The Pentose Phosphate Pathway & Other Pathways of Hexose Metabolism - Bioenergetics & the Metabolism of Carbohydrates & Lipids - Harper’s Illustrated Biochemistry, 29th Edition (2012)

Harper’s Illustrated Biochemistry, 29th Edition (2012)

SECTION II. Bioenergetics & the Metabolism of Carbohydrates & Lipids

Chapter 21. The Pentose Phosphate Pathway & Other Pathways of Hexose Metabolism

David A. Bender, PhD & Peter A. Mayes, PhD, DSc

OBJECTIVES

After studying this chapter, you should be able to:

Image Describe the pentose phosphate pathway and its roles as a source of NADPH and in the synthesis of ribose for nucleotide synthesis.

Image Describe the uronic acid pathway and its importance for synthesis of glucuronic acid for conjugation reactions and (in animals for which it is not a vitamin) vitamin C.

Image Describe and explain the consequences of large intakes of fructose.

Image Describe the synthesis and physiological importance of galactose.

Image Explain the consequences of genetic defects of glucose 6-phosphate dehydrogenase deficiency (favism), the uronic acid pathway (essential pentosuria), and fructose and galactose metabolism.

BIOMEDICAL IMPORTANCE

The pentose phosphate pathway 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 maintaining reduced glutathione for antioxidant activity, 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 from dietary starch, sucrose, and lactose, respectively. Fructose and galactose can be converted to glucose, mainly in the liver.

Genetic deficiency of glucose 6-phosphate dehydrogenase, the first enzyme of the pentose phosphate pathway, is a major cause of acute hemolysis of red blood cells, resulting in hemolytic anemia. Glucuronic acid is synthesized from glucose via the uronic acid pathway, of minor quantitative importance, but of major significance for the conjugation and excretion of metabolites and foreign chemicals (xenobiotics) as glucuronides. A deficiency in the pathway leads to the condition of essential pentosuria. The lack of one enzyme of the pathway (gulonolactone oxidase) in primates and some other animals explains why ascorbic acid (vitamin C) is a dietary requirement for humans but not most other mammals. Deficiencies in the enzymes of fructose and galactose metabolism lead to metabolic diseases such as essential fructosuria, hereditary fructose intolerance, and galactosemia.

THE PENTOSE PHOSPHATE PATHWAY FORMS NADPH & RIBOSE PHOSPHATE

The pentose phosphate pathway (hexose monophosphate shunt) is a more complex pathway than glycolysis (Figure 21–1). Three molecules of glucose 6-phosphate give rise to three molecules of CO2 and three 5-carbon sugars. 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.

Image

FIGURE 21–1 Flow chart of pentose phosphate pathway and its connections with the pathway of glycolysis. The full pathway, as indicated, consists of three interconnected cycles in which glucose 6-phosphate is both substrate and end-product. The reactions above the broken line are nonreversible, whereas all reactions under that line are freely reversible apart from that catalyzed by fructose 1,6-bisphosphatase.

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 irreversible oxidative phase and a reversible nonoxidative phase. 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 Figure 21–1).

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 and 21-2). The hydrolysis of 6-phosphogluconolactone is accomplished by the enzyme gluconolactone hydrolase. 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.

In the endoplasmic reticulum, an isoenzyme of glucose 6-phosphate dehydrogenase, hexose 6-phosphate dehydrogenase, provides NADPH for hydroxylation (mixed function oxidase) reactions, and also for 11-β-hydroxysteroid dehydrogenase-1. This enzyme catalyzes the reduction of (inactive) cortisone to (active) cortisol in liver, the nervous system, and adipose tissue. It is the major source of intracellular cortisol in these tissues and may be important in obesity and the metabolic syndrome.

