Harper's Biochemistry Chapter 20 - The Pentose Phosphate Pathway & Other Pathways of Hexose Metabolism.PDF

C H A P T E R The Pentose Phosphate Pathway & Other Pathways of Hexose Metabolism Owen P. McGuinness, PhD 20 OBJ E C TI VE S Describe the pentose phosphate...

C H A P T E R The Pentose Phosphate Pathway & Other Pathways of Hexose Metabolism Owen P. McGuinness, PhD 20 OBJ E C TI VE S Describe the pentose phosphate pathway and its roles as a source of NADPH and of ribose for nucleotide synthesis. After studying this chapter, Describe the uronic acid pathway and its importance for synthesis of glucuronic you should be able to: acid for conjugation reactions and (in animals for which it is not a vitamin) vitamin C. Describe the metabolism of fructose and the impact of high sugar intake on metabolic disease risk. Describe the synthesis and physiologic importance of galactose. Explain the consequences of genetic defects of glucose-6-phosphate dehydrogenase (favism), the uronic acid pathway (essential pentosuria), and fructose and galactose metabolism. BIOMEDICAL IMPORTANCE enzyme of the pathway (guonoactone oxiase) in primates an some other animas expains why ascorbic acid (vitamin C; The pentose phosphate pathway is an aternative route for the see Chapter 44) is a ietary requirement for human beings but metaboism of gucose. It oes not ea to formation of ATP not most other mammas. Deficiencies in the enzymes of fruc- but has two major functions: (1) the formation of NADPH tose an gaactose metaboism ea to metaboic iseases such for synthesis of fatty acis (see Chapter 23) an sterois (see as essential fructosuria, hereditary fructose intolerance, Chapter 26), an maintaining reuce gutathione for antioxi- and galactosemia. ant activity, an (2) the synthesis of ribose for nuceotie an nuceic aci formation (see Chapter 32). Gucose, fructose, an gaactose are the main hexoses absorbe from the gastro- THE PENTOSE PHOSPHATE intestina tract, erive from ietary starch, sucrose, an ac- PATHWAY FORMS NADPH & tose, respectivey. Fructose an gaactose can be converte to RIBOSE PHOSPHATE gucose, mainy in the iver. Genetic eficiency of glucose-6-phosphate dehydro- The pentose phosphate pathway (hexose monophosphate genase, the first enzyme of the pentose phosphate pathway, shunt, Figure 20–1) is a more compex pathway than gycoy- causes acute hemoysis of re boo ces, resuting in hemo- sis (see Chapter 17). Three moecues of gucose-6-phosphate lytic anemia. Gucuronic aci is synthesize from gucose via give rise to three moecues of CO2 an three five-carbon the uronic acid pathway, of minor quantitative importance, sugars. These are rearrange to regenerate two moecues of but of major significance for the conjugation an excre- gucose-6-phosphate an one moecue of the gycoytic inter- tion of metaboites an foreign chemicas (xenobiotics; see meiate, gyceraehye-3-phosphate. Since two moecues Chapter 47) as glucuronides. A eficiency in the pathway of gyceraehye-3-phosphate can regenerate gucose-6- eas to the conition of essential pentosuria. The ack of one phosphate, the pathway can account for the compete oxia- tion of gucose. If this cyce is repeate gucose wi eventuay be converte to carbon ioxie an water an NADPH wi be This was aapte from the 30th eition by Davi A. Bener, PhD & generate (C6H12O6 + 12 NADP+ + 6 H2O → 6 CO2 +12 H + Peter A. Mayes, PhD, DSc 12 NADPH). 