Pentose phosphate pathway, 82-87,

The Pentose Phosphate Pathway is an alternate pathway for glucose oxidation which is used to provide reducing equivalents in support of biosynthesis. Thus although it involves the catabolism of glucose, it is generally going to be active only when anabolism is taking place (Fig. 9.9). 

This pathway is usually treated in two parts the oxidative portion, and the sugar interconversions portion. In the oxidative part, glucose is first oxidized to a lactone, and then oxidatively decarboxylated. Note that in each case NADP+ is the oxidant as opposed to NAD+. Note also that the two DH reactions are both physiologically irreversible, due in part to the very low concentrations of NADPH in cells. 

Next Gluconolactonase opens the ring with the addition of a molecule of water. Then 6-P-gluconate DH oxidizes the 3 carbon to a ketone. This results in the 2 carbon becoming somewhat acidic, thus destabilizing the carboxyl group, which is then lost to give the five carbon ribulose-5-P. 

In the non-oxidative portion of the Pentose Phosphate Pathway a series of sugar interconversions takes the RU-5-P to intermediates of other pathways Ribose-5-P for nucleotide biosynthesis, and F-6-P and Ga-3-P for glycolysis/ gluconeogenesis. All of these reactions are near equilibrium, with fluxes driven by supply and use of the three intermediates listed above. 

In the first two reactions of this phase Ribulose-5-phosphate is converted either to Ribose-5-P via a 1,2-enediol intermediate, or to Xylulose-5-P via a 2,3-enediol intermediate. 

The pentose phosphate pathway (PPP), also called the hexose monophosphate shunt, is an alternate pathway of glucose metabolism that supplies the NAD PH required by many biosynthetic pathways. 

The main purpose of the PPP is to generate NADPH to be used in pathways for synthesis of important molecules, eg, amino acids, lipids, and nucleotides. 

NADPH derived from the PPP is also important for detoxification of reactive oxygen species. 

The PPP also is responsible for synthesis of ribose 5-phosphate for nucleotide biosynthesis. 

The PPP operates in two phases an oxidative phase and a nonoxidative phase. 

The pentose phosphate pathway (PPP, also known as the hexose monophosphate pathway) is an oxidative metabolic pathway located in the cytoplasm, which, like glycolysis, starts from glucose 6-phosphate. It supplies two important precursors for anabolic pathways NADPH+H+, which is required for the biosynthesis of fatty acids and isopren-oids, for example (see p. 168), and ribose 5-phosphate, a precursor in nucleotide biosynthesis (see p. 188). 

The oxidative segment of the PPP converts glucose 6-phosphate to ribulose 5-phosphate. One CO2 and two NADPH+H are formed in the process. Depending on the metabolic state, the much more complex regenerative part of the pathway (see B) can convert some of the pentose phosphates back to hexose phosphates, or it can pass them on to glycolysis for breakdown. In most cells, less than 10% of glucose 6-phosphate is degraded via the pentose phosphate pathway. 

The regenerative part of the PPP is only shown here schematically. A complete reaction scheme is given on p. 408. The function 

In the recombination of sugar phosphates in the regenerative part of the PPP, there are two enzymes that are particularly important  

The reactions in the regenerative segment of the PPP are freely reversible. It is therefore easily possible to use the regenerative part of the pathway to convert hexose phosphates into pentose phosphates. This can occur when there is a high demand for pentose phosphates—e.g., during DNA replication in the S phase of the cell cycle (see p. 394). 

The series of cytoplasmic reactions known as the pentose phosphate pathway is also called the hexose monophosphate (HMP) shunt (or cycle) or the phosphogluconate pathway. The qualitative interconversions that take place 

Summary of some interconversions and synthetic reactions in which amino sugars participate. Substrates for the pathway can be derived from glucose, glycogen, and gluconeogenesis. 

Summary of the pentose phosphate pathway. This diagram is intended to show the two major parts of the pathway oxidation and decarboxylation of glucose-6-phosphate to ribulose 5-phosphate, and resynthesis of the former from the latter. The stoichiometry of the pathway is ignored. 

The pentose phosphate pathway can be thought of as two separate pathways  

The oxidative conversion of glucose-6-phosphate to ribulose 5-phosphate and CO2 and 

Although most of the glucose catabolised in animal tissues is via glycolysis to pyruvate which then enters the Krebs cycle, there are some minor metabolic pathways which lead to alternative products. One of the most important of these is the Pentose Phosphate pathway (also known as the pentose shunt or the phosphogluconate pathway). In this pathway, glucose-6-phosphate is oxidised to ribose-5-phosphate with the generation of two molecules of NADPH. The overall equation may be written as 

Glucose-6-phosphate + 2NADP -i- H2O D-ribose-5-phosphate -1- 2H+ -1- 2NaDPH + CO2 (11.69) 

Ribulose-5-phosphate is first generated as in Equation 11.70 and then undergoes enzyme-catalysed isomerisation to give ribose-5-phosphate (11.71). 

Connections To glycolysis and glycogen through glucose 6-phos-phate. 

To DNA-RNA synthesis through ribose 5-phosphate. Regulation NADPH inhibits. 

The hexose monophosphate pathway has several names just to confuse you. It s called the hexose monophosphate shunt or pathway (HMP shunt or pathway), or the pentose phosphate pathway, or the phospho-gluconate pathway (Fig. 15-1). The pathway in its full form is complicated and has complicated stoichiometry. Usually it s not necessary to remember all of it. The important points are that it makes NADPH for biosynthesis and riboses (C-5 sugars) for DNA and RNA synthesis. 