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 ketoisomeraseconverts ribulose 5-phosphate to the corresponding aldopentose, ribose 5-phosphate, which is used for nucleotide and nucleic acid synthesis. 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. Measurement of erythrocyte transketolase and its activation by thiamin diphosphate provides an index of vitamin B1 nutritional status (Chapter 44). 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. 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. Transaldolase has no cofactor, and the reaction proceeds via the intermediate formation of a Schiff base of dihydroxyacetone to the ε-amino group of a lysine residue in the enzyme. 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.

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.

The Two Major Pathways for the Catabolism of Glucose Have Little in Common

Although glucose 6-phosphate is common to both pathways, the pentose phosphate pathway is markedly different from glycolysis. Oxidation utilizes NADP rather than NAD, and CO2, which is not produced in glycolysis, is a characteristic product. No ATP is generated in the pentose phosphate pathway, whereas it is a major product of glycolysis.

The two pathways are, however, connected. Xylulose 5-phosphate activates the protein phosphatase that dephosphorylates the 6-phosphofructo-2-kinase/fructose 2,6-bisphophatase bifunctional enzyme (Chapter 18). This activates the kinase and inactivates the phosphatase, leading to increased formation of fructose 2,6-bisphosphate, increased activity of phosphofructokinase-1, and hence increased glycolytic flux. Xylulose 5-phosphate also activates the protein phosphatase that initiates the nuclear translocation and DNA binding of the carbohydrate response element binding protein, leading to increased synthesis of fatty acids (Chapter 23) in response to a high carbohydrate diet.

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. Those tissues in which the pathway is active use NADPH in reductive syntheses, for example, 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.

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. 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.

Image

FIGURE 21–2 The pentose phosphate pathway. (Image PRPP, 5-phosphoribosyl 1-pyrophosphate.)

THE PENTOSE PHOSPHATE PATHWAY & GLUTATHIONE PEROXIDASE PROTECT ERYTHROCYTES AGAINST HEMOLYSIS

In red blood cells, the pentose phosphate pathway is the sole source of NADPH for the reduction of oxidized glutathione catalyzed by glutathione reductase, a flavoprotein containing FAD. Reduced glutathione removes H2O2 in a reaction catalyzed by glutathione peroxidase, an enzyme that contains the selenium analog 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. In other tissues, NADPH can also be generated by the reaction catalyzed by the malic enzyme.

Image

FIGURE 21–3 Role of the pentose phosphate pathway in the glutathione peroxidase reaction of erythrocytes. (G-SH, reduced glutathione; G-S-S-G, oxidized glutathione; Se, selenium-containing enzyme.)

GLUCURONATE, A PRECURSOR OF PROTEOGLYCANS & CONJUGATED GLUCURONIDES, IS A PRODUCT OF THE URONIC ACID PATHWAY

In liver, the uronic acid pathway catalyzes the conversion of glucose to glucuronic acid, ascorbic acid (except in human beings and other species for which ascorbate is a vitamin), and pentoses (Figure 21–4). It is also an alternative oxidative pathway for glucose that, like the pentose phosphate pathway, does not lead to the formation of ATP. Glucose 6-phosphate is isomerized to glucose 1-phosphate, which then reacts with uridine triphosphate (UTP) to form uridine diphosphate glucose (UDPGlc) in a reaction catalyzed by UDPGlc pyrophosphorylase, as occurs in glycogen synthesis (Chapter 19). UDPGlc is oxidized at carbon 6 by NAD-dependent UDPGlc dehydrogenase in a two-step reaction to yield UDP-glucuronate.

Image

FIGURE 21–4 Uronic acid pathway. (*Indicates the fate of carbon 1 of glucose; Image,—PO32-.)

UDP-glucuronate is the source of glucuronate for reactions involving its incorporation into proteoglycans or for reaction with substrates such as steroid hormones, bilirubin, and a number of drugs that are excreted in urine or bile as glucuronide conjugates (Figure 31–13).

