Pentose phosphate pathway NADPH generation

Figure 21.3 Fates of glucose 6-phosphate. Glucose 6-phosphate derived from glycogen can (1) be used as a fuel for anaerobic or aerobic metabolism as in. for instance, muscle (2) be converted into free glucose in the liver and subsequently released into the blood (3) be processed by the pentose phosphate pathway to generate NADPH or ribose n a variety of tissues.

List the two phases of the pentose phosphate pathway (oxidative generation of NADPH and nonoxidative interconversion of sugars). List the biochemical pathways that require NADPH from the pentose phosphate pathway. 

Cholesterol is made in the liver from glucose via the pentose phosphate pathway (which generates NADPH) and glycolysis, which produces acetyl CoA (Fig. 38.1). Acetyl Co A is then metabolised to 3-hydroxy-3-methylglutaryl CoA (HMGCoA) which is reduced by NADPH in the presence of HMGCoA reductase (the regulatory enzyme for cholesterol synthesis) to form mevalonate. Mevalonate is then metabolised via more than two dozen intermediates (not shown) to form cholesterol. 

The pentose phosphate pathway is an alternative route for the metabolism of glucose. It does not generate ATP but has two major functions (1) The formation of NADPH for synthesis of fatty acids and steroids and (2) the synthesis of ribose for nucleotide and nucleic acid formation. Glucose, fructose, and galactose are the main hexoses absorbed from the gastrointestinal tract, derived principally from dietary starch, sucrose, and lactose, respectively. Fructose and galactose are converted to glucose, mainly in the liver. 

THE PENTOSE PHOSPHATE PATHWAY GENERATES NADPH RIBOSE PHOSPHATE (Figure 20-1)... 

Pentose phosphate pathway (= hexose monophosphate shunt) generation of NADPH G6PDH deficiency... 

The deoxyribonucleotides, except for deoxythymidine nucleotide, are formed from the ribonucleotides by the action of an enzyme complex, which comprises two enzymes, ribonucleoside diphosphate reductase and thioredoxin reductase (Figure 20.11). The removal of a hydroxyl group in the ribose part of the molecule is a reduction reaction, which requires NADPH. This is generated in the pentose phosphate pathway. (Note, this pathway is important in proliferating cells not only for generation... 

In hepatocytes and adipocytes, cytosolic NADPH is largely generated by the pentose phosphate pathway (see Fig. 14-21) and by malic enzyme (Fig. 21-9a). The NADP-linked malic enzyme that operates in the carbon-assimilation pathway of C4 plants (see Fig. 20-23) is unrelated in function. The pyruvate produced in the reaction shown in Figure 21-9a reenters the mitochondrion. In hepatocytes and in the mammary gland of lactating animals, the NADPH required for fatty acid biosynthesis is supplied primarily by the pentose phosphate pathway (Fig. 21-9b). 

Two NADPH Molecules Are Generated by the Pentose Phosphate Pathway Transaldolase and Transketolase Catalyze the Interconversion of Many Phosphorylated Sugars Production of Ribose-5-phosphate and Xylulose-5-phosphate... 

Many kinds of organisms and some mammalian organs, notably liver, possess an alternative pathway for the oxidation of hexoses which results in a pentose phosphate and carbon dioxide. This pentose can be used as a precursor of the ribose found in nucleic acids or other sugars containing from three to seven carbon atoms which are needed in smaller amounts. The first and third reactions in the pentose phosphate pathway generate NADPH which is a major source of reducing power in many cells. 

Cells differ considerably in their use of the pentose f phosphate pathway. In muscle, a tissue in which carbohydrates are utilized almost exclusively for generation of mechanical energy, the enzymes of the pentose phosphate pathway are lacking. By contrast, red blood cells are totally dependent on the pentose phosphate pathway as a source of NADPH for which they need to keep the iron of hemoglobin in its normal +2 valence state. A deficiency in glucose-6-phosphate dehydrogenase, the first enzyme in the pentose phosphate pathway, can lead to the wholesale destruction of red blood cells and a condition known as hemolytic anemia. 

Two NADPH Molecules Are Generated by the Pentose Phosphate Pathway... 

The plant can also use the pentose phosphate pathway to break down glucose, but the main purpose of this pathway is the generation of reducing power in the form of NADPH (nicotinamide adenine dinucleotide... 

So in summary, three glucose-6-phosphate (3.1) molecules (3 x C6) are oxidized to three ribulose-5-phosphate (3.13) residues (3 x C5) and three molecules of C02 (3 x Ci) under generation of six molecules of NADPH. The three ribulose-5-phosphate residues are then converted to one glyceraldehyde-3-phosphate (3.14) molecule (lx C3) and two fructose-6-phosphate (3.2) molecules (2 x C6). Fructose-6-phosphate can be converted to glucose-6-phosphate and reenter the oxidative part of the pentose phosphate pathway. Fructose-6-phosphate and glyceraldehydes can also serve as intermediates in glycolysis (Section 5.1), which offers the cell considerable flexibility in terms of its metabolic flux. 

Role of the Pentose Phosphate Pathway If the oxidation of glucose 6-phosphate via the pentose phosphate pathway were being used primarily to generate NADPH for biosynthesis, the other product, ribose 5-phosphate, would accumulate. What problems might this cause ... 

NADPH is also generated by the cytosolic pentose phosphate pathway that achieves the following ... 

The pentose phosphate pathway meets the need of all organisms for a source of NADPH to use in reductive biosynthesis (Table 20.2). This pathway consists of two phases the oxidative generation of NADPH and the nonoxidative interconversion of sugars (Figure 20.19). In the oxidative phase, NADPH is generated when glucose 6-phosphate is oxidized to ribose 5-phosphate. This five-carbon sugar and its derivatives are components of RNA and DNA, as well as ATP, NADH, FAD, and coenzyme A. 

Figure 20.19. Pentose Phosphate Pathway. The pathway consists of (1) an oxidative phase that generates NADPH and (2) a nonoxidative phase that interconverts phosphorylated sugars.

Figure 20.20. Oxidative Phase of the Pentose Phosphate Pathway. Glucose 6-phosphate is oxidized to 6-phosphoglucono-6-lactone to generate one molecule of NADPH. The lactone product is hydrolyzed to 6-phosphogluconate, which is oxidatively decarboxylated to ribulose 5-phosphate with the generation of a second molecule ofNADPH.

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