Even better than my textbooks.. In the last step where phosphoenol pyruvate is converted to pyruvic acid! Where is the Hydrogen atom coming from? Thank you very much, I thought triose phosphate was the main intermediate which continues glycolysis. Thanks fr clearing this dilemma.
Honestly, I can feel how you really want to let the readers understand the concepts in a friendly language to help them keep up with every step. Thanks a lot! Honestly this is amazing.
Thanks alot. In simple words most of the food items contains glucose or its combined forms like sucrose. To be honest before I found this, I suffered a lot on how to understand this thing. Thank You so much. Do you have the same excelently written Krebs Cycle as you have done in the glycolisis cycle?. You have done an outstanding job. Well written notes. Please mark on structure how the six carbon breaks into 3carbons compounds in step 4.
Kindly describe the process in the mitochondria as well. Also please do the same for gluconeogenesis, glycogenesis and glucogenolysis.
I like the way all the steps have been outlined for easy understanding. I found this very helpful. With some level of effort, I now have all the 10 steps on my finger tips for my biochemistry class.
Thank you so much for sharing. I have a doubt,from where does the phosphate in step 6 come from? It just says that phosphate is added. Anyway the answer was useful,Thank you! The role is clear that it shields the highly reactive negative charge phosphate from reacting with ADP molecules but how does the cofactor and enzyme distinguish between ADP and ATP when both have a difference of one phosphate group.
But Pyruvate has 4 H. Does 2H reenter PEP. Am happy to get this note thanks sir Ghana Kumasi polytechnic please I want to know this since there were two molecules of PEP,was two molecules of pyruvate compound formed?
Archea can srvive in harsh environmenatl conditions because of its specific Cell wall and cell membrane compositions. Thanx for the illustration. I have a query regarding structure of glucose. You have placed hydroxyl group in structure of glucose down in first carbon. Same is the case in second carbon, but you have placed hydroxyl group in third carbon up. Does it have to be so specific? I mean, cant we place hydroxyl group in first carbon up or hydroxyl group in third carbon down? I have save same question regarding placement of hydroxyl group in 3 carbon structures ie left or right.
In contrast, intracellular calcium induces mitochondrial swelling and aging. How does this relate to Diabetes? Can you connect the dot for the general public? I am glad to see that you included the delta-G values in the principal figure.
These are very important for helping students appreciate how the flow operates in these pathways, but the values are often left out of figures for the sake of simplicity. At the same time, I would recommend adding arrows for the reverse reactions, perhaps with length indicating the free energy vector, to further emphasize and distinguish the freely reversible from essentially irreversible reactions. It might also help to add both the free energy values and the reverse arrows to the single-step figures, as well.
Overall, this is a pretty good study review. Save my name and email in this browser for the next time I comment. Details: Here, the glucose ring is phosphorylated. Step 2: Phosphoglucose Isomerase The second reaction of glycolysis is the rearrangement of glucose 6-phosphate G6P into fructose 6-phosphate F6P by glucose phosphate isomerase Phosphoglucose Isomerase.
Details: The second step of glycolysis involves the conversion of glucosephosphate to fructosephosphate F6P. Step 3: Phosphofructokinase Phosphofructokinase, with magnesium as a cofactor, changes fructose 6-phosphate into fructose 1,6-bisphosphate.
Details: In the third step of glycolysis, fructosephosphate is converted to fructose- 1,6- bi sphosphate FBP. Step 4: Aldolase The enzyme Aldolase splits fructose 1, 6-bisphosphate into two sugars that are isomers of each other.
Details: This step utilizes the enzyme aldolase, which catalyzes the cleavage of FBP to yield two 3-carbon molecules. Step 5: Triosephosphate isomerase The enzyme triosephosphate isomerase rapidly inter- converts the molecules dihydroxyacetone phosphate DHAP and glyceraldehyde 3-phosphate GAP.
Details: GAP is the only molecule that continues in the glycolytic pathway. Similar to the reaction that occurs in step 1 of glycolysis, a second molecule of ATP provides the phosphate group that is added on to the F6P molecule. SparkTeach Teacher's Handbook. Summary Stage 1: Glucose Breakdown. Page 1 Page 2. Step 1: Hexokinase In the first step of glycolysis, the glucose ring is phosphorylated.