191 192 SECTION IV Metabolism of Carbohydrates Glucose-6-phosphate Glucose-6-phosphate Glucose-6-phosphate C6 C6 C6 NADP+ + H2O NADP + + H 2O NADP+ + H 2O Glucose-6-phosphate dehydrogenase NADPH + H+ NADPH + H+ NADPH + H+ 6-Phosphogluconate 6-Phosphogluconate 6-Phosphogluconate C6 C6 C6 NADP+ NADP+ NADP+ 6-Phospho- gluconate dehydrogenase NADPH + H+ NADPH + H+ NADPH + H + CO2 CO2 CO2 Ribulose-5-phosphate Ribulose-5-phosphate Ribulose-5-phosphate C5 C5 C5 3-Epimerase Keto-isomerase 3-Epimerase Xylulose-5-phosphate Ribose-5-phosphate Xylulose-5-phosphate C5 C5 C5 Transketolase Synthesis of nucleotides, RNA, DNA Glyceraldehyde-3-phosphate Sedoheptulose-7-phosphate C3 C7 Transaldolase Fructose-6-phosphate Erythrose-4-phosphate C6 C4 Transketolase Fructose-6-phosphate Glyceraldehyde-3-phosphate C6 C3 Phosphotriose Aldolase isomerase Phosphohexose Phosphohexose 1 /2 Fructose 1,6-bisphosphate isomerase isomerase C6 Fructose 1,6- bisphosphatase 1/2 Fructose-6-phosphate C6 Phosphohexose isomerase Glucose-6-phosphate Glucose-6-phosphate 1/2 Glucose-6-phosphate C6 C6 C6 FIGURE 20–1 Flowchart of pentose phosphate pathway and its connections with the pathway of glycolysis. The full pathway, as indi- cated, 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 be ivie into two phases: an irreversible oxidative phase PHOSPHATE PATHWAY OCCUR an a reversible nonoxidative phase. In the first phase, gucose-6-phosphate unergoes ehyrogenation an IN THE CYTOSOL ecarboxyation to yie a pentose, ribuose-5-phosphate. Like gycoysis, the enzymes of the pentose phosphate path- In the secon phase, ribuose-5-phosphate is converte way are cytosoic. Unike gycoysis, oxiation is achieve back to gucose-6-phosphate by a series of reactions invov- by ehyrogenation using NADP+, not NAD+, as the hyro- ing mainy two enzymes: transketolase an transaldolase gen acceptor. The sequence of reactions of the pathway may (see Figure 20–1).  CHAPTER 20 The Pentose Phosphate Pathway & Other Pathways of Hexose Metabolism 193 The Oxidative Phase Generates NADPH gluconolactone hydrolase. A secon oxiative step is cata- yze by 6-phosphogluconate dehydrogenase, which aso Dehyrogenation of gucose-6-phosphate to 6-phosphoguconate requires NADP+ as hyrogen acceptor. Decarboxyation forms occurs via the formation of 6-phosphoguconoactone, cata- the ketopentose ribuose-5-phosphate. yze by glucose-6-phosphate dehydrogenase, an NADP- In the enopasmic reticuum, an isoenzyme of gucose- epenent enzyme (Figures 20–1 an 20–2). The hyroysis 6-phosphate ehyrogenase, hexose-6-phosphate ehyrogenase, of 6-phosphoguconoactone is accompishe by the enzyme O – HO C H NADP+ NADPH + H+ C H2O COO H C OH Mg2+ H C OH Mg2+, Mn2+, H C OH or Ca2+ or Ca2+ HO C H HO C H HO C H O O H C OH Glucose-6-phosphate H C OH Gluconolactone H C OH dehydrogenase hydrolase H C H C H C OH CH2 O P CH2 O P CH2 O P -D-Glucose-6-phosphate 6-Phosphogluconolactone 6-Phosphogluconate NADP+ 6-Phosphogluconate Mg , Mn2+, 2+ dehydrogenase or Ca2+ NADP+ + H+ – COO CHOH CH2OH H C OH Ribose-5-phosphate C OH ketoisomerase C O C O H C OH H C OH H C OH H C OH H C OH H C OH CH2 O P CH2 O P CO2 CH2 O P Enediol form Ribulose-5-phosphate 3-Keto 6-phosphogluconate Ribulose-5-phosphate 3-epimerase CH2OH CH2OH C O C O H C OH HO C H HO *C H H C OH H C OH H *C OH H C OH O H C OH *CH2 O P H C Xylulose-5-phosphate H C OH CH2 O P CH2 O P Ribose-5-phosphate Sedoheptulose-7-phosphate ATP Transketolase Mg2+ PRPP Thiamin– P H *C O synthetase 2 AMP Mg2+ H *C OH CH2OH H C O P P *CH2 O P C O H C OH Glyceraldehyde-3-phosphate HO C H H C OH O Transaldolase H *C OH H C H C O H *C OH CH2 O P H C OH *CH2 O P PRPP H C OH Fructose-6-phosphate CH2 O P Erythrose-4-phosphate CH2OH CH2OH C O C O Transketolase HO C H HO C H Thiamin– P 2 H C O H C OH Mg2+ H C OH H C OH H C OH CH2 O P CH2 O P CH2 O P Xylulose-5-phosphate Glyceraldehyde-3-phosphate Fructose-6-phosphate FIGURE 20–2 The pentose phosphate pathway. (P, —PO3 2–; PRPP, 5-phosphoribosyl 1-pyrophosphate.) 194 SECTION IV Metabolism of Carbohydrates provies NADPH for hyroxyation (mixe function oxiase) generate in the pentose phosphate pathway, whereas it is a reactions, an aso for 11-β-hyroxysteroi ehyrogenase-1. prouct of gycoysis. This enzyme catayzes the reuction of (inactive) cortisone to The two pathways are, however, connecte. Xyuose (active) cortiso in iver, the nervous system, an aipose tissue. 