Harpers

THE PENTOSE PHOSPHATE PATHWAY & OTHER PATHWAYS OF HEXOSE METABOLISM / 167NADPH + H +GSSG2H 2 OPENTOSEPHOSPHATEPATHWAYFADGLUTATHIONEREDUCTASESeGLUTATHIONEPEROXIDASE2HNADP +2GSHH 2 O 2Figure 20–3. Role of the pentose phosphate pathway in the glutathione peroxidase reactionof erythrocytes. (G-S-S-G, oxidized glutathione; G-SH, reduced glutathione; Se, seleniumcofactor.)Glucuronate is reduced to L-gulonate in an NADPHdependentreaction; L-gulonate is the direct precursor ofascorbate in those animals capable of synthesizing thisvitamin. In humans and other primates as well as guineapigs, ascorbic acid cannot be synthesized because of theabsence of L-gulonolactone oxidase. L-Gulonate is metabolizedultimately to D-xylulose 5-phosphate, a constituentof the pentose phosphate pathway.INGESTION OF LARGE QUANTITIESOF FRUCTOSE HAS PROFOUNDMETABOLIC CONSEQUENCESDiets high in sucrose or in high-fructose syrups used inmanufactured foods and beverages lead to large amountsof fructose (and glucose) entering the hepatic portal vein.Fructose undergoes more rapid glycolysis in the liver thandoes glucose because it bypasses the regulatory step catalyzedby phosphofructokinase (Figure 20–5). This allowsfructose to flood the pathways in the liver, leading to enhancedfatty acid synthesis, increased esterification of fattyacids, and increased VLDL secretion, which may raiseserum triacylglycerols and ultimately raise LDL cholesterolconcentrations (Figure 25–6). A specific kinase,fructokinase, in liver (and kidney and intestine) catalyzesthe 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 bloodof diabetic patients at a normal rate. Fructose 1-phosphateis cleaved to D-glyceraldehyde and dihydroxyacetonephosphate by aldolase B, an enzyme found in theliver, which also functions in glycolysis by cleaving fructose1,6-bisphosphate. D-Glyceraldehyde enters glycolysisvia phosphorylation to glyceraldehyde 3-phosphate, catalyzedby triokinase. The two triose phosphates, dihydroxyacetonephosphate and glyceraldehyde 3-phosphate,may be degraded by glycolysis or may be substrates for aldolaseand hence gluconeogenesis, which is the fate ofmuch of the fructose metabolized in the liver.In extrahepatic tissues, hexokinase catalyzes thephosphorylation of most hexose sugars, including fructose.However, glucose inhibits the phosphorylation offructose since it is a better substrate for hexokinase.Nevertheless, some fructose can be metabolized in adiposetissue and muscle. Fructose, a potential fuel, isfound in seminal plasma and in the fetal circulation ofungulates and whales. Aldose reductase is found in theplacenta of the ewe and is responsible for the secretionof sorbitol into the fetal blood. The presence of sorbitoldehydrogenase in the liver, including the fetalliver, is responsible for the conversion of sorbitol intofructose. This pathway is also responsible for the occurrenceof fructose in seminal fluid.GALACTOSE IS NEEDED FOR THESYNTHESIS OF LACTOSE, GLYCOLIPIDS,PROTEOGLYCANS, & GLYCOPROTEINSGalactose is derived from intestinal hydrolysis of thedisaccharide lactose, the sugar of milk. It is readily convertedin the liver to glucose. Galactokinase catalyzesthe phosphorylation of galactose, using ATP as phosphatedonor (Figure 20–6A). Galactose 1-phosphate reactswith uridine diphosphate glucose (UDPGlc) toform uridine diphosphate galactose (UDPGal) and glucose1-phosphate, in a reaction catalyzed by galactose1-phosphate uridyl transferase. The conversion ofUDPGal to UDPGlc is catalyzed by UDPGal 4-epimerase.Epimerization involves an oxidation and reductionat carbon 4 with NAD + as coenzyme. Finally, glucoseis liberated from UDPGlc after conversion toglucose 1-phosphate, probably via incorporation intoglycogen followed by phosphorolysis (Chapter 18).Since the epimerase reaction is freely reversible, glucosecan be converted to galactose, so that galactose isnot a dietary essential. Galactose is required in the bodynot only in the formation of lactose but also as a constituentof glycolipids (cerebrosides), proteoglycans,and glycoproteins. In the synthesis of lactose in themammary gland, UDPGal condenses with glucose toyield lactose, catalyzed by lactose synthase (Figure20–6B).