Let's turn our attention to metabolic regulation. Now, it turns out there's kind of a sweet spot in substrate concentration. It tends to be close to the Km (Michaelis constant) of that substrate's respective enzyme. And this essentially ensures that enzyme activity is going to noticeably fluctuate with small changes in substrate concentration. Just the slope of the line, tangential to the Michaelis-Menten curve and you're basically at your most elastic slope, your greatest elasticity coefficient in this range of 0 to Km. So, if you were to place a line tangent to this curve at some point, that's your elasticity coefficient at that particular point is the slope of this line. You don't really need to worry too much about the details. It's just the main concept that's important here. That's basically that your cells want to work with substrate concentrations that are going to cause noticeable fluctuations in enzyme activity and the reason for this is regulation, right? So ADP and ATP, for example, their concentration doesn't fluctuate too much in the cell. AMP on the other hand, AMP's concentration can fluctuate pretty drastically. So, AMP, for example, is going to be one of the most important indicators of energy status in a cell because its substrate concentration is going to have a big fluctuation. Now, AMP-activated protein kinase, that's going to basically, you know, be something that detects this change in AMP concentration and actually has a really wide range of effects on metabolism. Just one example, for example, the heart happens to be the only organ that can survive solely off fatty acid oxidation. Now, the enzymes that tend to be regulated are the enzymes that are not readily reversible, right? The readily reversible enzymes are generally not regulated because these enzymes drive reactions. These enzymes that are not readily reversible are the ones that really drive these metabolic pathways. So, they're the more important points to regulate because if you shut them off, you can shut off the whole pathway really easily, right? So, with that in mind, let's turn our attention to glycolysis and gluconeogenesis. 2 metabolic pathways that require very tight control because if you don't, well, you can wind up with futile cycles, where you just are expending energy and constantly just taking the product of one reaction and flipping it back to the substrate and then flipping it back to the product and it just wastes energy for the cell. You're spinning your wheels. So, we want to avoid that and the way we avoid that is by very tightly regulating these two cycles. So, hexokinase 1, right? The first enzyme of glycolysis is actually the most influential enzyme on the rate of glycolysis. It's followed by phosphofructokinase 1 which has a noticeable impact on the rate of glycolysis but hexokinase 1 has a really significant influence. It is far and away the most influential enzyme on the rate of glycolysis. And glucose 6-phosphate, the product of hexokinase's reaction with glucose actually inhibits hexokinase. So, again, we're seeing that pattern where the product of the reaction serves as an inhibitor for the enzyme that carries out that reaction. Now, there's another enzyme that we need to talk about, and that is glucokinase, also is known as Hexokinase form. It is an isozymes form of hexokinase 1. Your book might use the term might prefer the term hexokinase 4. I am just used to calling it glucokinase, just easier to say. So I'm going to call it Glucokinase in these videos but I'm always just talking about hexokinase 4. They're the same enzyme. So this enzyme is actually only in liver cells and it's stored in the nucleus of liver cells and it's called out when it's needed and what's cool about it is it has a much higher Km than hexokinase 1. So glucose causes glucokinase. Glucose stimulates glucokinase to move from the nucleus to the cytoplasm. Glucokinase is going to do the same thing that hexokinase does, right? It's going to add a phosphate group on the glucose to make glucose 6-phosphate. What's cool is glucokinase is not inhibited by glucose 6-phosphate. So what's important about that is basically it means that, in the liver cells anyway, this is only present in liver cells. So not in other parts of the body but in liver cells. The supply of glucose is what determines the rate of production of glucose 6-phosphate. Not the energy demand. Not the demand for glucose but rather the supply of glucose is used to gauge that reaction rate. So basically, liver cells can continue to convert glucose to glucose 6-phosphate even when they have crazy high amounts of glucose 6-phosphate. So hexokinase will shut down, right? You know, if glucose 6-phosphate gets to be too high in concentration, it's going to inhibit hexokinase but not glucokinase. So glucokinase is going to keep producing it and this is important because the liver's main job in the body is to really control the glucose supply. It needs to make sure that it can deliver glucose to all the cells of the body. So, it is very important that there is this relationship in the liver where, basically the production of glucose 6-phosphate is determined by the supply of glucose rather than demand for glucose like all the other cells of the body. So that's what this figure here is trying to show. We have our reaction rate, right? Our reaction velocity and you can see that the Km of hexokinase is way lower than that of glucokinase, right? Glucokinase Km is like over here somewhere in hexokinase like I can't even really draw it in that well. So Km of glucokinase is way higher. That's what this figure is trying to show. So hexokinase is going to reach maximum velocity at much lower concentrations.
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