5-phosphate activates the protein phosphatase that ephosphor- It is the major source of intraceuar cortiso in these tissues an yates the 6-phosphofructo-2-kinase/fructose 2,6-bisphophatase may be important in obesity an the metaboic synrome. bifunctiona enzyme (see Chapter 17). This activates the kinase an inactivates the phosphatase, eaing to increase formation The Nonoxidative Phase Generates of fructose 2,6-bisphosphate, increase activity of phospho- Ribose Precursors fructokinase-1, an hence increase gycoytic fux. Xyuose Ribuose-5-phosphate is the substrate for two enzymes. Ribulose- 5-phosphate aso activates the protein phosphatase that initiates 5-phosphate 3-epimerase aters the configuration about carbon the nucear transocation an DNA bining of the carbohyrate 3, forming the epimer xyuose 5-phosphate, aso a ketopentose. response eement-bining protein, eaing to increase synthesis Ribose-5-phosphate ketoisomerase converts ribuose-5- of fatty acis (see Chapter 23) in response to a high-carbohyrate phosphate to the corresponing aopentose, ribose-5-phosphate, iet. This coupes the eman for NADPH for ipogenesis an which is use for nuceotie an nuceic aci synthesis. Trans- activation of the ipogenic enzymatic machinery. ketolase transfers the two-carbon unit comprising carbons 1 an 2 of a ketose onto the aehye carbon of an aose sugar. It Reducing Equivalents Are Generated in therefore affects the conversion of a ketose sugar into an aose Those Tissues Specializing in Reductive with two carbons ess an an aose sugar into a ketose with two Syntheses carbons more. The reaction requires Mg2+ an thiamin diphos- The pentose phosphate pathway is active in iver, aipose tis- phate (vitamin B1) as coenzyme. Measurement of erythrocyte sue, arena cortex, thyroi, erythrocytes, testis, an actating transketoase an its activation by thiamin iphosphate provies mammary gan. Its activity is ow in nonactating mammary an inex of vitamin B1 nutritiona status (see Chapter 44). The gan an skeeta musce. Those tissues in which the pathway two-carbon moiety is transferre as gycoaehye boun to is active use NADPH in reuctive syntheses, for exampe, of thiamin iphosphate. Thus, transketoase catayzes the transfer fatty acis, sterois, amino acis via gutamate ehyrogenase, of the two-carbon unit from xyuose 5-phosphate to ribose-5- an reuce gutathione. The synthesis of gucose-6-phosphate phosphate, proucing the seven-carbon ketose seoheptuose- ehyrogenase an 6-phosphoguconate ehyrogenase may 7-phosphate an the aose gyceraehye-3-phosphate. These aso be inuce by insuin in the fe state, when ipogenesis two proucts then unergo transaoation. Transaldolase cat- increases. NADPH is aso use by NADPH oxiase in phago- ayzes the transfer of a three-carbon ihyroxyacetone moiety cytes an neutrophis to estroy “respiratory burst” engufe (carbons 1–3) from the ketose seoheptuose-7-phosphate onto ces an bacteria using superoxie (see Chapter 54). the aose gyceraehye-3-phosphate to form the ketose fructose-6-phosphate an the four-carbon aose erythrose- Ribose Can Be Synthesized 4-phosphate. Transaoase has no cofactor, an the reaction in Virtually All Tissues procees via the intermeiate formation of a Schiff base of ihy- Litte or no ribose circuates in the boostream, so tissues roxyacetone to the ε-amino group of a ysine resiue in the have to synthesize the ribose they require for nuceotie an enzyme. In a further reaction catayze by transketolase, xyuose nuceic aci synthesis using the pentose phosphate pathway 5-phosphate serves as a onor of gycoaehye. In this case, (see Figure 20–2). It is not necessary to have a competey func- erythrose-4-phosphate is the acceptor, an the proucts of the reac- tioning pentose phosphate pathway for a tissue to synthesize tion are fructose-6-phosphate an gyceraehye-3-phosphate. ribose-5-phosphate. Musce has