Step 2: Phosphoglucose Isomerase The second step of glycolysis involves the conversion of glucosephosphate to fructosephosphate F6P. Step 3: Phosphofructokinase In the third step of glycolysis, fructosephosphate is converted to fructose- 1,6- bi sphosphate FBP. Take a Study Break.
Once in the venous circulation, monosaccharides reach the liver through the portal vein; this organ is the main site where they are metabolized. Regarding the phosphorolytic breakdown of starch and endogenous glycogen refer to the corresponding articles. Under physiological conditions, the liver removes much of the ingested fructose from the bloodstream before it can reach extrahepatic tissues. The hepatic pathway for the conversion of the monosaccharide to intermediates of glycolysis consists of several steps.
In the first step fructose is phosphorylated to fructose 1-phosphate at the expense of one ATP. This reaction is catalyzed by fructokinase EC 2. As for glucose, fructose phosphorylation traps the molecule inside the cell. In the second step fructose 1-phosphate aldolase catalyzes the hydrolysis , an aldol cleavage, of fructose 1-phosphate to dihydroxyacetone phosphate and glyceraldehyde.
Dihydroxyacetone phosphate is an intermediate of the glycolytic pathway and, after conversion to glyceraldehyde 3-phosphate, may flow through the pathway. Conversely, glyceraldehyde is not an intermediate of the glycolysis, and is phosphorylated to glyceraldehyde 3-phosphate at the expense of one ATP.
The reaction is catalyzed by triose kinase EC 2. In hepatocytes, therefore, a molecule of fructose is converted to two molecules of glyceraldehyde 3-phosphate , at the expense of two ATP, as for glucose. In extrahepatic sites , such as skeletal muscle, kidney or adipose tissue, fructokinase is not present, and fructose enters the glycolytic pathway as fructose 6-phosphate.
In fact, as previously seen, hexokinase can catalyzes the phosphorylation of fructose at C However, the affinity of the enzyme for fructose is about 20 times lower than for glucose, so in the hepatocyte, where glucose is much more abundant than fructose, or in the skeletal muscle under anaerobic conditions, that is, when glucose is the preferred fuel, little amounts of fructose 6-phosphate are formed.
Conversely, in adipose tissue , fructose is more abundant than glucose, so that its phosphorylation by hexokinase is not competitively inhibited to a significant extent by glucose. In this tissue, therefore, fructose 6-phosphate synthesis is the entry point into glycolysis for the monosaccharide. With regard to the metabolic effects of fructose, it is important to underline that in the liver the monosaccharide, being phosphorylated at C-1, enters glycolysis at triose phosphate level, thus downstream to the reaction catalyzed by PFK-1, an enzyme that plays a key role in the regulation of the flow of carbon through this metabolic pathway.
Conversely, when fructose is phosphorylated at C-6, it enters the glycolytic pathway upstream of PFK Fructose is the entry point into glycolysis for sorbitol , a sugar present in many fruits and vegetables, and used as a sweetener and stabilizer, too. In the liver, sorbitol dehydrogenase EC 1.
Galactose , for the most part derived from intestinal digestion of the lactose , once in the liver is converted, via the Leloir pathway, to glucose 1-phosphate. For a more in-depth discussion of the Leloir pathway, see the article on galactose. The metabolic fate of glucose 1-phosphate depends on the energy status of the cell.
Under conditions promoting glucose storage, glucose 1-phosphate can be channeled to glycogen synthesis. Conversely, under conditions that favor the use of glucose as fuel, glucose 1-phosphate is isomerized to glucose 6-phosphate in the reversible reaction catalyzed by phosphoglucomutase EC 5.
In turn, glucose 6-phosphate can be channeled to glycolysis and be used for energy production, or dephosphorylated to glucose in the reaction catalyzed by glucose 6-phosphatase, and then released into the bloodstream. Mannose is present in various dietary polysaccharides, glycolipids and glycoproteins. In the intestine, it is released from these molecules, absorbed, and, once reached the liver, is phosphorylated at C-6 to form mannose 6-phosphate, in the reaction catalyzed by hexokinase.
