole bunch of others. But the point is that those are regenerated each time the cycle turns around. You don't need to

keep adding them in. But you do need to keep adding in acetylcoa. So acetylcoa can always be fed into the citric acid cycle and converted into energy and carbon dioxide. So the carbons go into carbon dioxide and the energy from those carbon carbon bonds is extracted and stored as NADH. Importantly, this is true regardless of where the acetalcoa came from. So I just said that acetalcoa comes from glycolysis and that's true if we're talking about carbohydrate metabolism. But as we'll see later, you can get acetalcoa from other sources as well. In fact, it can come from protein metabolism and from lipid metabolism. And whatever the source of it, it can be fed into the citric acid cycle to produce energy. So let's leave the citric acid cycle now. It will still be

relevant because of its role in extracting energy from acetalcoa. But for the moment, let's talk about a couple of other important aspects of carbohydrate metabolism. In particular, something called the pentose phosphate pathway. So this is what's called a parallel metabolic pathway to glycolysis. So in other words, when we're breaking down a glucose molecule, it can proceed via the normal glycolysis pathway or an alternative parallel pathway, the pentose phosphate pathway. The pentose phosphate pathway also generates high-energy intermediate molecules. In this case, NAD pH. That's distinct from NADH, so they're two slightly different versions.

This one is phosphorylated NADPH, and it has slightly different sort of use cases than NADH. But don't worry too much about that here. the real important part of the pentose phosphate pathway is that it allows the conversion of a glucose molecule, which is a six carbon molecule, into a pentose molecule, which is a five carbon sugar. So it converts your six into your five carbon sugars. Now, why is that important? Because nucleotides, which are found in DNA and RNA, so nucleic acids, nucleotides have as part of their, a key part of their structure, five carbon sugars.

The nucleotide bases require those. those five carbon sugars. And so you can't just sort of slot glucose into there. It needs to be first converted into a five carbon sugar, and then you can use those five carbon sugars to synthesize nucleotide bases. And that's what the pentose phosphate pathway is for. It can convert your six carbon sugars into five carbons and thence onto nucleotide biosynthesis. It can also go the other way. You can convert nucleotides five carbon sugars into six carbons by effectively the reverse process, or it's part of the pentose phosphate pathway, but it's like the reverse reaction. So it can extract from or feed back into glycolysis, depending on which way we need to go.

So if the body needs more nucleotides, it will effectively divert some glucose away from glycolysis into the pentose phosphate pathway, turning the six carbons into five carbons and then into nucleotides as needed. Or if there's an excess of nucleotides and we need more sugar, we can convert some of those back in the other direction, feeding them into glycolysis as other intermediates and thence into acetylcoa. By the way, and when I talk about things like feeding into or out of glycolysis, I don't mean that everything's converted directly from glucose to something else. Rather, what happens is various intermediates. The conversion of glucose to pyruvate via glycolysis is a 10-step reaction,

so there's 10 different molecules as part of that process. And many different of those intermediates can be taken away and input into other metabolic processes or other metabolic processes can generate those intermediates, which can then be fed back into glycolysis. You can think of glycolysis or likewise other metabolic pathways as conveyor belts, which progressively perform some operation to modify, you know, whatever the product is that you're producing. But at any stage in that process, you can take out one of the intermediaries and put it on a different convey belt, which will do something different different with it. Or you can grab something from a different conveyabout and put it at the

correct stage in the glycolysis convey about and then it will keep going on. So it's not like these pathways are purely linear that they just go all the way from the start to the end with a single molecule. There's a lot of swapping out with intermediates in the middle, depending on the metabolic needs of the organism. And this all has to be very tightly regulated to control to ensure that we get the right amounts of all of the different molecules that we need at the right place, at the right time. So it's all a very complex process of regulation and balancing. That concludes what I wanted to talk about regarding carbohydrates for the moment, carbohydrate catabolism. Let's now move on to lipid catabolism. So lipids are fatty molecules that consist of

water insoluble substances. And here we're particularly going to focus on the metabolism of triglycerides. So triglyceride is a very common type of lipid, which is found in adipose cell. fat cells and is a way that we store energy long term so effectively when you put on weight much of that is stored as triglycerides we also consume that in food when we eat fatty foods a lot of that's also in the form of triglycerides there are many other types of lipids as well such as steroids which have quite a different structure but we'll just focus on triglycerides for simplicity here so triglycerides as the name indicates consists of three components although it's not three glycerides confusingly it's three fatty acid chains which are long

long carbon chains, which are held together by a glycerol molecule. A glacial molecule is effectively a special type of sugar molecule, or it's a carbohydrate molecule, but we don't need to worry too much about its precise structure here, but the point is triglyceride, three fatty acid chains connected together via glycerol. So this process of metabolizing triglycerides is known as lipolysis. In lipolisis, we split up the triglyceride into glycerol and it's three fatty acid components. We actually pull off one fatty acid at a time to reduce it down from a tri-triacyl glycerol to a dioceylylylyl to a monoacylylylylyl and then just the glycerol.