ony ow activity of gucose- In orer to oxiize gucose competey to CO2 via the pen- 6-phosphate ehyrogenase an 6-phosphoguconate ehyro- tose phosphate pathway, there must be enzymes present in genase, but, ike most other tissues, it is capabe of synthesizing the tissue to convert gyceraehye-3-phosphate to gucose- ribose-5-phosphate by reversa of the nonoxiative phase of the 6-phosphate. This invoves reversa of gycoysis an the gu- pentose phosphate pathway utiizing fructose-6-phosphate. coneogenic enzyme fructose 1,6-bisphosphatase. In tissues that ack this enzyme, gyceraehye-3-phosphate foows the norma pathway of gycoysis to pyruvate. THE PENTOSE PHOSPHATE The Two Major Pathways for the PATHWAY & GLUTATHIONE Catabolism of Glucose Have Little in PEROXIDASE PROTECT Common ERYTHROCYTES AGAINST Athough gucose-6-phosphate is common to both pathways, HEMOLYSIS the pentose phosphate pathway is markey ifferent from gy- In re boo ces, the pentose phosphate pathway is the soe coysis. Oxiation utiizes NADP+ rather than NAD+, an CO2, source of NADPH for the reuction of oxiize gutathione which is not prouce in gycoysis, is prouce. No ATP is catayze by glutathione reductase, a favoprotein containing  CHAPTER 20 The Pentose Phosphate Pathway & Other Pathways of Hexose Metabolism 195 Gucuronate is reuce to l-guonate, the irect precur- sor of ascorbate in those animas capabe of synthesizing this vitamin, in an NADPH-epenent reaction. In human beings an other primates, as we as guinea pigs, bats, an some birs an fishes, ascorbic aci cannot be synthesize because of the absence of l-gulonolactone oxidase. l-Guonate is oxiize to 3-keto-l-guonate, which is then ecarboxyate to l-xyuose. l-Xyuose is converte to the d-isomer by an NADPH- epenent reuction to xyito, foowe by oxiation in an NAD-epenent reaction to d-xyuose. After conversion to d-xyuose 5-phosphate, it is metaboize via the pentose phosphate pathway. INGESTION OF LARGE QUANTITIES OF FRUCTOSE HAS PROFOUND METABOLIC CONSEQUENCES FIGURE 20–3 Role of the pentose phosphate pathway in the glutathione peroxidase reaction of erythrocytes. (GSH, reduced Diets high in sucrose or in high-fructose syrups (HFCS 42 an glutathione; GSSG, oxidized glutathione; Se, selenium-containing HFCS55) use in manufacture foos an beverages ea to enzyme.) arge amounts of fructose (an gucose) entering the hepatic porta vein. Note that high fructose corn syrup espite the name favin aenine inuceotie (FAD). Reuce gutathione removes oes not have much more fructose than sucrose (50% fructose). H2O2 in a reaction catayze by glutathione peroxidase, an In fact, other ietary sources of sugar have more fructose enzyme that contains the selenium anaog of cysteine (seeno- (eg, appes 73%). The important issue is the tota quantity of cysteine) at the active site (Figure 20–3). The reaction is impor- simpe sugars ingeste is too high. In 1900 Americans ingeste tant since accumuation of H2O2 may ecrease the ife span of about 15 g/ay of fructose (50 kca/ay) primariy from fruits the erythrocyte by causing oxiative amage to the ce mem- an vegetabes, in 2020 it is 77 g/ay an in chiren it is about brane, eaing to hemoysis. In other tissues, NADPH can aso 81 g/ay (~300 kcas/ay), a sixfo increase. The American be generate by the reaction catayze by the maic enzyme. Heart Association recommene keeping the intake beow 25 g/ay (100 kca/ay) for women an chiren an 37 g/ay (150 kca/ay) for men, as the risk of obesity, hyperuriaciemia, GLUCURONATE, A PRECURSOR OF high boo pressure, an iabetes are increase when simpe PROTEOGLYCANS & CONJUGATED sugar intake is high. GLUCURONIDES, IS A PRODUCT Neary 90% of the ietary fructose is metaboize by the iver. Fructose unergoes more rapi gycoysis in the iver OF THE URONIC ACID PATHWAY than oes gucose because it bypasses the reguatory step In iver, the uronic acid pathway catayzes the conversion of