Mannose 6-phosphate is then isomerized to fructose 6-phosphate in the reaction catalyzed by mannose 6-phosphate isomerase EC 5. The flow of carbon through the glycolytic pathway is regulated in response to metabolic conditions, both inside and outside the cell, essentially to meet two needs: the production of ATP and the supply of precursors for biosynthetic reactions.
And in the liver, to avoid wasting energy, glycolysis and gluconeogenesis are reciprocally regulated so that when one pathway is active, the other slows down. As explained in the article on gluconeogenesis, during evolution this was achieved by selecting different enzymes to catalyze the essentially irreversible reactions of the two pathways, whose activity are regulated separately. Indeed, if these reactions proceeded simultaneously at high speed, they would create a futile cycle or substrate cycle.
A such fine regulation could not be achieved if a single enzyme operates in both directions. The control of the glycolytic pathway involves essentially the reactions catalyzed by hexokinase , PFK-1 , and pyruvate kinase , whose activity is regulated through:. Note: The main regulatory enzymes of gluconeogenesis are pyruvate carboxylase EC 6. Hexokinase IV, also known as glucokinase EC 2. In the liver it catalyzes, with glucose 6-phosphatase, the substrate cycle between glucose and glucose 6-phosphate.
Glucokinase differs from the other hexokinase isozymes in kinetic and regulatory properties. Note: Isoenzymes or isozymes are different proteins that catalyze the same reaction, and that generally differ in kinetic and regulatory properties, subcellular distribution, or in the cofactors used. They may be present in the same species, in the same tissue or even in the same cell. Hexokinase I and II have a K m for glucose of 0.
Therefore these isoenzymes work very efficiently at normal blood glucose levels, mM. Conversely, glucokinase has a high K m for glucose, approximately 10 mM ; this means that the enzyme works efficiently only when blood glucose concentration is high, for example after a meal rich in carbohydrates with a high glycemic index.
Hexokinases I-III are allosterically inhibited by glucose 6-phosphate , the product of their reaction. This ensures that glucose 6-phosphate does not accumulate in the cytosol when glucose is not needed for energy, for glycogen synthesis, for the pentose phosphate pathway, or as a source of precursors for biosynthetic pathways, leaving, at the same time, the monosaccharide in the blood, available for other organs and tissues.
For example, when PFK-1 is inhibited, fructose 6-phosphate accumulates and then, due to phosphoglucose isomerase reaction, glucose 6-phosphate accumulates. In skeletal muscle , the activity of hexokinase I and II is coordinated with that of GLUT4 , a low K m glucose transporter 5mM , whose translocation to the plasma membrane is induced by both insulin and physical activity. The combined action of GLUT4 on plasma membrane and hexokinase in the cytosol maintains a balance between glucose uptake and its phosphorylation.
Glucokinase differs in three respects from hexokinases I-III, and is particularly suitable for the role that the liver plays in glycemic control. The binding between glucokinase and GKRP is much tighter in the presence of fructose 6-phosphate , whereas it is weakened by glucose and fructose 1-phosphate. In the absence of glucose, glucokinase is in its super-opened conformation that has low activity.
The rise in cytosolic glucose concentration causes a concentration dependent transition of glucokinase to its close conformation, namely, its active conformation that is not accessible for glucokinase regulatory protein. Hence, glucokinase is active and no longer inhibited. Notice that fructose 1-phosphate is present in the hepatocyte only when fructose is metabolized. Hence, fructose relieves the inhibition of glucokinase by glucokinase regulatory protein.
Example After a meal rich in carbohydrates, blood glucose levels rise, glucose enters the hepatocyte through GLUT2, and then moves inside the nucleus through the nuclear pores. In the nucleus glucose determines the transition of glucokinase to its close conformation, active and not accessible to GKRP, allowing glucokinase to diffuse in the cytosol where it phosphorylates glucose.
