Fructose 1,6-bisphosphate glycolysis

F6P is a phosphorylated form of fructose commonly found in cells. F6P is an intermediate in glycolysis, gluconeogenesis, the pentose phosphate pathway, and the Calvin cycle. F6P is a substrate in biosynthesis of the important allosteric factor regulating glycolysis, fructose-2,6-bisphosphate and is also an important precursor of amino sugars (last enzyme below). 

See also Oxidative Phosphorylation (from Chapter 15), Regulation of Glycolysis, Fructose-2,6-Bisphosphate Regulation (from Chapter 16), Reactions/Energies of Glycolysis, Lactic Acid fermentation. Pyruvate Decarboxylase, Alcohol Dehydrogenase, Alcoholic Fermentation, Aerobic vs. Anaerobic Glycolysis... 

This reaction is followed by another phosphorylation with ATP catalyzed by the enzyme phosphofructoki-nase (phosphofructokinase-1), forming fructose 1,6-bisphosphate. The phosphofructokinase reaction may be considered to be functionally irreversible under physiologic conditions it is both inducible and subject to allosteric regulation and has a major role in regulating the rate of glycolysis. Fructose 1,6-bisphosphate is cleaved by aldolase (fructose 1,6-bisphosphate aldolase) into two triose phosphates, glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. Glyceraldehyde 3-phosphate and dihydroxyacetone phosphate are inter-converted by the enzyme phosphotriose isomerase. 

Type I aldolases, which include the most studied mammalian enzymes, have a more complex mechanism involving intermediate Schiff base forms (Eq. 13-36, steps a, V, c, d ).m The best known members of this group are the fructose bisphosphate aldolases (often referred to simply as aldolases), which cleave fructose-1,6-P2 during glycolysis (Fig. 10-2, step e). 

Reaction 2 of Fig. 17-7 is a simple isomerization that moves the carbonyl group to C-2 so that (1 cleavage to two three-carbon fragments can occur. Before cleavage a second phosphorylation (reaction 3) takes place to form fructose 1,6-bisphosphate. This ensures that when fructose bisphosphate is cleaved by aldolase each of the two halves will have a phosphate handle. This second priming reaction (reaction 3) is the first step in the series that is unique to glycolysis. The catalyst for the reaction, phosphofructokinase, is carefully controlled, as discussed in Chapter 11 (see Fig. 11-2). 

Glucagon and epinephrine also regulate pseudocycle II so as to stimulate gluconeogenesis while inhibiting glycolysis. They do this through a chain of reactions that results in a lowering of the concentration of the allosteric effector fructose-2,6-bisphosphate. This effector stimulates phosphofructokinase while it inhibits fructose bisphosphate phosphatase. 

The pathway of glycolysis is shown in Figure 5.10. Although the aim of glucose oxidation is to phosphorylate ADP to ATP, the pathway involves two steps in which ATP is used, one to form glucose 6-phosphate when glucose is the substrate and the other to form fructose bisphosphate. In other words, there is a modest cost of ATP to initiate the metabolism of glucose. 

For all of these reactions, the equilibrium is in the direction of glycolysis, because of the utilization of ATP in the reaction and the high ratio of ATP to ADP in the cell. The reactions of phosphofructokinase and hexokinase are reversed in gluconeogenesis by simple hydrolysis of fructose bisphosphate to fructose 6-phosphate plus phosphate (catalysed by fructose bisphosphatase) and of glucose 6-phosphate to glucose plus phosphate (catalysed by glucose 6-phosphatase). 

As described in Chapter 19, Emile Van Schaftingen and Henri-Gery Hers demonstrated in 1980 that fructose-2,6-bisphosphate is a potent stimulator of phosphofructokinase. Cognizant of the reciprocal nature of regulation in glycolysis and gluconeogenesis. Van Schaftingen and Hers also considered the... 

Figure 10.18 Enzymatic in situ generation of dihydroxyacetone phosphate from fructose 1,6-bisphosphate (b), with extension to an in vitro artificial metabolism for its preparation from inexpensive sugars alongthe glycolysis cascade (a), and utilization for subsequent stereoselective carbon-carbon bond formation using an aldolase with distinct stereoselectivity (c).

Figure 17-2. The pathway of glycolysis. ( ,—P, HOPOj " .inhibition.) At asterisk Carbon atoms 1-3 of fructose bisphosphateform dihydroxyacetone phosphate, whereas carbons 4-6 form glyceraldehyde 3-phosphate. The term "bis-," as in bisphosphate, indicates that the phosphate groups are separated, whereas diphosphate, as in adenosine diphosphate, indicates that they are joined.

The convetsion of fructose 1,6-bisphosphate to fructose 6-phosphate, to achieve a reversal of glycolysis, is catalyzed by fructose-l,6-bi pho pbatase. Its ptesence determines whether or not a tissue is capable of synthesizing glycogen not only from pymvate but also from ttiosephosphates. It is present in hvet, kidney, and skeletal muscle but is probably absent from heart and smooth muscle. 

Fructose 2,6-Bisphosphate Plays a Unique Role in the Regulation of Glycolysis Gluconeogenesis in Liver... 

Fructose 2,6-bisphosphate is formed by phosphorylation of fructose 6-phosphate by phosphofructoki-nase-2. The same enzyme protein is also responsible for its breakdown, since it has fructose-2,6-hisphos-phatase activity. This hifrmctional enzyme is under the allosteric control of fructose 6-phosphate, which stimulates the kinase and inhibits the phosphatase. Hence, when glucose is abundant, the concentration of fructose 2,6-bisphosphate increases, stimulating glycolysis by activating phosphofructokinase-1 and inhibiting... 

Figure 19-3. Control of glycolysis and gluconeoge-nesis in the liver by fructose 2,6-bisphosphate and the bifunctional enzyme PFK-2/F-2,6-Pase (6-phospho-fructo-2-kinase/fructose-2,6-bisphosphatase). (PFK-1, phosphofructokinase-1 [6-phosphofructo-1 -kinase] ...

All of the glycolysis reactions ranging from phosphoenolpyruvate to fructose 1,6-bisphosphate are reversible, and the phosphoenolpyruvate molecules formed are consumed for producing fructose 1,6-bisphosphate by making use of the same glycolysis enzymes. 

How does phosphorylation affect the activity of phosphofructo-2-kinase (PFK-2), the enzyme that synthesizes fructose 2,6-bisphosphate, a regulator of glycolysis There are two possible answers it either activates it or inactivates it. The simplest approach to the question is just to flip a coin. You should stand a 50 50 chance of getting it right. The next simplest way is to figure it out. 

Fructose 2,6-bisphosphate stimulates glycolysis by allosterically activating phosphofructo-1-kinase (PFK-1). First, decide what should... 

In liver, cAMP activates gluconeogenesis, but in muscle, it activates glycolysis. Let s do liver first, and the muscle answer will just be the opposite. So, we want to activate gluconeogenesis in liver in response to increased phosphorylation (increased levels of cAMP). Phosphorylation of our enzyme (PFK-2) must have an effect that is consistent with the activation of gluconeogenesis. If gluconeogenesis is on and glycolysis is off, the level of fructose 2,6-bisphosphate (an activator of glycolysis) must fall. If fructose 2,6-bisphosphate is to fall, the PFK-2 that synthesizes it must be made inactive. So, in liver, phosphorylation of PFK-2 must inactivate the enzyme. 

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