gu- catayze by phosphofructokinase (Figure 20–5). This aows cose to gucuronic aci, ascorbic aci (except in human beings fructose to foo the pathways in the iver, eaing to increase an other species for which ascorbate is a vitamin, vitamin C), fatty aci synthesis, esterification of fatty acis, an secretion an pentoses (Figure 20–4). It is aso an aternative oxiative of very-ow-ensity ipoprotein (VLDL), which may raise pathway for gucose that, ike the pentose phosphate pathway, serum triacygyceros an utimatey raise LDL choestero oes not ea to the formation of ATP. Gucose-6-phosphate is concentrations. Fructokinase in iver, kiney, an intestine isomerize to gucose-1-phosphate, which then reacts with uri- catayzes the phosphoryation of fructose to fructose-1- ine triphosphate (UTP) to form uriine iphosphate gucose phosphate. This enzyme oes not act on gucose, an, unike (UDPGc) in a reaction catayze by UDPGlc pyrophosphory- gucokinase, its activity is not affecte by fasting or by insuin, lase, as occurs in gycogen synthesis (see Chapter 18). UDPGc which may expain why fructose is ceare from the boo of ia- is oxiize at carbon 6 by NAD-epenent UDPGlc dehydro- betic patients at a norma rate. Fructose-1-phosphate is ceave to genase in a two-step reaction to yie UDP-gucuronate. d-gyceraehye an ihyroxyacetone phosphate by aldolase B, UDP-gucuronate is the source of gucuronate for reac- an enzyme foun in the iver, which aso functions in gycoysis in tions invoving its incorporation into proteogycans (see the iver by ceaving fructose 1,6-bisphosphate. d-Gyceraehye Chapter 46) or for reaction with substrates such as steroi enters gycoysis via phosphoryation to gyceraehye-3- hormones, biirubin, an a number of rugs that are excrete phosphate catayze by triokinase. The two triose phosphates, in urine or bie as gucuronie conjugates (see Figure 31–13 ihyroxyacetone phosphate an gyceraehye-3-phosphate, an Chapter 47). may either be egrae by gycoysis or may be substrates for 196 SECTION IV Metabolism of Carbohydrates FIGURE 20–4 Uronic acid pathway. (*Indicates the fate of carbon 1 of glucose.) aoase an hence guconeogenesis, which is the fate of much of most hexose sugars, incuing fructose, but gucose inhibits of the fructose metaboize in the iver. To ampify the carbo- the phosphoryation of fructose since it is a better substrate for hyrate oaing effect of fructose, fructose-1-phosphate acti- hexokinase. Nevertheess, some fructose can be metaboize vates gucokinase an thus ampifies ietary gucose entry into in aipose tissue an musce. Fructose is foun in semina iver. In aition, because of the rapi entry an phosphorya- pasma an in the feta circuation of unguates an whaes. tion of fructose the consumption of ATP is very fast causing a Aose reuctase is foun in the pacenta of the ewe an is rise in ADP an AMP. AMP can be converte to hypoxanthine responsibe for the secretion of sorbito into the feta boo. in the iver an to uric aci (xanthine oxiase) that can cause The presence of sorbito ehyrogenase in the iver, incuing gout (see Chapter 33). the feta iver, is responsibe for the conversion of sorbito into Extrahepatic tissues generay o not see much fructose. fructose. This pathway is aso responsibe for the occurrence However in those tissues hexokinase catayzes the phosphoryation of fructose in semina fui.  