1. Pentose phosphate path way & other pathways of hexose metabolism
The pentose phosphate pathway (phosphogluconate, hexose monophosphate shunt (HMS)) is an alternative route for the metabolism of glucose. It does not lead to formation of 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.

2. Glucose, fructose, and galactose are the main hexoses absorbed from the gastrointestinal tract, derived from dietary starch, sucrose, and lactose, respectively.
Fructose and galactose can be converted to glucose, mainly in the liver.

3. Genetic deficiency of glucose 6-phosphate dehydrogenase, the first enzyme of the pentose phosphate pathway, is a major cause of hemolysis of red blood cells, resulting in hemolytic anemia. Deficiencies in the enzymes of fructose and galactose metabolism lead to metabolic diseases such as essential fructosuria, hereditary fructose intolerance, and galactosemia.

4. THE PENTOSE PHOSPHATE PATHWAY FORMS NADPH & RIBOSE PHOSPHATE
The pentose phosphate pathway (hexose monophosphate shunt) is a more complex pathway than glycolysis as shown in (Figure 21–1). Three molecules of glucose 6-phosphate give rise to three molecules of CO2 and three 5-carbonsugars.

5. These are rearranged to regenerate two molecules of glucose 6-phosphate and one molecule of the glycolytic intermediate, glyceraldehyde 3 -phosphate. Since two molecules of glyceraldehyde 3-phosphate can regenerate glucose 6-phosphate, the pathway can account for the complete oxidation of glucose.

8. REACTIONS OF THE PENTOSE PHOSPHATE PATHWAY OCCUR IN THE CYTOSOL
Like glycolysis, the enzymes of the pentose phosphate pathway are cytosolic. Unlike glycolysis, oxidation is achieved by dehydrogenation using NADP + , not NAD + , as the hydrogen acceptor. The sequence of reactions of the pathway may be divided into two phases: an oxidative nonreversible phase and a nonoxidative reversible phase.

9. In the first phase, glucose 6-phosphate undergoes dehydrogenation and decarboxylation to yield a pentose, ribulose 5-phosphate. In the second phase, ribulose 5-phosphate is converted back to glucose 6-phosphate by a series of reactions involving mainly two enzymes: transketolase and transaldolase (see Figure21–1).

10. The Oxidative Phase Generates NADPH
Dehydrogenation of glucose 6-phosphate to 6-phosphogluconate occurs via the formation of 6-phosphogluconolactone catalyzed by glucose 6-phosphate dehydrogenase, an NADP-dependent enzyme (Figures 21–1 & 21–2). The hydrolysis of 6-phosphogluconolactone is accomplished by the enzyme gluconolactone hydrolase.

11. A second oxidative step is catalyzed by 6-phosphogluconate dehydrogenase, which also requires NADP+ as hydrogen acceptor. Decarboxylation follows with the formation of the ketopentose ribulose 5-phosphate.Figure 21–2.

13. The Nonoxidative Phase Generates Ribose Precursors
Ribulose 5-phosphate is the substrate for two enzymes. Ribulose 5-phosphate 3-epimerase alters the configuration about carbon 3, forming the epimer xylulose 5-phosphate, also a ketopentose. Ribose 5-phosphate ketoisomerase converts ribulose 5-phosphate to the corresponding aldopentose, ribose 5-phosphate, which is used for nucleotide and nucleic acid synthesis.

14. Transketolase transfers the two-carbon unit comprising carbons 1 and 2 of a ketose onto the aldehyde carbon of an aldose sugar. It therefore affects the conversion of a ketose sugar into an aldose with two carbons less and an aldose sugar into a ketose with two carbons more. The reaction requires Mg2+ and thiamin diphosphate (vitamin B1 ) as coenzyme. The two-carbon moiety transferred is probably glycolaldehyde bound to thiamin diphosphate.

15. The two-carbon moiety transferred is probably glycolaldehyde bound to thiamin diphosphate. Thus, transketolase catalyzes the transfer of the two carbon unit from xylulose 5-phosphate to ribose 5-phosphate, producing the seven-carbon ketose sedoheptulose 7-phosphate and the aldose glyceraldehyde 3-phosphate.

16. These two products then undergo transaldolation
These two products then undergo transaldolation. Transaldolase catalyzes the transfer of a three-carbon dihydroxyacetone moiety (carbons 1–3) from the ketose sedoheptulose 7-phosphate onto the aldose glyceraldehyde 3-phosphate to form the ketose fructose 6-phosphate and the four-carbon aldose erythrose 4-phosphate. In a further reaction catalyzed by transketolase, xylulose 5-phosphate serves as a donor of glycolaldehyde. In this case erythrose 4-phosphate is the acceptor, and the products of the reaction are fructose 6-phosphate and glyceraldehyde 3-phosphate.