So we split each of the fatty acid chains off one at a time. So once we've done that, the glycerol molecule can be inputted as an intermediate into glycolysis and then broken down to acetylco as we've discussed. Fatty acids are very different to glycerol or to glucose or other sugar molecules and so they can't be broken down in glycolysis. So what happens to them? Well, first they need to be transported because,

because typically or at least commonly the place where lipolysis occurs isn't always the same as the place where the fatty acids are finally broken down. So they're often transported, potentially through the bloodstream to a different cell. Most cells in the body can metabolize fatty acids, but they need to do so in the mitochondria. So there's a special transport mechanism, which once the fatty acids have reached the cell that they need to be at, transports the fatty acid into the mitochondria, and that's a bit of a process as well, because fatty acids can be rather large. So once we've finally got our single fatty acid chains into the mitochondria of whatever cell is going to process them,

then what happens is that there is a special reaction called beta oxidation, which breaks down the fatty acid into smaller components. So fatty acid chains are fairly long. Often they might have something like 20 carbons in them, or longer, but I think they're typically cut down first. And the way beta oxidation works is it cuts them up progressively in two carbon units at a time. So it chops off two carbons at the tail end and converts them into acetylcoa. As it does so, it also extracts energy, so it produces NATH and FATH2, which act as a store of energy.

Because as I mentioned, energy is effectively stored in carbon-to-carbon bonds, and so when you're cutting those, you can release energy, and you can store that in high-energy intermediates, but the carbons themselves go into acetal coa. So two carbons are chopped off each time, beta oxidation iterates, and you can start off each time, beta oxidation iterates, and you can't and those two carbons go into a unit of acetol coer, leaving a chain that's two carbons shorter than before. And so then the process just iterates over and over until the entire fatty acid has been chopped up. Now, there's a couple of little complexities here. In particular, odd chain fatty acids have a different process, because as I said, beta oxidation chops off two carbons at each time. But what happens if there's an odd number of carbons in your fatty acid chain?

What do you do then? while there's actually a separate series of reactions that deals with those, and odd chain fatty acids actually are chopped out to yield one product being acetylcoa and the other being propanilcoa, which can actually be converted into pyruvate, and we'll see in a moment why this is important. So just bear in mind that there is a bit of a different process for even-numbered and unnumbered fatty acid chains. Now, while beta oxidation can occur, as far as I know in any cell that has a nucleus and mitochondria,

The breakdown of glycerol, so remember that's the sugar-like unit that connects the three fatty acids together to form a triglyceride, the glycerol is broken down only by the liver, and it's there that it's fed into glycolysis and ultimately can either be converted to glucose or it can be broken down into acetalko, depending on which sort of direction the pathway runs. But we'll talk more about that in a moment when we get to anabolism. And we'll also note that many of the reactions that we're about to discuss from now on from now onwards occur, typically in the liver. Let's now move on to talk about protein catabolism, or more specifically amino acid catabolism. So this is the breakdown of amino acids. We've talked in the previous episode about how proteins are denatured and they can be chopped up into their constituent amino acids, but what do we do with those amino acids? Amino acids are quite different in some ways from the two

types of molecules that we've talked about so far, carbohydrates and lipids. The big difference being that amino acids are made up not only of carbon, hydrogen and oxygens, which are the primary and really overwhelming constituents of carbohydrates and lipids. In addition, proteins or amino acids also have nitrogen as a major component. This is extremely important because if you're going to convert to or from amino acids from other types of biomolecules, you need to deal with this hydrogen. So if I'm converting from carbohydrates or from lipids to amino acids, I need to get nitrogen from somewhere. Conversely, if I'm converting from amino acid to carbohydrates or lipids, I need some way of getting rid of this nitrogen. One way that nitrogen is sort of readily found in nature is ammonia,

so NH3, and ammonia is highly toxic to biological systems. So our body has developed a way of handling this extra nitrogen very carefully, because it can't just kind of build up and sit around. It needs to be dealt with. You may know that ammonia is converted compound called urea, which is excreted in the urine. So urination isn't just a way of managing the, urination is not only a way of managing the quantity of water in the body, but it's also a way of managing the relative quantities of nitrogen in the body. So if we have too much, we excrete excess in urine. So balancing nitrogen is very important for this exact reason that it's a crucial component of amino acids and therefore proteins, but not found in carbohydrates or lipids. So what do we do with this extra complication of these

nitrogen's then. How does that work? So what happens when we're breaking down amino acids is that the first step that occurs is removal of these of these nitrogens. And this process is called deamination. And this works with, as with everything else, with special enzymes that allow the amino component, like amino group of an amino acid, the thing that makes it amino acid, to be chopped off and handed over to a different molecule. Enzymes called amino transferases, chop off. Chop off. the amino group and the residual bit of the amino acid, which is now no longer an amino acid because we chopped off the amino group, is called an alpha keto acid. So an alpha keto acids is basically just an amino acid but without the amino bit, right? And so this residual bit, the alpha