CHAPTER 20 The Pentose Phosphate Pathway & Other Pathways of Hexose Metabolism 197 ATP Glycogen Hexokinase Glucokinase Aldose * reductase Glucose-6-phosphate D-Glucose D-Sorbitol NAD+ NADPH NADP+ Glucose-6-phosphatase + H+ Phosphohexose isomerase Sorbitol dehydrogenase NADH + H+ Hexokinase Fructose-6-phosphate D-Fructose Diet ATP Fructose 1,6- Fructokinase ATP ATP Phosphofructokinase bisphosphatase Block in essential fructosuria Fructose 1,6-bisphosphate Fructose 1-phosphate Block in hereditary fructose intolerance Aldolase B Dihydroxyacetone-phosphate Aldolase A Phospho- Fatty acid Aldolase B triose esterification isomerase ATP Glyceraldehyde-3-phosphate D-Glyceraldehyde Triokinase 2-Phosphoglycerate Pyruvate Fatty acid synthesis FIGURE 20–5 Metabolism of fructose. Aldolase A is found in all tissues, whereas aldolase B is the predominant form in liver. (*Not found in liver.) GALACTOSE IS NEEDED FOR The epimerase reaction is freey reversibe, so gucose can be converte to gaactose, an gaactose is not a ietary THE SYNTHESIS OF LACTOSE, essentia. Gaactose is require in the boy not ony for the GLYCOLIPIDS, PROTEOGLYCANS, formation of actose in actation but aso as a constituent of & GLYCOPROTEINS gycoipis (cerebrosies), proteogycans, an gycoproteins. In the synthesis of actose in the mammary gan, UDPGa Gaactose is erive from intestina hyroysis of the isac- conenses with gucose to yie actose, catayze by lactose charie lactose, the sugar foun in mik. It is reaiy converte synthase (see Figure 20–6). in the iver to gucose after being transporte by GLUT5. So ike fructose the majority of ietary gaactose is metaboize by the iver. Galactokinase catayzes the phosphoryation Glucose Is the Precursor of Amino of gaactose, using ATP as phosphate onor (Figure 20–6). Sugars (Hexosamines) Gaactose-1-phosphate reacts with UDPGc to form uriine Amino sugars are important components of glycoproteins iphosphate gaactose (UDPGa) an gucose-1-phosphate, in (see Chapter 46), of certain glycosphingolipids (eg, gan- a reaction catayze by galactose-1-phosphate uridyl trans- giosies; see Chapter 21), an of gycosaminogycans (see ferase. The conversion of UDPGa to UDPGc is catayze by Chapter 50). The major amino sugars are the hexosamines UDPGal 4-epimerase. The reaction invoves oxiation, an glucosamine, galactosamine, an mannosamine, an the then reuction, at carbon 4, with NAD+ as a coenzyme. The nine-carbon compoun sialic acid. The principa siaic aci UDPGc is then incorporate into gycogen (see Chapter 18). foun in human tissues is N-acetyneuraminic aci (NeuAc). 198 SECTION IV Metabolism of Carbohydrates A Galactose Glycogen Glycogen synthase ATP Pi Phosphorylase Mg2+ Galactokinase ADP Glucose-1-phosphate Block in Galactose- galactosemia Phosphoglucomutase 1-phosphate UDPGlc Galactose- Uridine 1-phosphate NAD+ diphosphogalactose uridyl transferase 4-epimerase Glucose- 6-phosphatase Glucose- 1-phosphate UDPGal Glucose-6-phosphate Glucose B NAD+ Glucose UDPGlc UDPGal Uridine ATP diphosphogalactose 4-epimerase UDPGlc Mg2+ Hexokinase Lactose pyrophosphorylase PP i Lactose synthase ADP Phosphoglucomutase Glucose-6-phosphate Glucose-1-phosphate Glucose FIGURE 20–6 Pathway of conversion of (A) galactose to glucose in the liver and (B) glucose to lactose in the lactating mammary gland. A summary of the metaboic interreationships among the variants of favism. In the Afro-Caribbean variant, the enzyme amino sugars is shown in Figure 20–7. is unstabe, so that whie average re-ce activities are ow, it is ony the oer erythrocytes that are affecte by oxiative stress, CLINICAL ASPECTS an the hemoytic crises ten to be sef-imiting. By contrast, in the Meiterranean variant the enzyme is stabe, but has ow Impairment of the Pentose Phosphate activity in a erythrocytes. Hemoytic crises in these peope are more severe an can be fata. Gutathione peroxiase is Pathway Leads to Erythrocyte epenent on a suppy of NADPH, which in erythrocytes can Hemolysis ony be forme via the pentose phosphate pathway. It reuces Genetic efects of gucose-6-phosphate ehyrogenase, with organic peroxies an H2O2 as part of the boy’s efense consequent impairment of the generation of NADPH, are com- against ipi peroxiation. Measurement of erythrocyte glu- mon in popuations of Meiterranean an Afro-Caribbean origin. tathione reductase, an its activation by FAD is use to assess The gene is on the X chromosome, so it is mainy maes who