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Gluconeogenesis: unique reactions

Video transcript
- [Voiceover] Alright, so in the previous study we talked about the big picture of gluconeogenesis, or the creation of new glucose and I brought up this diagram of glycolysis and I said to you essentially glycolysis, which starts off with glucose that you can see in the kind of top middle left and it's broken down oxidized into pyruvate the molecule kind of in the top left there, I said that this pathway is essentially the reverse of gluconeogensis, that is to say we wanna start off with pyruvate and we wanna essentially reverse the pathways to produce glucose, which we can pump into our blood in times of fasting. But notably, in this video I wanna get a little bit more detail oriented and talk about kind of three unique reactions to gluconeogenesis that overcome the three irreversible steps indicated by the orange arrows in this diagram of glycolysis. So let's talk about the first roadblock that we need to overcome, which is in the conversion of pyruvate to phosphoenolpyruvate. So remember it can't just use pyruvate kinase to reverse this reaction. So it actually uses an entirely separate set of enzymes and pathway to get to phosphoenolpyruvate and the first step is the conversion of pyruvate to a molecule called oxaloacetate, which is abbreviated usually as OAA and this is a molecule that you will meet when you learn about the Krebs cycle and it's an intermediate in one of those steps and notably this is why amino acids are able to be used to produce glucose because amino acids once they're broken down can be actually converted to oxaloacetate and from there of course they can continue down this pathway. Notably, another precursor molecule that I mentioned before, lactate, can be interchangeably produced from pyruvate or going from lactate to pyruvate. So that's another way that that metabolite contributes to gluconeogenesis. But back to oxaloacetate. So once this is produced, oxaloacetate can then be catalyzed to form phosphoenolpyruvate using another enzyme. And the names of these enzymes aren't terribly important but I will mention them because they do sometimes come up. So the first step involves an enzyme called pyruvate carboxylase. And notably, kind of one way that I remember this is because oxaloacetate is actually a four-carbon molecule. So pyruvate recall is a three-carbon molecule so this carboxylase enzyme is essentially adding another carbon through a carboxy group to this oxaloacetate molecule and then this oxaloacetate molecule is converted back to a three-carbon intermediate by an enzyme called PEP, which stands for phosphoenolpyruvate for short PEP, is converted by PEP carboxykinase. And of course kinase involves the phosphorylation of something and so we know actually intuitively that because gluconeogenesis is an anabolic process, we're building something up, it requires energy and energy comes usually in the form of ATP and it turns out that this first step of the reaction does involve ATP so I'm gonna say plus ATP and this second step where this kinase is involved also involves energy in the form of GTP, which is pretty much the equivalent of ATP but of course we have this G which is just guanine, a different nucleotide base but of course we know the energy is derived from these phosphate groups so essentially we can think of these things as being the same. Alright, so one roadblock down and two left to go. So once we have our phosphoenolpyruvate we're good to go, we shuttle down this pathway until we hit our next roadblock which is in the conversion of fructose one, six-bisphosphate to fructose six-phosphate. So the way our body does this is it actually uses a different enzyme. So normally phosphofructokinase is used to convert fructose six-phosphate to fructose one, six-bisphosphate and instead in gluconeogenesis, going the opposite direction the body uses an enzyme called fructose one, six, so we're talking about the same molecule here, but instead of kinase, we're using a biphosphotase. It's kind of a mouthful but just recognize that a phosphotase is the exact opposite of a kinase. So whereas kinases involve phosphorylation usually using phosphate groups from molecules like ATP, a phosphatase takes these phosphates away. So naturally it makes sense that if a kinase is used in going from fructose six-phosphate to fructose one, six-bisphosphate we'd wanna take a phosphate group off going the opposite direction. So that's exactly what we do. Now one kind of point of confusion that kind of I had when I was learning this was, you know we always learn that the enzyme of a reaction can't really change whether a reaction is irreversible or not. So I wanna point out that it's not just an enzyme that we're switching out and going and kind of circumventing this irreversible reaction because that really wouldn't do anything. If a reaction has a negative delta G value it will always have a negative delta G value and changing the enzyme won't change the delta G value. Remember kinetics and thermodynamics are separate entities. And so I wanna point out to you that it's really this entire reaction pathway that's changing. And notably notice remember that ATP in this step is hydrolyzed to ADP and this reaction is coupled normally to the phosphorylation with the enzyme phosphofructokinase. But this hydrolysis of ATP is absent in gluconeogenesis. So we can essentially think about this switch in enzyme as really encompassing a larger change in the entire pathway going from fructose one, six-bisphosphate to fructose six-phosphate. So I hope that's clear. So now that we have gotten past this second roadblock we continue down until we hit our final and last roadblock in going from glucose six-phosphate to glucose. And again, essentially just like we did for our previous reaction our body has come up with a different reaction pathway involving a different enzyme. So normally you remember hexokinase is used in converting glucose to glucose six-phosphate but our body uses a different enzyme. In this case I'm gonna write it out here. It uses the enzyme glucose-six and remember if we used a kinase we have to be using a, exactly, we're using a phosphatase. So glucose-six-phosphatase, which will remove this phosphate group from the glucose to remove this phosphate group from the glucose its phosphate to form the glucose. Now just as a fun kind of intriguing fact, it turns out that some people are actually missing this enzyme glucose-six-phosphatase. So can you imagine what would happen if they're missing this enzyme? And indeed without this enzyme we can't produce glucose so it's kind of sad right? Because those individuals can perform all of these reactions leading up to glucose-six-phosphate but it can't ever produce glucose. And what's actually even more interesting about this enzyme is this enzyme is also used in the breakdown of glycogen. Which if you remember we mentioned earlier as that polymer of glucose that's used kind of as a first-line dumping mechanism for glucose into the blood during our fasting state. So not only are these individuals unable to produce glucose using gluconeogenesis but they're also unable to break down their glycogen. Which means that they're severely hypoglycemic. So without this enzyme, gotta have an arrow and cross it out, without this enzyme individuals are hypo or low in glucose and of course this is a very life-threatening condition because our body needs glucose to survive. Alright, so just kind of as one final word I wanna say that when I was first learning about gluconeogenesis and glycolysis I wanted to memorize all of the names of all the molecules and all the enzymes and speaking of enzymes I think I spelled one wrong here, this is supposed to be one, six-bisphosphate, but despite that really I guess the key point I wanna say is that you know these names can be important when we're talking about specific diseases like this deficiency of glucose-six-phosphatase but conceptually it's I think enough to realize at this point that gluconeogenesis and glycolysis are essentially opposites minus these three irreversible steps for which our body has created three unique reaction pathways for which gluconeogenesis can occur. So that's kind of the big, big takeaway from this video.