keto acids, can then be fed into the citric acid cycle at various points. It depends on the exact amino acid, different amino acids or different alpha keto acids after they've had their amino group chopped off, are fed at different points into the citric acid cycle or two related compounds. I won't describe all of the details of that here because there are 20 different amino acids and they all go in at different points. But the important thing to understand is once we've chopped off that amino group, then what we've got left is essentially a carbohydrate or something very similar to it. And so it's relatively easy to deal with that by feeding it into the citric acid cycle or converting it into something else. So these alpha keto acids, some of them can be used

to synthesize glucose, for example, or they can be used to synthesize other amino acids. But you may be wondering, well, all we've done is transfer this amino group from the initial amino acid to some other molecule. I mean, what happens with it in the long run? What do we ultimately do with it? Well, essentially what happens is that the amino group from the amino acids is transferred by this amino transferase to a molecule of glutamate. So glutamate is an amino acid, but it is the special amino acid, I suppose, you can think of it that way. It's a special amino acid that serves as the repository of excess amino groups. So the version of glutamate without the amino group is alpha-ketagluterate,

because remember it's an alpha-keto acid. And when it picks up the amino group via the amino transferase, it turns into glutamate. When it loses that amino group, it goes back to being alpha-kita-gluturate. So it's kind of a cycle. You can think of the glutamate as people pass. amino acids pass their no longer needed amino groups to it and it passes them off to somewhere else and then it can pick up another one and then pass them off so it's a sort of a central repository or these glutamate molecules serve as a repository

or temporary repository for the to the amine groups before they are passed on to somewhere else and where do they ultimately go well through another through a further series of reactions they're handed off and converted into ammonia which then ultimately, as I said, is converted into urea or sometimes uric acid and excreted in the urine. Or the excess ammonia can also then be used to synthesize amino acids or nucleotides, which also have nitrogen as a component, so they need nitrogen too. So it's a little bit of a complicated process, but essentially, in order for amino acids to be converted to other macromolecules,

you first need to chop off the amino group. the amino group is held by glutamate and then passed off as ammonium to either synthesize further amino acids or to convert into urea, which is excreted in the urine if it's in excess. So the body has to carefully manage the quantity of nitrogen that it has, and this is the process that it uses to do it, this process of deamination. And as I said, once deanimation has occurred, then it's fairly easy to deal with the kind of residues or leftover bits of the amino acids, which are now now.

alpha keto acids, they can just be fed into the citric acid cycle at various points into that. And they can also be used to synthesize lipids, which we'll talk about in a moment. So let's pause here, because we've now gone through all of the major macromolecules, and we've seen how they can all be converted down to acetalcoa. When I say converted, I mean that their energy is extracted, and the carbon backbone or core carbon components, if you like, of the molecules become the two carbons in acetylcoa. In the case of amino acids, that requires first removing the amino groups, converting the amino acids into alpha-keto acids, and then they can be fed into the citric acid-acetyl-coa, or converted directly into acetal-coa.

So some amino acids go straight into the citric-acet-acetyl-cycle, others are converted to acetal-coa, which can then be fed into the citric acid cycle. But either way, acidalcoa is a core component of that. In the case of lipids, we don't have to worry about those extra nitrogens. all we have to do is break off the glycerol. We first remove the glycerol and separate out the three different fatty acids, and then the fatty acids are broken down two carbon units at a time in the process called beta oxidation to form acetal coer. In this case, in the case of at least even numbered lipids,

all of the carbons eventually end up as acetylcoa. That's also the same in the case of carbohydrates. Eventually, every carbon that was present in glucose eventually ends up in acetal coa or in carbon dioxide. Once acetal coa is processed through the citric acid cycle, eventually all of the carbons end up as carbon dioxide. But technically, of the six carbons that are initially present in glucose, four of them will end up in acetal coa, and then two of them, by that point, have already been converted into carbon dioxide. So there's already some terminal oxidation occurring by that point. So we see here all of these three different pathways converging on acetal coa.

It's a little bit more complicated in the case of amino acids, because some of the amino acids, as I said, converted into alpha-quito acids, which are then, fed directly into the citric acid cycle without going via acetylcoa. But for simplicity, we can think of it as the large majority of these metabolic processes converging on acetylcoa. So there's simple molecule of two carbons, an oxygen, and some hydrogens. What can we do with this acetylcoa molecule? Well, as I said, it's kind of a central molecule in metabolism because it can be fed directly into the citric acid cycle and used to extract energy from. But what if I don't want to just extract energy from my acetyl coer. Sometimes that's fine. I need energy. I oxidize the carbon in in acetar coa and I get a lot of energy from it and then I can create my ATP through oxidative