NADPH is a reducing agent that is reserved for biosynthetic pathways—notably fatty acid synthesis. Thus, the HMP pathway is called upon when reducing equivalents and fatty acid synthesis are turned on. Primarily, the regulation of the pathway is through the supply and demand of NADPH. 

NADPH is also used to keep the cellular (and mitochondrial) glutathione in the reduced form through the action of glutathione reductase  

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This is not the place to expose in detail the problems and the solutions already obtained in studying biochemical reaction networks. However, because of the importance of this problem and the great recent interest in understanding metabolic networks, we hope to throw a little light on this area. Figure 10.3-23 shows a model for the metabolic pathways involved in the central carbon metabolism of Escherichia coli through glycolysis and the pentose phosphate pathway [22]. 

Figure 10.3-23. Metabolic model of glycolysis and tbe pentose phosphate pathway in E. coli. Squares Indicate enzyme activities circles indicate regulatory effects,...

Most of the enzymes mediating the reactions of the Calvin cycle also participate in either glycolysis (Chapter 19) or the pentose phosphate pathway (Chapter 23). The aim of the Calvin scheme is to account for hexose formation from 3-phosphoglycerate. In the course of this metabolic sequence, the NADPH and ATP produced in the light reactions are consumed, as indicated earlier in Equation (22.3). 

Gluconeogenesis, Glycogen Metabolism, and the Pentose Phosphate Pathway... 

Vnother pathway of glucose catabolism, the pentose phosphate pathway, is the primary source of N/ E)PH, the reduced coenzyme essential to most reductive biosynthetic processes. For example, N/VDPH is crucial to the biosynthesis of... 

Cells require a constant supply of N/ X)PH for reductive reactions vital to biosynthetic purposes. Much of this requirement is met by a glucose-based metabolic sequence variously called the pentose phosphate pathway, the hexose monophosphate shunt, or the phosphogluconate pathway. In addition to providing N/VDPH for biosynthetic processes, this pathway produces ribos 5-phosphate, which is essential for nucleic acid synthesis. Several metabolites of the pentose phosphate pathway can also be shuttled into glycolysis. 

FIGURE 23.26 The pentose phosphate pathway. The numerals in the blue circles indicate the steps discussed in the text. 

FIGURE 23.27 The glucose-6-phosphate dehydrogenase reaction is the committed step in the pentose phosphate pathway. 

This enzyme interconverts ribulose-5-P and ribose-5-P via an enediol intermediate (Figure 23.30). The reaction (and mechanism) is quite similar to the phosphoglucoisomerase reaction of glycolysis, which interconverts glucose-6-P and fructose-6-P. The ribose-5-P produced in this reaction is utilized in the biosynthesis of coenzymes (including N/ DH, N/ DPH, F/ D, and Big), nucleotides, and nucleic acids (DNA and RNA). The net reaction for the first four steps of the pentose phosphate pathway is... 

Even when the latter choice has been made, however, the cell must still be cognizant of the relative needs for ribose-5-phosphate and N/VDPH (as well as ATP). Depending on these relative needs, the reactions of glycolysis and the pentose phosphate pathway can be combined in novel ways to emphasize the synthesis of needed metabolites. There are four principal possibilities. 

BOTH RIBOSE-5-P AND NADPH ARE NEEDED BY THE CELL In this case, the first four reactions of the pentose phosphate pathway predominate (Figure 23.37). N/VDPH is produced by the oxidative reactions of the pathway, and ribose-5-P is the principal product of carbon metabolism. As stated earlier, the net reaction for these processes is... 

MORE RIBOSE-5-P THAN NADPH IS NEEDED BY THE CELL Synthesis of ribose-5-P can be accomplished without production of N/VDPH if the oxidative steps of the pentose phosphate pathway are bypassed. The key to this route is the extrac-... 

FIGURE 23.37 Wlien biosynthetic demands dictate, the first four reactions of the pentose phosphate pathway predominate and the principal products are ribose-5-P and NADPH. 

MORE NADPH THAN RmOSE-5-P IS NEEDED BY THE CELL Large amounts of N/VDPH can be supplied for biosynthesis without concomitant production of ribose-5-P, if ribose-5-P produced in the pentose phosphate pathway is recycled to produce glycolytic intermediates. As shown in Figure 23.39, this alternative involves a complex interplay between the transketolase and transaldolase reac-... 

FIGURE 23.38 The oxidative steps of the pentose phosphate pathway can be bypassed if the primary need is for ribose-5-P. 

NADPH can be produced in the pentose phosphate pathway as well as by malic enzyme (Figure 25.1). Reducing equivalents (electrons) derived from glycolysis in the form of NADH can be transformed into NADPH by the combined action of malate dehydrogenase and malic enzyme ... 

How many of the 14 NADPH needed to form one palmitate (Eq. 25.1) can be made in this way The answer depends on the status of malate. Every citrate entering the cytosol produces one acetyl-CoA and one malate (Figure 25.1). Every malate oxidized by malic enzyme produces one NADPH, at the expense of a decarboxylation to pyruvate. Thus, when malate is oxidized, one NADPH is produced for every acetyl-CoA. Conversion of 8 acetyl-CoA units to one palmitate would then be accompanied by production of 8 NADPH. (The other 6 NADPH required [Eq. 25.1] would be provided by the pentose phosphate pathway.) On the other hand, for every malate returned to the mitochondria, one NADPH fewer is produced. 

The following compound is an intermediate in the pentose phosphate pathway, an alternative route for glucose metabolism. Identify the sugar it is derived from. 

Another step in the pentose phosphate pathway for degrading sugars (see Problem 29.38) is the conversion of ribose S-phosphate to glyceraldehyde 3-phosphate. What kind of organic process is occurring Propose a mechanism for the conversion. 

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