17. In order to oxidize glucose completely to CO₂ via the pentose phosphate pathway, there must be enzymes present in the tissue to convert glyceraldehyde 3-phosphate to glucose 6-phosphate. This involves reversal of glycolysis and the gluconeogenic enzyme fructose 1,6-bisphosphatase. In tissues that lack this enzyme, glyceraldehyde 3-phosphate follows the normal pathway of glycolysis to pyruvate.

18. The overall process, six molecules of hexoses (glucose) are utilized to give six molecules of CO2 and six molecules of pentoses. These pentoses are rearranged to give four molecules of fructose-6-phosphate and two molecules of glyceraldehyde-3-phosphate, which also forms a molecule of hexose(by the reversal of glycolysis),thus regenerating five molecules of hexoses as shown below:

19. (Glucose6-phosphate)6 (pentose5-phosphate)6 (Hexose-6-phosphate)5
12NADPH+H+
12NADP+
(Glucose6-phosphate)6
(pentose5-phosphate)6
(CO2)6
(Hexose-6-phosphate)5

20. Reducing Equivalents Are Generated in Those Tissues Specializing in
Reductive Syntheses
The pentose phosphate pathway is active in liver, adipose tissue, adrenal cortex, thyroid, erythrocytes, testis, and lactating mammary gland. Its activity is low in nonlactating mammary gland and skeletal muscle.

21. Those tissues in which the pathway is active use NADPH in reductive syntheses, eg, of fatty acids, steroids, amino acids via glutamate dehydrogenase, and reduced glutathione. The synthesis of glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase may also be induced by insulin in the fed state, when lipogenesis increases.

22. Ribose Can Be Synthesized in Virtually All Tissues
Little or no ribose circulates in the bloodstream, so tissues have to synthesize the ribose they require for nucleotide and nucleic acid synthesis using the pentose phosphate pathway (see Figure 21–2). It is not necessary to have a completely functioning pentose phosphate pathway for a tissue to synthesize ribose 5-phosphate.

23. Muscle has only low activity of glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, but, like most other tissues, it is capable of synthesizing ribose 5-phosphate by reversal of the nonoxidative phase of the pentose phosphate pathway utilizing fructose 6-phosphate.

24. THE PENTOSE PHOSPHATE PATHWAY &GLUTATHIONE PEROXIDASE PROTECT ERYTHROCYTES AGAINST HEMOLYSIS
In red blood cells the pentose phosphate pathway provides NADPH for the reduction of oxidized glutathione catalyzed by glutathione reductase, a flavoprotein containing FAD.

25. Reduced glutathione (GSH) removes H2 O2 in a reaction catalyzed by glutathione peroxidase, an enzyme that contains the selenium analogue of cysteine (selenocysteine) at the active site (Figure 21–3). The reaction is important, since accumulation of H₂O₂ may decrease the life span of the erythrocyte by causing oxidative damage to the cell membrane, leading to hemolysis.

27. Metabolism of fructose
Fructose is obtained to the body either directly from the diet or from sucrose in the intestine.
Fructose is converted to glucose, for its utilization by the body, by various routes (21.4).
1. Fructose is changed to fructose 1- phosphate by fructokinase present in the liver, muscle, intestine and kidney.
Fructose Fructose 1-phosphate
Fructokinase
Mg+2
ATP
ADP

28. Fructose Fig(21.4)Fructose Metabolism ATP ATP Hexokinase Mg+2
Fructokinase
Mg+2
ADP
ADP
Fructose 6-phosphate
Aldolase B
Fructose1-phosphate
Dihydroxy acetone
phosphate
Phosphohexose
isomerase
ATP +
1-phospho
fructokinase
D-Glyceraldehyde
ATP
Glucose 6-phosphate
Triose
Kinase
ADP
Mg+2
Fructose 1,6-Bisphosphate
ADP
Glucose 6-
phosphatase
D-Glyceraldehyde-
3-Phosphate Pi
Glycolysis
D-Glucose
Fig(21.4)Fructose Metabolism

29. Essential Fructosuria
Fructokinase deficiency results in essential fructosuria. As a result of it, fructose appears in the urine after a high fructose or sucrose diet. Thereafter, Fructose 1-phosphate is cleaved by Aldolase B. Aldolase B splits fructose-1-phosphate to Dihydroxyacetone phosphate and D-glyceraldehyde.
Fructose1-phosphate
Aldolase B
Dihydroxy acetone phosphate +
D-Glyceraldehyde

