Aldolase Cleaves Fructose-1,6-bisphosphate

Fructose-1,6-bisphosphate is cleaved by aldolase into two molecules of triose phosphate. This reaction represents the reversal of an aldol condensation (fig. 12.20). Most aldolases are highly specific for the upper end of the substrate molecule, requiring a phosphate group at C-l, a carbonyl at C-2, and specific steric configurations at C-3 and C-4. The nature of the remainder of the molecule is unimportant as far as the enzyme action is concerned. 

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Aldolase Cleaves Fructose-1,6-bisphosphate Triose Phosphate Isomerase Interconverts the Two... 

In this reversible reaction, aldolase (or fructose-1,6-bisphosphate aldolase) cleaves fructose-1,6-bisphosphate into two isomers ... 

Subsequent action by fructose-l-phosphate aldolase cleaves fructose-l-P in a manner like the fructose bisphosphate aldolase reaction to produce dihy-droxyacetone phosphate and D-glyceraldehyde ... 

Aldolase A cleaves fructose 1,6-bisphosphate to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate (see Figure 8.16). The... 

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). 

Fructose bisphosphate is cleaved by action of an aldolase (reaction 4) to give glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. These two triose phosphates are then equilibrated by triose phosphate isomerase (reaction 5 see also Chapter 13). As a result, both halves of the hexose can be metabolized further via glyceraldehyde 3-P to pyruvate. The oxidation of glyceraldehyde 3-P to the corresponding carboxylic acid, 3-phosphoglyceric acid (Fig. 17-7, reactions 6 and 7), is coupled to synthesis of a molecule of ATP from ADP and P . This means that two molecules of ATP are formed per hexose cleaved, and that two molecules of NAD+ are converted to NADH in the process. 

Fig. 8.21. Aldolases catalyze carbon-carbon cleavage in reactions that are usually reversible. In glycolysis, the enzyme fructose 1,6-bisphosphate aldolase cleaves a carbon-carbon bond in fructose 1,6-bisphosphate. Aldolases have a lysine epsilon amino group in the active site that participates in the reaction.

The metabolism of fructose occurs principally in the liver and to a lesser extent in the small intestinal mucosa and proximal epithelium of the renal tnbnle, becanse these tissues have both fructokinase and aldolase B. Aldolase exists as several isoforms aldolases A, B, C, and fetal aldolase. Although all of these aldolase isoforms can cleave fructose 1,6-bisphosphate, the intermediate of glycolysis, only aldolase B can also cleave fructose 1-phosphate. Aldolase A, present in muscle and most other tissues, and aldolase C, present in brain, have almost no ability to cleave fructose 1-phosphate. Fetal aldolase, present in the liver before birth, is similar to aldolase C. 

The substrate for the first enzyme-catalyzed reaction in the series of reactions known as glycolysis is D-glucose (a six-carbon compound). The final product of glycolysis is two molecules of pyruvate (a three-carbon compound). Therefore, at some point in the series of enzyme-catalyzed reactions, a six-carbon compound must be cleaved into two three-carbon compounds. The enzyme aldolase catalyzes this cleavage. (Aldolase converts fructose-1,6-bisphosphate into glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. The enzyme is called aldolase because the reaction it catalyzes is a retro-aldol addition—that is, it is the reverse of an aldol addition (Section 18.10). 

In the splitting stage, fructose 1,6-bisphosphate, a six-carbon molecule, is cleaved into two three-carbon molecules, glycerone phosphate (also called dihydroxyacetone phosphate) and glyceraldehyde 3-phosphate, by the enzyme fructose-bisphosphate aldolase. The name of the enzyme is derived from... 

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. 

Cleavage of Fructose 1,6-Bisphosphate The enzyme fructose 1,6-bisphosphate aldolase, often called simply aldolase, catalyzes a reversible aldol condensation (p. 485). Fructose 1,6-bisphosphate is cleaved to yield two different triose phosphates, glyceraldehyde 3-phosphate, an aldose, and dihydroxyacetone phosphate, a lcetose ... 

Some lactic acid bacteria of the genus Lactobacillus, as well as Leuconostoc mesenteroides and Zymomonas mobilis, carry out the heterolactic fermentation (Eq. 17-33) which is based on the reactions of the pentose phosphate pathway. These organisms lack aldolase, the key enzyme necessary for cleavage of fructose 1,6-bisphosphate to the triose phosphates. Glucose is converted to ribulose 5-P using the oxidative reactions of the pentose phosphate pathway. The ribulose-phosphate is cleaved by phosphoketolase (Eq. 14-23) to acetyl-phosphate and glyceraldehyde 3-phosphate, which are converted to ethanol and lactate, respectively. The overall yield is only one ATP per glucose fermented. 

Fructose-6-phosphate formed from the isomerization discussed above is further phos-phorylated during glycolysis to fructose-1,6-diphosphate (108), which is then cleaved by fructose-1,6-bisphosphate aldolase to afford dihydroxy acetone phosphate (109) and glyceraldehyde-3-phosphate (110). This cleavage reaction is the reverse of an aldol condensation discussed in Section II.C and during gluconeogenesis. In the latter case, fructose-1,6-bisphosphate aldolase catalyzes the reverse reaction herein via aldol condensation of the ketose 109 and the aldose 110 to form linear fructose-1,6-bisphosphate (108) . 

After fructose-1,6-bisphosphate is cleaved by aldolase to afford dihydroxyacetone phosphate (122) and glyceraldehyde-3-phosphate (124), the former is further converted to the latter by trlosephosphate isomerase (TIM). The structure of this enzyme has the prototypical TIM fold as an (a/ )s barrel (Figure 12), with the active site in one side of the barrel. This protein folding pattern is also found in the structures of hexose isomerases. 

STEP 4 Fructose 1,6-bisphosphate is cleaved into two three-carbon pieces by the enzyme aldolase. 

Cleavage and isomerization. Fructose 1,6-bisphosphate is cleaved in step 4 into two, three-carbon monophosphates, one an aldose and one a ketose. The bond between carbons 3 and 4 of fructose 1,6-bisphosphate breaks, and a C-0 group is formed. Mechanistically, the cleavage is the reverse of an aldol reaction (Section 23.2) and is carried out by an aldolase enzyme. (A forward aldoI reaction joins two aldehydes or ketones to give a /1-hydroxy carbonyl compound a retro aldol reaction cleaves a -hydroxy carbonyl compound into two aldehydes or ketones.)... 

Fig. 29.3. Fructose metabolism. The pathway for the conversion of fructose to dihydroxy-acetone phosphate and glyceraldehyde 3-phosphate is shown in blue. These two compounds are intermediates of glycolysis and are converted in the liver principally to glucose, glycogen, or fatty acids. In the liver, aldolase B cleaves both fructose 1-phosphate in the pathway for fructose metabolism, and fructose 1,6-bisphosphate in the pathway for glycolysis.

Fructose-1,6-bisphosphate, the product of this reaction, is then cleaved by aldolase to two 3-carbon compounds ... 

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