Glucuronate is reduced to L-gulonate, the direct precursor of ascorbate in those animals capable of synthesizing this vitamin, in an NADPH-dependent reaction. In human beings and other primates, as well as guinea pigs, bats, and some birds and fishes, ascorbic acid cannot be synthesized because of the absence of L-gulonolactone oxidase. L-Gulonate is oxidized to 3-keto-L-gulonate, which is then decarboxylated to L-xylulose. L-Xylulose is converted to the D isomer by an NADPH-dependent reduction to xylitol, followed by oxidation in an NAD-dependent reaction to D-xylulose. After conversion to D-xylulose 5-phosphate, it is metabolized via the pentose phosphate pathway.

INGESTION OF LARGE QUANTITIES OF FRUCTOSE HAS PROFOUND METABOLIC CONSEQUENCES

Diets high in sucrose or in high-fructose syrups (HFS) used in manufactured foods and beverages lead to large amounts of fructose (and glucose) entering the hepatic portal vein.

Fructose undergoes more rapid glycolysis in the liver than does glucose because it bypasses the regulatory step catalyzed by phosphofructokinase (Figure 21–5). This allows fructose to flood the pathways in the liver, leading to increased fatty acid synthesis, esterification of fatty acids, and secretion of VLDL, which may raise serum triacylglycerols and ultimately raise LDL cholesterol concentrations. A specific kinase, fructokinase, in liver, kidney, and intestine, catalyzes the phosphorylation of fructose to fructose 1-phosphate. This enzyme does not act on glucose, and, unlike glucokinase, its activity is not affected by fasting or by insulin, which may explain why fructose is cleared from the blood of diabetic patients at a normal rate. Fructose 1-phosphate is cleaved to D-glyceraldehyde and dihydroxyacetone phosphate by aldolase B, an enzyme found in the liver, which also functions in glycolysis in the liver by cleaving fructose 1,6-bisphosphate. D-Glyceraldehyde enters glycolysis via phosphorylation to glyceraldehyde 3-phosphate catalyzed by triokinase. The two triose phosphates, dihydroxyacetone phosphate, and glyceraldehyde 3-phosphate, may either be degraded by glycolysis or may be substrates for aldolase and hence gluconeogenesis, which is the fate of much of the fructose metabolized in the liver.

Image

FIGURE 21–5 Metabolism of fructose. Aldolase A is found in all tissues, whereas aldolase B is the predominant form in liver. (*Not found in liver.)

In extrahepatic tissues, hexokinase catalyzes the phosphorylation of most hexose sugars, including fructose, but glucose inhibits the phosphorylation of fructose since it is a better substrate for hexokinase. Nevertheless, some fructose can be metabolized in adipose tissue and muscle. Fructose is found in seminal plasma and in the fetal circulation of ungulates and whales. Aldose reductase is found in the placenta of the ewe and is responsible for the secretion of sorbitol into the fetal blood. The presence of sorbitol dehydrogenase in the liver, including the fetal liver, is responsible for the conversion of sorbitol into fructose. This pathway is also responsible for the occurrence of fructose in seminal fluid.

GALACTOSE IS NEEDED FOR THE SYNTHESIS OF LACTOSE, GLYCOLIPIDS, PROTEOGLYCANS, & GLYCOPROTEINS

Galactose is derived from intestinal hydrolysis of the disaccharide lactose, the sugar of milk. It is readily converted in the liver to glucose. Galactokinase catalyzes the phosphorylation of galactose, using ATP as phosphate donor (Figure 21–6). Galactose 1-phosphate reacts with UDPGlc to form uridine diphosphate galactose (UDPGal) and glucose 1-phosphate, in a reaction catalyzed by galactose 1-phosphate uridyl transferase. The conversion of UDP-Gal to UDPGlc is catalyzed by UDPGal 4-epimerase. The reaction involves oxidation, and then reduction, at carbon 4, with NAD+ as a coenzyme. The UDPGlc is then incorporated into glycogen (Chapter 19).

