Harpers

The Pentose PhosphatePathway & Other Pathwaysof Hexose Metabolism20Peter A. Mayes, PhD, DSc, & David A. Bender, PhDBIOMEDICAL IMPORTANCEThe pentose phosphate pathway is an alternative routefor the metabolism of glucose. It does not generateATP but has two major functions: (1) The formation ofNADPH for synthesis of fatty acids and steroids and(2) the synthesis of ribose for nucleotide and nucleicacid formation. Glucose, fructose, and galactose are themain hexoses absorbed from the gastrointestinal tract,derived principally from dietary starch, sucrose, andlactose, respectively. Fructose and galactose are convertedto 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 hemolysis of red blood cells, resultingin hemolytic anemia and affecting approximately100 million people worldwide. Glucuronic acid is synthesizedfrom glucose via the uronic acid pathway, of majorsignificance for the excretion of metabolites and foreignchemicals (xenobiotics) as glucuronides. A deficiency inthe pathway leads to essential pentosuria. The lack ofone enzyme of the pathway (gulonolactone oxidase) inprimates and some other animals explains why ascorbicacid (vitamin C) is a dietary requirement for humans butnot most other mammals. Deficiencies in the enzymes offructose and galactose metabolism lead to essential fructosuriaand the galactosemias.THE PENTOSE PHOSPHATE PATHWAYGENERATES NADPH & RIBOSEPHOSPHATE (Figure 20–1)The pentose phosphate pathway (hexose monophosphateshunt) is a more complex pathway than glycolysis.Three molecules of glucose 6-phosphate give rise tothree molecules of CO 2 and three five-carbon sugars.These are rearranged to regenerate two molecules ofglucose 6-phosphate and one molecule of the glycolyticintermediate, glyceraldehyde 3-phosphate. Since twomolecules of glyceraldehyde 3-phosphate can regenerateglucose 6-phosphate, the pathway can account for thecomplete oxidation of glucose.163REACTIONS OF THE PENTOSEPHOSPHATE PATHWAY OCCURIN THE CYTOSOLThe enzymes of the pentose phosphate pathway, as ofglycolysis, are cytosolic. As in glycolysis, oxidationis achieved by dehydrogenation; but NADP + and notNAD + is the hydrogen acceptor. The sequence of reactionsof the pathway may be divided into two phases: anoxidative nonreversible phase and a nonoxidative reversiblephase. In the first phase, glucose 6-phosphateundergoes dehydrogenation and decarboxylation to yielda pentose, ribulose 5-phosphate. In the second phase,ribulose 5-phosphate is converted back to glucose 6-phosphateby a series of reactions involving mainly two enzymes:transketolase and transaldolase (Figure 20–1).The Oxidative Phase Generates NADPH(Figures 20–1 and 20–2)Dehydrogenation of glucose 6-phosphate to 6-phosphogluconateoccurs via the formation of 6-phosphogluconolactone,catalyzed by glucose-6-phosphatedehydrogenase, an NADP-dependent enzyme. Thehydrolysis of 6-phosphogluconolactone is accomplishedby the enzyme gluconolactone hydrolase. A secondoxidative step is catalyzed by 6-phosphogluconate dehydrogenase,which also requires NADP + as hydrogenacceptor and involves decarboxylation followed by formationof the ketopentose, ribulose 5-phosphate.The Nonoxidative Phase GeneratesRibose PrecursorsRibulose 5-phosphate is the substrate for two enzymes.Ribulose 5-phosphate 3-epimerase alters the configurationabout carbon 3, forming another ketopentose,xylulose 5-phosphate. Ribose 5-phosphate ketoisomeraseconverts ribulose 5-phosphate to the correspondingaldopentose, ribose 5-phosphate, which is the precursorof the ribose required for nucleotide and nucleicacid synthesis. Transketolase transfers the two-carbon