Pentose Phosphate Pathway - Notes

Also known as:Pentose shuntHexose monophosphate pathwayHMP.It occurs in the cytosol. The pentose pathway is a shunt.The pathway begins with theglycolytic intermediate glucose 6-P.It reconnects with glycolysisbecause two of the end products ofthe pentose pathway areglyceraldehyde 3-P and fructose 6- -P; two intermediates further downin the glycolytic pathway.It is for this reason that thepentose pathway is often referredto as a shunt. It's a shuntGlucoseATP1Hexokinase (Mg )ADPAlternative pathway:Glucose 6-phosphatePentose phosphatePhosphoglucosepathway2isomeraseFructose 6-phosphateATP3PhosphofructokinaseADPFructose 1,6-bisphosphate4AldolaseDihydroxyacetoneGlyceraldehydephosphate3-phosphateTriose phosphateisomerase5 What does the pentosephosphate pathway achieve?The pathway yields reducing potential inthe form of NADPH to be used in anabolicreactions requiring electrons.The pathway yields ribose 5-phosphate.- Nucleotide biosynthesis leading to:DNARNAVarious cofactors (CoA, FAD, SAM,NAD+/NADP*).. TABLE 20.2Pathways requiringNADPHSynthesisFatty acid biosynthesisCholesterol biosynthesisNeurotransmitter biosynthesisNucleotide biosynthesisDetoxificationReduction of oxidized glutathioneCytochrome P450 monooxygenases TABLE 20.4 Tissues with active pentose phosphate pathwaysTissueFunctionAdrenal glandSteroid synthesisLiverFatty acid and cholesterol synthesisTestesSteroid synthesisAdipose tissueFatty acid synthesisOvarySteroid synthesisMammary glandFatty acid synthesisRed blood cellsMaintenance of reduced glutathione HHNADPH is aHCCONH2phosphorylatedHCCHoNform of NADH.CH2OHHHHNADH is used to driveOH OHthe phosphorylationNH2Cof ADP to ATP.NNCHHCCNADPH is used whereNNreducing potential isoCH3OHHrequired for syntheticHHOHoreactions.Reduced nicotinamideadenine dinucleotidephosphate (NADPH) Oxidative phaseDehydrogenation of glucose-6-phosphate to6phosphogluconate catalyzed by glucose 6-phosphatedehydrogenaseFollowed by hydrolysis of 6-phosphogluconolactone toRibulose-5-phosphate catalyzed by 6-phosphogluconatedehydrogenaseDecarboxylation follows with the formation of theketopentose ribulose-5-phosphateBoth this step requires NADP+ as hydrogen acceptor Oxidative Stage of Pentose Phosphate PathwayGlucose-6-phosphateNADP+Glucose-6-phosphatedehydrogenase Regulatory enzymeNADPH6-PhosphogluconolactoneH2OGluconolactonaseH+6-PhosphogluconateNADP+6-phosphogluconateNADPHdehydrogenaseCO2Ribulose-5-phosphate5 carbon atomsNon-oxidative reactionscopyright 1996 M.W.King Non-oxidative PhaseRibulose-5-phosphateis the substrate for twoenzymesRibose-5-phosphate ketoisomerase:ribulose5-phosphate to the correspondingribose-5-phosphate -used for nucleotideand nucleic acid synthesisRibulose-5-phosphate epimerase: altersthe configuration about carbon givingxylulose5-phosphate PENTOSE PHOSPHATA PATHWAY2- non oxidative synthesis of 5-carbonsugares.Ribulose 5-Phosphat is converted back to Glucose 6- -phosphate by a series of reactions involving especiallytwo enzymes1. Transketolase :Transfer of the 2-C fragment2. Transaldolase : Transfer of the 3-C fragment Non-Oxidative Stage of Pentose Phosphate PathwayRibulose-5-phosphateRibulose-ophosphateRibulose-ophosphateSepiecrastisoneraseXylulose-5-phosphateRibose-5-phosphateTransketolaseSedaheptulose-7-phosphateGlyceraldehyde-3-phosphateTransaldolaseErythrose4-PhosphateTransketolaseFructoseGlyceraldehydeFructose6-phosphate3-phosphate6-phosphatecopyright 1996 M.W.King Regulation of the Pentose PathwayGlucose 6-phosphate DH is theregulatory enzyme.NADPH is a potent competitiveinhibitor of the enzyme.Usually the ratio NADPH/NADP+ ishigh so the enzyme is inhibited.But, with increased demand forNADPH, the ratio decreases andenzyme activity is stimulated. . The reactions of the non-oxidativeportion of the pentose pathway arereadily reversible.The concentrations of the productsand reactants can shift dependingon the metabolic needs of aparticular cell or tissue. Glutathione and NADPHWhat is glutathione?Why is it important?How is it related to NADPH? GlutamateGlutathione is aATPCysteinetripeptide composedADP + Pi+of glutamate,y-Glutamylcysteinecystein, glycine.ATPGlycineADP + PiReduced glutathioneSH(GSH) maintains theiCH2 onormal reducedIINHCHNH-CH2state of the cell.CH2coo 8CH2GlutathioneCH-NH3Reducedcooglutathione(GSH) Glutathione FunctionsIt serves as a reductant.Conjugates to drugs making them watersoluble. The sulfhydryl of GSH is used toreduce peroxides (ROS) formed duringoxygen transport.- Reactive oxygen species (ROS) damagemacromolecules (DNA, RNA, andprotein) and ultimately lead to celldeath.The resulting oxidized form of GSH is tw omolecules linked by a disulfide bridge(GSSG).. NH3OOC-CHThe enzymeeglutathioneCH2COCreductase usesCH2CH2NADPH as aIO=CNHcofactor to reduceNHC=OGSSG back to tw omoles of GSH.S-S-CH2-CHThus, the pentoseO=CNHpathway is linkedNHC=Oto the supply ofCH2CH2adequate amountsCH2of GSH.CH-COO©NH3Glutathione disulfide (GSSG) So, what happens if glucose 6-phosphate DH is defective?Insufficient production of NADPH.Which translates into insufficientglutathione.Is this a medical problem?YES O2When erythrocytes are exposedMitochondrial respiration, ionizingto chemicals that generate highradiation, sulfa drugs, herbicides,antimalarials, divicinelevels of superoxide radicals,Superoxide'O2GSH (Reduced Glutathione) isradical2Herequired to reduce theseYdamaging compoundsHydrogenglutathione peroxidaseH2O22H20Glutathione PeroxidaseperoxideHcatalyzes degradation ofeorganic hydroperoxides byH202GSHGSSGreduction, as two glutathioneHydroxylmolecules are oxidized to aOHfree radicaldisulfide GSSGglutathionereductaseThe PPP is responsible forOxidative damage toNADPNADPH + H'maintaining high levels oflipids, proteins, DNANADPH in red blood cells foruse as a reductant in theGlucose6-Phospho-6-phosphateglucoseglucono-6-lactoneglutathione reductase reaction.6-phosphatedehydrogenase(G6PD) Glutathione and ErythrocytesGSH is extremely important particularlyin the highly oxidizing environment ofthe red blood cell.Mature RBCs are totally dependent onNADPH from the pentose phosphatepathway to regenerate GSH from GSSGvia glutathione reductase. Glutathione and ErythrocytesThe reduced form of glutathione servesas a sulfhydryl buffer.It maintains cysteine residues inhemoglobin and other proteins in areduced state.GSH is essential for normal RBCstructure and keeping hemoglobin inFe++ state.