phosphorylation and, you know, have the energy that I need to move my muscles or keep my neurons firing or whatever else that I need to do. But sometimes you actually don't want to convert those carbons into carbon dioxide when effectively, once something's converted to carbon dioxide is ultimately breathed out. So that's lost to the body. eventually. You actually want that carbon to serve as the structural components of macromolecules, like proteins or carbohydrates or lipids. So this is, this moves us from catabolism to talking about anabolism, so building up complex from the simple. So how do we do that? So far we've always been talking about breaking up going from complex to simple, but what if we want to go in the opposite

direction? Well, the simple answer is that many of the reactions that I've been talking about can run in reverse. Many of these reactions can actually run in either direction. and which direction they run in effectively depends on the concentrations. So if there is a reaction that can go in two directions, their reaction will exist in a dynamic equilibrium. Let's imagine that the reactants and the products are on the left side and the right side. If I take some of the molecules on the left-hand side, the reaction will move towards the left, and so I'll get more of the left.

Or conversely, if I remove some of the stuff on the right-hand side, the reaction will move towards the right, and I'll get more of the stuff on the right. It sort of balances out. This is called Le Chalteer's principle, by the way, which we have discussed before if you've listened to some of the chemistry episodes. But the point is the relative concentration of different components is one of the mechanisms. There's many others, but it's one of the mechanisms that allows the body to move reactions around so that we get what we need. In some cases, I might need to break up, catabolize a complex molecule into simpler ones, because I don't have enough of the simpler components, so the reaction kind of naturally moves in that direction.

But other times I may have a relative surplus of the simple ones, but I need some of the complex ones. And so the reaction moves in the opposite direction. And that's actually one of the major processes that allows us to construct the complex molecules from the simpler ingredients, or construct, say, an amino acid from other types of simple molecules, simple ingredients, is because many of these interactions, that these chemical reactions can run in either direction. Now, that's not true for all reactions, or technically. Technically, any chemical reaction can run in both directions to some degree, but it may be so slow in one direction that it essentially never happens.

So for those irreversible reactions, we have to bypass them. So we have to find a new reaction that allows us to go in the opposite direction. And usually the way that you do that is by coupling the reaction that you want to happen with something else that's energenically much more favorable. So the basic idea here is that in a catabolic process, there will be some steps that release a large amount of energy, and those will be very favorable. it's very hard for those to go in the opposite direction because the slope downhill, so to speak, is so steep that you just can't climb back upwards.

So instead what we do is we find a route around. Instead of trying to climb back up the very steep cliff, we just find a different way, which still allows us to get back to the initial place, but through an easier process, that easier process usually looks like coupling the reaction I want with a series of energetically favourable interaction, so this requires energy input. So an example would be if I fall down a cliff, that releases a large amount of energy because of gravitational potential energy, right? I've fallen down a large distance.

If I want to get back up the cliff, I can't just jump straight back up. That's too difficult. It's too energenically costly. In order to get back up, I'll need to find an alternate route around. Now, doing that will consume energy. I'll have to climb up, and I'll be out of breath and so forth. But that energy is consumed in a different way. It's not just the opposite of jumping down the cliff.

So you can think of irreversible reactions as like jumping down a cliff. To get around that, we need to find an alternative route, which still consumes energy, but it's not the direct reverse of the process that got us there. Whereas other interactions are more like steps. You can step up or you can step down, and it can go in either direction. So many of the reactions that we've been talking about are reversible.

They like the steps. Some of them, some of the catabolic reactions, the ones that release large amounts of energy, that's like jumping down a cliff. To get back up, you need to take the longer route around, which consumes energy, but in a different way. So we can understand that in a concrete example by talking about glycolysis.

The direct opposite of glycolysis, a process called gluconeogenesis. So glycolysis produces pyruvate from glucose and extracts energy along the way in a series of 10 reactions. Gluconeogenesis starts with pyruvate and goes back and produces glucose out of it in a series of 10 reactions, but it will also consume energy along the way. So glycolysis releases energy, gluconeogenesis consumes energy. Now, I did say that we go from pyruvate to glucose. Technically pyruvate because it's a three-carbon molecule, we actually need two units of pyruvate to go up to a single molecule of glucose. Bear that in mind, but sometimes I'll just simplify it a bit. But of the 10 reactions that form the pathway of glycolysis, six of them are reversible.

And so those are just the same in glycolysis and in gluconeogenesis. There are four reactions which are not reversible and which need an alternate pathway to go around. And so gluconeogenesis is a process where a few extra enzymes come in to do the pathway around, to get around the irreversible reactions, and they consume energy in the process. But otherwise, apart from that complexity of needing extra enzymes, we can go either from glucose to pyruvate or from pyruvate up to glucose. So if we have extra pyruvate molecules, we can synthesize glucose from that, and then from the glucose, we can synthesize other types of more complex carbohydrates. like glucose is just a monosaccharide, but we can form disaccharides, trisaccharides, and then much more complicated carbohydrates as well. Another process that's directly related to gluconeogenesis is something called glycogenesis.