are vitamin B2 nutritiona status (see Chapter 44). affecte. Some 400 miion peope carry a mutate gene for gucose-6-phosphate ehyrogenase, making it the most com- Disruption of the Uronic Acid Pathway mon genetic efect, but most are asymptomatic. In some popua- tions, gucose-6-phosphatase eficiency is common enough for Is Caused by Enzyme Defects & Some it to be regare as a genetic poymorphism. The istribution of Drugs mutant genes paraes that of maaria, suggesting that being het- In the rare benign hereitary conition essential pentosuria, erozygous confers resistance against maaria. The efect is mani- consierabe quantities of xylulose appear in the urine because feste as re ce hemoysis (hemolytic anemia) when susceptibe of a ack of xyuose reuctase, the enzyme necessary to reuce iniviuas are subjecte to oxiative stress (see Chapter 45) from xyuose to xyito. Athough pentosuria is benign, with no infection, rugs such as the antimaaria primaquine, an sufon- cinica consequences, xyuose is a reucing sugar an can amies, or when they have eaten fava beans (Vicia faba—hence give fase-positive resuts when urinary gucose is measure the name of the isease, favism). using akaine copper reagents (see Chapter 48). Various rugs Many ifferent mutations are known in the gene for increase the rate at which gucose enters the uronic aci path- gucose-6-phosphate ehyrogenase, eaing to two main way. For exampe, aministration of barbita or chorobutano  CHAPTER 20 The Pentose Phosphate Pathway & Other Pathways of Hexose Metabolism 199 Glycogen Glucose-1-phosphate ATP ADP Glucose Glucose-6-phosphate Fructose-6-phosphate Glutamine Amidotransferase ATP ADP UTP Glutamate Glucosamine Glucosamine Glucosamine UDP- 6-phosphate Phosphogluco- 1-phosphate glucosamine* mutase Acetyl-CoA PP i – Acetyl-CoA ATP ADP N-Acetyl- N-Acetyl- N-Acetyl- glucosamine glucosamine glucosamine Glycosaminoglycans 6-phosphate 1-phosphate (eg, heparin) UTP Epimerase PP i N-Acetyl- mannosamine UDP- Glycosaminoglycans 6-phosphate N-acetylglucosamine* (hyaluronic acid), glycoproteins Phosphoenolpyruvate NAD+ Epimerase N-Acetyl- UDP- neuraminic acid N-acetylgalactosamine* 9-phosphate Inhibiting – allosteric effect Sialic acid, Glycosaminoglycans gangliosides, (chondroitins), glycoproteins glycoproteins FIGURE 20–7 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. to rats resuts in a significant increase in the conversion of (see Chapter 17). In aition, acute oaing of the iver with gucose to gucuronate, l-guonate, an ascorbate. Aminopy- fructose, as can occur with intravenous infusion or foowing rine an antipyrine increase the excretion of xyuose in pen- very high fructose intakes, causes sequestration of inorganic tosuric subjects. Pentosuria aso occurs after consumption of phosphate in fructose-1-phosphate an iminishe ATP reativey arge amounts of fruits such as pears that are rich synthesis. As a resut, there is ess inhibition of e novo purine sources of pentoses (alimentary pentosuria). synthesis by ATP, an uric aci formation is increase, causing hyperuricemia, which is the cause of gout (see Chapter 33). Loading of the Liver With Fructose May Since fructose is absorbe from the sma intestine by (passive) carrier-meiate iffusion, high ora oses may ea Potentiate Hypertriacylglycerolemia, to osmotic iarrhea. Hypercholesterolemia, & Hyperuricemia In the iver, fructose increases fatty aci an triacygycero synthe- sis an VLDL secretion, eaing to hypertriacygyceroemia—an Defects in Fructose Metabolism increase LDL choestero—which can be regare as potentiay Cause Disease atherogenic (see Chapter 26). This is because fructose enters gy- A ack of hepatic fructokinase causes essential fructosuria, coysis via fructokinase, an the resuting fructose-1-phosphate which is a benign an asymptomatic conition. The absence bypasses the reguatory step catayze by phosphofructokinase of