30. Fructose Intolerance
Aldolase B(an enzyme found in the liver) is different from aldolase(also called as aldolase A, which acts on Fructose 1,6 Bisphosphate). Individuals with Aldolase B deficiency suffer from hereditary Fructose intolerance. Subsequently, Glyceraldehyde is phosphorylated by ATP , in the presence of triose kinase and is changed to 3-phosphoglyceraldehyde
Triose Kinase
D-Glyceraldehyde3-Phosphate
D-Glyceraldehyde
Mg+2
ATP
ADP

31. 3-phopsphoglyceraldehyde in turn gets conjugated with Dihydroxyacetone phosphate and forms glucose-6-phosphate,by the reversal of glycolytic reactions. 2-Alternatively, Fructose 1-phosphate may be phosphorylated to Fructose1,6 bisphosphate, by 1-phosphofructokinase. The latter then enters the glycolytic pathway
1-phosphofructokinase
Fructose1-phosphate Fructose 1,6-Bisphosphate
ADP
ATP

32. 3-Fructose may also be changed to Fructose-6- phosphate by Hexokinase
3-Fructose may also be changed to Fructose-6- phosphate by Hexokinase. The latter gets be isomerised to glucose-6-phoshate and either enters glycolysis or is hydrolyzed to glucose.

33. Metabolism of galactose
GALACTOSE IS NEEDED FOR THE SYNTHESIS OF LACTOSE
Galactose is derived from intestinal hydrolysis of the disaccharide lactose, the sugar of milk. Most of the dietary galactose is changed to glucose in the liver. Besides liver, it is also be utilized in the brain and the lactating mammary gland. It is readily converted in the liver to glucose. Galactokinase catalyses the phosphorylation of galactose, using ATP as phosphate donor(Figure 21–6).

34. Galactose 1-phosphate reacts with uridine diphosphate glucose (UDP-Glu) to form uridine diphosphate galactose (UDP-Gal) and glucose 1-phosphate, in a reaction catalyzed by galactose 1-phosphate uridyl transferase. The conversion of UDP-Gal to UDP-Glu is catalyzed by UDP-Gal 4-epimerase. The reaction involves oxidation, then reduction, at carbon 4, with NAD+ as coenzyme.

35. The UDP-Glu is then incorporated into glycogen. Figure 21–6
The UDP-Glu is then incorporated into glycogen. Figure 21–6. Since the epimerase reaction is freely reversible, glucose can be converted to galactose, so that galactose is not a dietary essential. Galactose is required in the body not only in the formation of lactose but also as a constituent of glycolipids (cerebrosides), proteoglycans, and glycoproteins. In the synthesis of lactose in the mammary gland, UDP-Gal condenses with glucose to yield lactose, catalyzed by lactose synthase (see Figure 21–6).

36. Figure 21–6 Pathway of conversion of (A) galactose to glucose in the liver and (B) glucose to lactose in the lactating mammary gland.

37. Fructose & Sorbitol in the Lens Are Associated with Diabetic Cataract
Both fructose and sorbitol are found in the lens of the eye in increased concentrations in diabetes mellitus, and may be involved in the pathogenesis of diabetic cataract. The sorbitol (polyol) pathway (not found in liver) responsible is for fructose formation from glucose (see Figure 21–5) and increases in activity as the glucose concentration rises in those tissues that are not insulin-sensitive, ie, the lens, peripheral nerves, and renal glomeruli.

38. Glucose is reduced to sorbitol by aldose reductase, followed by oxidation of sorbitol to fructose in the presence of NAD+ and sorbitol dehydrogenase (polyol dehydrogenase). Sorbitol does not diffuse through cell membranes, but accumulates, causing osmotic damage.

39. Metabolism of fructose
Metabolism of fructose. Aldolase A is found in all tissues, whereas aldolase B is the predominant form in liver. (*Not found in liver)

40. Enzyme Deficiencies in the Galactose Pathway Cause Galactosemia
Inability to metabolize galactose occurs in the galactosemias, which may be caused by inherited defects of galactokinase, uridyl transferase, or 4-epimerase (Figure 21–6A), though deficiency of uridyl transferase is the best known. Galactose is a substrate for aldose reductase, forming galactitol, which accumulates in the lens of the eye, causing cataract. Congenital galactosemia thus can lead to mental retardation, premature cataract and death.