It sounds very similar, but it's actually quite different. Glycogenesis is the process of producing glycogen, so glycogen synthesis, and glycogen is a very complex molecule, which is essentially just a very large branched chain of glucose molecules added together. And the purpose is for glucose storage. So glycogen is used as a source of glucose when glucose is depleted. So we use it during exercise, for example. And lycogenesis takes place mostly in the liver where excess glucose is sent

and then stored in these large branched polysaccharide chains. So that's kind of the next level above gluconeogenesis. Although it can also occur if you just have glucose that's been digested and is available for storage. It doesn't have to occur after gluconeogenesis. but it's a similar process in the sense that it is a form of carbohydrate anabolism building up. Okay, so that's a bit about how we can build carbohydrates, essentially just by running glycolysis in reverse, so to speak, with a few adjustments to the processes that are irreversible.

But what about if we want to synthesize lipids or proteins for that matter? Well, it's more or less the same. So for lipid anabolism, so the way this works is that it is almost a reverse process of beta oxidation and lipolysis that we talked about. So remember, lipolis is when you break the triglyceride into the glycerol and then the fatty acid tails, and then beta oxidation is the process of gradually breaking apart those fatty acids into two carbon acetalcoa molecules, which can then be fed into the citric acid cycle. In fatty acid synthesis, these two processes more or less run in reverse. Again, there's some cases where different enzymes need to be used in order to overcome

energetically unfavorable processes, but the overall sequence is sort of similar to processes that we've discussed in lipid catabolism, but running backwards. So in particular, acetylcoa is converted into fatty acids through a series of reactions in which the chain gradually grows from the tail. So, again, it's the opposite of beta oxidation. In beta oxidation, we chop up the tail in two carbon units, and they become acetalcoa. In this case, acetalcoa actually adds on to the tail. two units at a time, growing the chain. Once the chain reaches sufficiently long, I think it's usually 16 carbons, then it can undergo further modifications like desaturations, so adding in double bonds, or it can be branched or elongated further. So there's additional enzymes that can do more complicated

things to get the exact right type of fatty acid that we need. And after the fatty acids have been formed, then they can be combined together with glycerol, which can be synthesized out of intermediates from glycolysis, as we discussed further. Fatty acids are combined with with glycerol to form a triglyceride, and then that's stored in an adipose cell, for example. Fatty acid synthesis is, at least sort of conceptually, a reverse of beta-oxidation and lipolisus. There's one little snag here, though, which is that the synthesis of fatty acids, which then go up to make the triglycerides, occurs in the cytoplasm,

which means that we need to have acetylcoa in the cytoplasm to then undergo fatty acid synthesis, adding in those two units of carbon at a time. But acetylchoa doesn't normally exist in the cytoplasm. The end product of glycolysis is pyruvate. That's a three carbon unit, which is then transported into the mitochondria where a carbon dioxide is cleaved off, and what's left is effectively acetal coa, the two carbon unit. So acetalcoa is normally formed inside the mitochondria, but when we're undergoing fatty acid synthesis, it's needed in the cytoplasm. So there's an extra step to get the acetylchola out of the mitochondria and into the cytoplasm. And it's not actually possible to transport it directly.

It actually needs to combine with oxaloacetate to form citric acid, which is transported out, and then separates off again into oxaloacetate and acetylcoa. So it doesn't fundamentally change the process, but it's an extra little step. And this sort of indirect process here where we need to get molecule A in a certain location, but it's not normally found there. And so we have to convert it to something else, transport there's something else, and then convert it back. This is actually quite common. It seems to be a way that the body's evolved to kind of reuse intermediaries without having to evolve, for example, a special transport

protein to transport acetyl coa into the cytoplasm. Instead, it does it indirectly by converting it into citric acid and then transporting the citric acid and then converting it back. So that's something to bear in mind as well that there's quite a lot of these kind of extra steps that are often involved here. So that's how we can synthesize fatty acids from carbohydrates. What about amino acids. Well, it's much the same thing. In fact, we've already kind of discussed this, because in amino acid catabolism, which we've talked about previously, we discussed how the amino group is cleaved off. It's given to alpha-keta-gluterate, which turns into glutamate. The glutamate kind of holds onto it until it can undergo further reactions, which split it off

and form urea or uric acid sometimes, which is then excreted. If we want to synthesize amino acids from carbohydrate predecessors, then all we need to do is, is pull the relevant intermediaries from, often the citric acid cycle or sometimes from acetylacoa or other similar compounds, oxaloacetates another one. So various carbohydrate intermediaries, which are generally part of the Krebs cycle or part of glycolysis, convert them into the relevant alpha-keto acid form and then give them the amino group that they need to turn into an amino acid. So it's really just the exact opposite of the series of reactions that I described before. You form the alpha-keto-acid part of the amino acid, and that can be done