Image

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

The epimerase reaction is freely reversible, so glucose can be converted to galactose, and galactose is not a dietary essential. Galactose is required in the body not only for the formation of lactose in lactation, but also as a constituent of glycolipids (cerebrosides), proteoglycans, and glycoproteins. In the synthesis of lactose in the mammary gland, UDPGal condenses with glucose to yield lactose, catalyzed by lactose synthase (see Figure 21–6).

Glucose Is the Precursor of Amino Sugars (Hexosamines)

Amino sugars are important components of glycoproteins (Chapter 47), of certain glycosphingolipids (eg, gangliosides; Chapter 15), and of glycosaminoglycans (Chapter 48). The major amino sugars are the hexosamines glucosamine, galactosamine, and mannosamine, and the nine-carbon compound sialic acid. The principal sialic acid found in human tissues is N-acetylneuraminic acid (NeuAc). A summary of the metabolic interrelationships among the amino sugars is shown in Figure 21–7.

Image

FIGURE 21–7 Summary of the interrelationships in metabolism of amino sugars. (*Analogous to UDPGlc.) Other purine or pyrimidine nucleotides may be similarly linked to sugars or amino sugars. Examples are thymidine diphosphate (TDP)-glucosamine and TDP-N-acetylglucosamine.

CLINICAL ASPECTS

Impairment of the Pentose Phosphate Pathway Leads to Erythrocyte Hemolysis

Genetic defects of glucose 6-phosphate dehydrogenase, with consequent impairment of the generation of NADPH, are common in populations of Mediterranean and Afro-Caribbean origin. The gene is on the X chromosome, so it is mainly males who are affected. Some 400 million people carry a mutated gene for glucose 6-phosphate dehydrogenase, making it the most common genetic defect, but most are asymptomatic. In some populations, glucose 6-phosphatase deficiency is common enough for it to be regarded as a genetic polymorphism. The distribution of mutant genes parallels that of malaria, suggesting that being heterozygous confers resistance against malaria. The defect is manifested as red cell hemolysis (hemolytic anemia) when susceptible individuals are subjected to oxidative stress (Chapter 52) from infection, drugs such as the antimalarial primaquine, and sulfonamides, or when they have eaten fava beans (Vicia faba—hence the name of the disease, favism).

There are two main variants of favism. In the Afro-Caribbean variant the enzyme is unstable, so that while average red-cell activities are low, it is only the older erythrocytes that are affected by oxidative stress, and the hemolytic crises tend to be self-limiting. By contrast, in the Mediterranean variant the enzyme is stable, but has low activity in all erythrocytes. Hemolytic crises in these people are more severe and can be fatal. Glutathione peroxidase is dependent upon a supply of NADPH, which in erythrocytes can be formed only via the pentose phosphate pathway. It reduces organic peroxides and H2O2, as part of the body’s defense against lipid peroxidation (Figure 15–21). Measurement of erythrocyte glutathione reductase, and its activation by FAD is used to assess vitamin B2 nutritional status (Chapter 44).

Disruption of the Uronic Acid Pathway Is Caused by Enzyme Defects & Some Drugs

In the rare benign hereditary condition essential pentosuria, considerable quantities of L-xylulose appear in the urine, because of the absence of the enzyme necessary to reduce L-xylulose to xylitol. Although pentosuria is benign, with no clinical consequences, xylulose is a reducing sugar and can give false positive results when urinary glucose is measured using alkaline copper reagents. Various drugs increase the rate at which glucose enters the uronic acid pathway. For example, administration of barbital or chlorobutanol to rats results in a significant increase in the conversion of glucose to glucuronate, L-gulonate, and ascorbate. Aminopyrine and antipyrine increase the excretion of L-xylulose in pentosuric subjects. Pentosuria also occurs after consumption of relatively large amounts of fruits such as pears that are rich sources of pentoses (alimentary pentosuria).