Conversely, when glucose concentration declines, such as during fasting when blood glucose levels may drop below 4 mM, glucose concentration in hepatocytes is low, and fructose 6-phosphate binds to GKRP allowing it to bind tighter to glucokinase. This results in a strong inhibition of the enzyme. This mechanism ensures that the liver, at low blood glucose levels, does not compete with other organs, primarily the brain, for glucose.
In the cell, fructose 6-phosphate is in equilibrium with glucose 6-phosphate, due to phosphoglucose isomerase reaction. Through its association with GKRP, fructose 6-phosphate allows the cell to decrease glucokinase activity, so preventing the accumulation of intermediates. To sum up, when blood glucose levels are normal, glucose is phosphorylated mainly by hexokinases I-III, whereas when blood glucose levels are high glucose can be phosphorylated by glucokinase as well.
Phosphofructokinase 1 is the key control point of carbon flow through the glycolytic pathway. The enzyme, in addition to substrate binding sites, has several binding sites for allosteric effectors. ATP, citrate, and hydrogen ions are allosteric inhibitors of the enzyme, whereas AMP, P i and fructose 2,6-bisphosphate are allosteric activators.
It should be noted that ATP, an end product of glycolysis, is also a substrate of phosphofructokinase 1. Indeed, the enzyme has two binding sites for the nucleotide: a low-affinity regulatory site, and a high affinity substrate site. What do allosteric effectors signal? The equilibrium constant, K eq , of the reaction is:. Therefore, considering that the total adenylate pool is constant over the short term, even a small reduction in ATP concentration leads, due to adenylate kinase activity, to a much larger relative increase in AMP concentration.
Therefore, the activity of phosphofructokinase 1 depends on the cellular energy status:. There are two reasons. A further control point of carbon flow through glycolysis and gluconeogenesis is the substrate cycle between phosphoenolpyruvate and pyruvate, catalyzed by pyruvate kinase for glycolysis, and by the combined action of pyruvate carboxylase and phosphoenolpyruvate carboxykinase EC 4.
All isozymes of pyruvate kinase are allosterically inhibited by high concentrations of ATP , long-chain fatty acids , and acetyl-CoA , all signs that the cell is in an optimal energy status. Alanine , too, that can be synthesized from pyruvate through a transamination reaction, is an allosteric inhibitor of pyruvate kinase; its accumulation signals that building blocks for biosynthetic pathways are abundant.
Conversely, pyruvate kinase is allosterically activated by fructose 1,6-bisphosphate , the product of the first committed step of glycolysis. Therefore, F-1,6-BP allows pyruvate kinase to keep pace with the flow of intermediates. It should be underlined that, at physiological concentration of PEP, ATP and alanine, the enzyme would be completely inhibited without the stimulating effect of F-1,6-BP.
The hepatic isoenzyme , but not the muscle isoenzyme, is also subject to regulation through phosphorylation by:. Phosphorylation of the enzyme decreases its activity, by increasing the K m for phosphoenolpyruvate, and slows down glycolysis.
For example, when the blood glucose levels are low, glucagon-induced phosphorylation decreases pyruvate kinase activity. The phosphorylated enzyme is also less readily stimulated by fructose 1,6-bisphosphate but more readily inhibited by alanine and ATP. Conversely, the dephosphorylated form of pyruvate kinase is more sensitive to fructose 1,6-bisphosphate, and less sensitive to ATP and alanine. In this way, when blood glucose levels are low, the use of glucose for energy in the liver slows down, and the sugar is available for other tissues and organs, such as the brain.
However, it should be noted that pyruvate kinase does not undergo glucagon-induced phosphorylation in the presence of fructose 1,6-bisphosphate. The dephosphorylated enzyme is more readily stimulated by its allosteric activators F-1,6-BP, and less readily inhibited by allosteric inhibitors alanine and ATP.
The role of the regulatory protein of glucokinase in the glucose sensory mechanism of the hepatocyte. J Biol Chem ; 14 Kabashima T. Xylulose 5-phosphate mediates glucose-induced lipogenesis by xylulose 5-phosphate-activated protein phosphatase in rat liver. Kaminski M. Glucose-induced dissociation of glucokinase from its regulatory protein in the nucleus of hepatocytes prior to nuclear export. Nelson D.
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