through reactions that act solely on carbohydrates, and then you add in the amino group as needed, using the alpha-quita-gluterate-glutrate-glutamate kind of cycle. You know, the glutamate holds onto the amino acid until it gives it up and it turns into alpha-keto-glutrate, and then alpha-kita-gliterate can pick up an amino group later on and convert back to glutamate. So that whole process essentially just works in reverse to synthesize the amino acids that we need. Okay, so that's all nice and simple, in theory. Of course, there's a lot of complexity that I'm brushing over here in terms of the exact pathways for the different amino acids, because there's 20 different amino acids, and they have different pathways for each of them,

but the overall idea is fairly similar. They can all be synthesized from starting points that begin with intermediaries, either in glycolysis or in the citric acid cycle. But there is a bit of a snag here, because I just said that we can synthesize all amino acids from intermediary. that exist in glycolysis or in the citric acid cycle. That is true, but not for all organisms. In particular, humans can only synthesize 11 of the 20 standard amino acids that we have in our bodies, which means that the other nine are called essential amino acids, meaning that they must be consumed in the diet. Although I believe some of the essential amino acids can be converted

from standard amino acids, but they can't be synthesized from scratch, so to speak. can synthesize some of the essential amino acids from other amino acids, but not from carbohydrate precursors. And the reason for that is essentially, as far as I understand, our ancestors would have possessed some or perhaps all of the enzymes necessary to synthesize all 20 amino acids, but some of those have been lost over evolutionary time because we had a rich enough source of those amino acids in our diet such that we didn't need to synthesize them. And so we lack certain enzymes for that. But other organisms do possess those enzymes. So you can kind of think of it, the biochemical pathways in some sense exist. It's just that we don't always have the

enzymes necessary to facilitate certain types of chemical reactions. So we can't actually synthesize all 20 of them. But the pathways are similar for those we can synthesize and those that we can lack some of the enzymes. So far, we've explained how we can synthesize glucose from pyruvate, so we can go, we can do glycolysis in reverse, so to speak. And we've also said how we can synthesize lipids from acetylcoa, which is basically just beta oxidation in reverse. And we've also explained how we can synthesize at least 11 of the 20 amino acids from carbohydrate precursors plus the nitrogen that needs to be added on. But this raises a question, what about the other possibilities? So we know that we can convert carbohydrate into pretty

much anything, except for those essential amino acids, at least in humans. But can we convert lipids to carbohydrates? Or what about amino acids to carbohydrates? So can we go in reverse? We can go from carbohydrates to amino acids, at least the non-essential ones, and to lipids, but what about the reverse? Is that possible? And the answer is mostly no. So lipids, particularly fatty acids we've been talking about, and amino acids, can all be

converted into acetylcoa, or some of the amino acids go directly into the citric acid cycle, but we won't get into the details of that. Close enough. So more or less everything can be converted to acetylcoa. That's this central metabolic molecule here, the two carbons and. one oxygen. But, and this is very important, you can't, at least humans can't, some other organisms can, but humans cannot convert acetylcholae back to pyruvate. We can convert pyruvate back to glucose, so that's what gluconeogenesis does. Remember pyruvate being the end product of glycolysis.

But once we move pyruvate into the mitochondria and convert it into acetylcoa plus some CO2, At that point, we can't go backwards anymore. So once the pyruvate has been transported into the mitochondrium and converted into acetal coa, then at that point the reaction is irreversible. We can't go backwards. We lack the enzymes to do that. There are metabolic ways to achieve that, but humans lack those enzymes. What it would require is transporting acetal coa itself back out of the mitochondria into the cytoplasm

and then combining it together with additional carbons. And the underlying issue here is that humans do not have the enzymes to allow us, so to speak, put acetylcoa back together, or specifically the two carbons and the oxygen, the acetyl part of acetal coa. We lack the enzymes to put that back together into a longer carbohydrate, which could then be used to convert back to glucose. So we can convert pyruvate the three carbon molecule back to glucose, but not acetylchua. Once it gets to that two carbon point, we don't have the enzymes that allow us to do that. There are some organisms that can do this, but humans are not able to. What this means is that any of the macromolecules that are converted into acetyl-coa, which includes lipids, as well as most of the amino acids, as well as many of the amino acids,

cannot be converted into glucose. They're converted into acetal coa, but because that's, so to speak, too far down the road, it's too far down the process of breaking down glucose. They can't go backwards. They've sort of, so-to-beak, jumped off a very high cliff, and we don't have the enzymes to get us back to that level. So in humans, there is no net conversion of lipids into glucose. Convert the lipids into acetylcoa and extract the energy there,

but you can't get them back into glucose. For amino acids, the story is a little bit more complicated. So there are two different types of amino acids. Well, actually, we just saw this essential and non-essential, but that relates to whether we can synthesize them from scratch or not. There's a different classification of amino acids into glucogenic and ketogenic amino acids. The majority of the amino acids are glucogenic, which means that they can actually be converted back into glucose. Some of them are ketogenic, which means they can't be converted back into