Loading of the Liver with Fructose May Potentiate Hypertriacylglycerolemia, Hypercholesterolemia, & Hyperuricemia

In the liver, fructose increases fatty acid and triacylglycerol synthesis and VLDL secretion, leading to hypertriacylglycerolemia—and increased LDL cholesterol—which can be regarded as potentially atherogenic (Chapter 26). This is because fructose enters glycolysis via fructokinase, and the resulting fructose 1-phosphate bypasses the regulatory step catalyzed by phosphofructokinase (Chapter 18). In addition, acute loading of the liver with fructose, as can occur with intravenous infusion or following very high fructose intakes, causes sequestration of inorganic phosphate in fructose 1-phosphate and diminished ATP synthesis. As a result, there is less inhibition of de novo purine synthesis by ATP, and uric acid formation is increased, causing hyperuricemia, which is the cause of gout (Chapter 33). Since fructose is absorbed from the small intestine by (passive) carrier-mediated diffusion, high oral doses may lead to osmotic diarrhea.

Defects in Fructose Metabolism Cause Disease

A lack of hepatic fructokinase causes essential fructosuria, which is a benign and asymptomatic condition. The absence of aldolase B, which cleaves fructose 1-phosphate, leads to hereditary fructose intolerance, which is characterized by profound hypoglycemia and vomiting after consumption of fructose (or sucrose, which yields fructose on digestion) (Figure 21–5). Diets low in fructose, sorbitol, and sucrose are beneficial for both conditions. One consequence of hereditary fructose intolerance and of a related condition as a result of fructose 1,6-bisphosphatase deficiency is fructose-induced hypoglycemia despite the presence of high glycogen reserves, because fructose 1-phosphate and 1,6-bisphosphate allosterically inhibit liver glycogen phosphorylase. The sequestration of inorganic phosphate also leads to depletion of ATP and hyperuricemia.

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) is responsible 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. 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. Simultaneously, myoinositol levels fall. In experimental animals, sorbitol accumulation and myoinositol depletion, as well as diabetic cataract, can be prevented by aldose reductase inhibitors. One inhibitor has been licensed in Japan for treatment of diabetic neuropathy, although there is little or no evidence that inhibitors are effective in preventing cataract or slowing the progression of diabetic neuropathy in human beings.

Enzyme Deficienciesin 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 best known. Galactose is a substrate for aldose reductase, forming galactitol, which accumulates in the lens of the eye, causing cataract. The condition is more severe if it is the result of a defect in the uridyl transferase since galactose 1-phosphate accumulates and depletes the liver of inorganic phosphate. Ultimately, liver failure and mental deterioration result. In uridyl transferase deficiency, the epimerase is present in adequate amounts, so that the galactosemic individual can still form UDPGal from glucose. This explains how it is possible for normal growth and development of affected children to occur despite the galactose-free diets used to control the symptoms of the disease.

SUMMARY

Image The pentose phosphate pathway, present in the cytosol, can account for the complete oxidation of glucose, producing NADPH and CO2 but not ATP.

Image The pathway has an oxidative phase, which is irreversible and generates NADPH, and a nonoxidative phase, which is reversible and provides ribose precursors for nucleotide synthesis. The complete pathway is present mainly in those tissues having a requirement for NADPH for reductive syntheses, eg, lipogenesis or steroidogenesis, whereas the nonoxidative phase is present in all cells requiring ribose.

Image In erythrocytes, the pathway has a major function in preventing hemolysis by providing NADPH to maintain glutathione in the reduced state as the substrate for glutathione peroxidase.

Image The uronic acid pathway is the source of glucuronic acid for conjugation of many endogenous and exogenous substances before excretion as glucuronides in urine and bile.

Image Fructose bypasses the main regulatory step in glycolysis, catalyzed by phosphofructokinase, and stimulates fatty acid synthesis and hepatic triacylglycerol secretion.

Image Galactose is synthesized from glucose in the lactating mammary gland and in other tissues where it is required for the synthesis of glycolipids, proteoglycans, and glycoproteins.

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