aoase B, which ceaves fructose-1-phosphate, eas to 200 SECTION IV Metabolism of Carbohydrates hereditary fructose intolerance, which is characterize by pro- though eficiency of uridyl transferase is best known. foun hypogycemia an vomiting after consumption of fruc- Gaactose is a substrate for aose reuctase, forming gaac- tose (or sucrose, which yies fructose on igestion). Diets ow tito, which accumuates in the ens of the eye, causing cata- in fructose, sorbito, an sucrose are beneficia for both coni- ract. The conition is more severe if it is the resut of a efect tions. One consequence of hereitary fructose intoerance an in the uriy transferase since gaactose-1-phosphate accu- of a reate conition as a resut of fructose 1,6-bisphosphatase muates an epetes the iver of inorganic phosphate. Uti- deficiency is fructose-inuce hypoglycemia espite the pres- matey, iver faiure an menta eterioration resut. In uriy ence of high gycogen reserves, because fructose-1-phosphate transferase eficiency, the epimerase is present in aequate an 1,6-bisphosphate aostericay inhibit iver gycogen amounts, so that the gaactosemic iniviua can sti form phosphoryase. The sequestration of inorganic phosphate aso UDPGa from gucose. This expains how it is possibe for eas to epetion of ATP an hyperuricemia. norma growth an eveopment of affecte chiren to occur espite the gaactose-free iets use to contro the Fructose & Sorbitol in the Lens Are symptoms of the isease. Associated With Diabetic Cataract Both fructose an sorbito are foun in the ens of the eye SUMMARY in increase concentrations in iabetes meitus an may be The pentose phosphate pathway, present in the cytoso, can account for the compete oxiation of gucose, proucing invove in the pathogenesis of diabetic cataract. The sorbitol NADPH an CO2 but no ATP. (polyol) pathway (not foun in iver) is responsibe for fruc- tose formation from gucose (see Figure 20–5) an increases The pathway has an oxiative phase, which is irreversibe an generates NADPH, an a nonoxiative phase, which in activity as the gucose concentration rises in those tissues is reversibe an provies ribose precursors for nuceotie that are not insuin sensitive—the ens, periphera nerves, synthesis. The compete pathway is present mainy in those an rena gomerui. Gucose is reuce to sorbito by aldose tissues having a requirement for NADPH for reuctive reductase, foowe by oxiation of sorbito to fructose in syntheses, for exampe, ipogenesis or steroiogenesis, whereas the presence of NAD+ an sorbito ehyrogenase (poyo the nonoxiative phase is present in a ces requiring ribose. ehyrogenase). Sorbito oes not iffuse through ce mem- In erythrocytes, the pathway has a major function in branes, but accumuates, causing osmotic amage. Simutane- preventing hemoysis by proviing NADPH to maintain ousy, myoinosito eves fa. In experimenta animas, sorbito gutathione in the reuce state as the substrate for gutathione accumuation an myoinosito epetion, as we as iabetic peroxiase. cataract, can be prevente by aose reuctase inhibitors. A The uronic aci pathway is the source of gucuronic aci for number of inhibitors are unergoing cinica trias for preven- conjugation of many enogenous an exogenous substances tion of averse effects of iabetes. before excretion as gucuronies in urine an bie. Fructose bypasses the main reguatory step in gycoysis, Enzyme Deficiencies in the Galactose catayze by phosphofructokinase, an stimuates iver gucose uptake, fatty aci synthesis, an hepatic triacygycero Pathway Cause Galactosemia secretion. Inabiity to metaboize gaactose occurs in the galactose- Gaactose is synthesize from gucose in the actating mias, which may be cause by inherite efects of gaactoki- mammary gan an in other tissues where it is require for nase, uriy transferase, or 4-epimerase (see Figure 20–6A), the synthesis of gycoipis, proteogycans, an gycoproteins.