glucose. You might wonder why is that. The difference is whether or not the amino acids, or more specifically the alpha-keto acids, remember the versions of them that have the amino group chopped off, whether or not those feed directly into acetyl-coa, or whether they feed into some other point of the citric acid cycle or pyruvate. If the amino acids are converted into pyruvate or one of the intermediates in the citric acid cycle, in all of those cases, these compounds are carbohydrates that are longer than two carbons long, which means that they're in a sense long enough for us to convert back into glucose. So pyruvate can be exported back out of the mitochondria, and the other intermediaries in the citric acid cycle can be converted one

into another because it's a cycle, right, and eventually reaching oxaloacetate, which can be exported into the cytoplasm and converted into glucose. So all of the glucogenic amino acids, the ones that feed into either pyruvate or the citric acid cycle directly, they are still long enough, once we've transformed them as needed, there's still enough carbons there for us to convert them back to glucose. But the ketogenic amino acids are converted straight to acetyl-coa, and those, as we've said, once they've been converted to acetal coa, there's, they're too small. I mean, it's not strictly a size issue, but you can think of it that way, that acetal coa is sort of too smaller. We don't have the enzymes to put those back together to make glucose again. As I said, other

organisms can do that. So it's not chemically impossible. It's just we're not able to. The ketogenic amino acids, the ones that go straight to acetylcoa, those cannot be converted back to glucose. They can be fed through the citric acid cycle and produce energy, but we can't use them as the building blocks for glucose. But glucogenic amino acids can because they are fed straight into the citric acid cycle or to pyruvate. And in either of those cases, they're still long enough to convert them back into glucose. So the overall picture here is a little bit complicated. Carbohydrates can be broken down into glucose, which then can be fed through glycolysis to form pyruvate, and that can then be fed back up into the gluconeogenesis pathway

to produce glucose, and then from there we can synthesize glycogen or other complex carbohydrates. So carbohydrates, you can go back either way. But once you pass from pyruvate to acetyl-Coa, which also corresponds to transporting pyruvate into the mitochondria, at that point, you can't go backwards. It's like a checkpoint in a game when you reach a new air, and you can't go back through the door because you found it's locked behind you. It's, you've gone too far, you can't go backwards. Acetylchlechua can be used to synthesize lipids, but it can't be used to synthesize carbohydrates. Amino acids are a bit complicated because there's two groups of them. There's two different groupings of them. There's those that we can synthesize and those that we can't,

and then there's those that can be used to synthesize glucose, the glucogenic ones, and there's those that go straight to acetalcoa and therefore can't. So this setup of metabolism has important implications for diets, or at least for certain types of diets, which we'll talk about in the episode we do on nutrition. But it turns out that if our body can't get enough glucose through carbohydrate metabolism, it has to resort to unusual mechanisms, because if your diet consists mostly of proteins and lipids, you won't actually have the ability to synthesize enough glucose for your body's needs. And so the question is, well, what does the body do then? Because it can't convert lipids and it can't convert all amino acids into glucose. So what happens

then. Well, that's something we'll talk about in the episode on nutrition, so stay tuned for that. That concludes most of what I wanted to talk about today, but before finishing, let's do a final review of the key metabolic processes that we've talked about, so hopefully everything kind of makes sense together. Remember that we've talked about two different types of metabolic reactions. There's catabolism, which is breaking down bigger, more complex molecules into smaller, simpler components and then there's anabalism which is building more complex units from the the simple components so breaking down and building up we discussed how there's three major types of macro molecules that we're interested in proteins carbohydrates and lipids and that all three of those go through a

series of reactions which reduce them down to acetylcoa which is a two carbon and one oxygen molecule which still has a fair bit of energy left in it and is fed into the citric acid cycle or the Krebs cycle to extract all of its energy and convert the carbons into carbon dioxide and store the energy in high energy intermediates like NADH, which ultimately will be converted to ATP. So that's ultimately kind of where everything goes in the catabolic cycles. It all goes down to acetalcoa. There's a slight complexity of there because some of the amino acids don't go directly to acetylcoa. Some of them go to pyruvate first and then to acetalcoa, and some of them go straight into the citric acid cycle. But other than that, everything goes

straight down to acetylcoa. In the case of carbohydrates, they get to acetylcoa through glycolysis, then pyruvate, which is imported into the mitochondria, converts into acetalcoa, which then goes into the citric acid cycle. In the case of proteins, the proteins are unfolded and then chopped up into amino acids. And then those amino acids have their amino groups stripped off them by the deamination reaction we talked about with alpha-keterate and glutamate as the kind of storage mechanism for those amino groups before they're ultimately converters. via the urea cycle into urea, and the residual components of the amino acids, basically the amino acid minus the amino bit, are called alpha-keto acids, and those are the bits

that are fed into either the citric acid cycle or to acetylcoa or sometimes pyruvate. The carbon bits of those amino acids all end up in effectively the same place, which is the citric acid cycle. And finally, lipids, first we have the process of lipolisis, where the glycerol is removed, and the fatty acids are separated, and then the fatty acids are chopped up two carbon units at a time in a process called beta oxidation, and the results are two carbon molecules, which are, lo and behold, acetylcoa, and so that all feeds into the acetal coa, which can then go into the citric acid cycle. So pretty much everything ends up at acetalcoa in the catabolic reactions. In the anabolic

reactions, many of these are the reverse of the catabolic reactions, except some steps, those that correspond to jumping down a very steep energy cliff, require us to take an alternate root back up, which consumes energy but allows us to get back to the state that we previously were, but it will require different enzymes and different reactions because you can't jump up an energy cliff in the same way you can jump down it, so to speak, it's too difficult. So that's generally how the anabolic processes work. It's catabolic in reverse plus some detours. And the overall result is that, for example, in order to produce lipids from acetalcoa, we just run beta oxidation in reverse, more or less. There are a few modifications, but that's essentially the idea. And likewise,

synthesizing amino acids, we run many of these same reactions just in reverse that are used to catabolize them in the first place. We just take the intermediaries from the citric acid cycle, or sometimes acetylacor, or sometimes lactic acid, or sometimes pyruvate, and we add on amino groups, and we form the relevant amino acids, although bearing in mind that humans cannot synthesize all of the amino acids we need. Some of them must be taken in via the diet, because we've lost the relevant enzymes. Also, in order to produce more complex carbohydrates, we can run glycolysis in reverse, a process called gluconeogenesis, and that allows us to produce glucose from the precursor of pyruvate. The main linkage point where all of these processes come together is acetalcoa,

and that also serves as a barrier and a limitation on what things can be converted into other things. So carbohydrates can be converted into anything else, again, except for the essential amino acids, and that's because carbohydrates can be converted to acetylcoa, which it can then be diverted into lipids or into the relevant amino acids. But, Lipids cannot be converted into carbohydrates because lipids are converted to acetylcoa and once we're at acetylcoa We lack the enzymes to put those two carbon units back together into anything bigger Likewise only some of the amino acids can be converted back to glucose Because some of them are converted straight to acetylcoa and those which are again, there's no way to go back to something bigger

So those are the ketogenic amino acids which aren't able to be converted back into glucose but the rest of But the rest of them, the glucogenic amino acids, are converted into either pyruvate or one of the intermediates of the citric acid cycle, which are still big enough. There's still longer molecules, and so those can be converted back into glucose, sometimes after being exported from mitochondria back into the cytoplasm. So in summary, most of the key nutrients that we consume can be converted one into another. Though there are some limitations. We can't synthesize all of the amino acids we need, and some of the amino acids cannot be converted back into glucose. and an important limitation is that we cannot synthesize glucose from lipids. Lipids can go to acetal coa and be consumed as fuel, but they can't be used to form carbohydrates.

And this has some important implications for diet and nutrition, as we'll talk about in a future episode. Another thing that we will discuss in a future episode is how the amino groups that are removed from amino acids are converted into urea and how that is ultimately removed from the body, because that's an important aspect of metabolism as well, but we'll talk about that in a later episode. And just a last reminder, I have talked a lot about high energy intermediate molecules like NADH or NADPH. Those are ultimately processed in oxidative phosphorylation, which occurs in their mitochondria as well. And in that process, the energy is gradually extracted from them to produce adenosine triphosphate or ATP, which is the kind of final energy carrying molecule in cells.

So don't forget that although I've just talked about feeding things into the citric acid cycle, eventually that product of all of this when we're extracting energy is going to be ATP, and that's used to then power reactions in the cell. I haven't talked too much about oxidative phosphorylation here, because that's the common endpoint of all of these reactions. It doesn't really matter at that point where the energy came from. It's all converted into ATP at the end of the day. So hopefully you found this episode interesting.

If so, you might consider giving the podcast a favorable review on iTunes or Spotify or whatever other aggregator you use. You can also send me an email, giving your feedback or asking for or giving recommendations or making other suggestions. My email is FODs12 at gmail.com. That's FOTES12 at gmail.com. I thought it might also be nice to talk about some of the upcoming episodes that are in various stages of preparation.

So I mentioned that there will be one on diet and nutrition, which will be coming out soon-ish. Some of the other episodes that I'm working on are one on climate change. So that has been one I've been wanting to do for many years. and I've finally got around to doing the relevant reading there. So that's in progress. Look forward to that one. Should be quite interesting. I also plan to do an episode soon on Black Holes as a follow-up to the introduction to general relativity in episode 136.

So that one should be fun and interesting as well. And something a little bit different. I'm planning to do an episode on cryptography and the blockchain, cryptocurrencies and all that, which I've been reading a bit more about recently and I think would make quite an interesting episode. stay tuned for that one as well. So there's a bit of a sneak peek as to what's coming up over the next, well, probably six months or so. And just to find a reminder that if you would like to support this show financially, you can make a one-off donation to my email address via PayPal, or you can become a Patreon supporter on my Patreon, The Science of Everything podcast.

I very much appreciate all of my generous donors who helped to fund the ongoing production of the show. Thanks very much for listening. Take care and I'll talk to you next time. You know,