Pentose Phosphate Pathway Biochem 4511 Pentose Phosphate Pathway The pentose phosphate pathway is an oxidative pathway for producing NADPH and converting glucose to ribose o NADPH is typically consumed in anabolic reactions including the formation of fatty acids o Ribose is the base sugar for nucleic acids RNA and DNA The reversible reactions of the pathway allow the interconversion of ribose and intermediates of glycolysis and gluconeogenesis OPO3 2 NADPH NADPH vs NADH NADP NAD NADPH is the source of bio synthetic reducing power Plays a major role in anabolic pathways Protects the cell from oxidative stress NADPH NADP is kept high NADH mostly participates in catabolic reactions for energy production NAD is utilized as an oxidizing agent NADH NAD is kept low The phosphate group does not affect the redox abilities of the molecule but it allows enzymes to discriminate between NADPH and NADH allowing concentrations for each to be regulated NADPH The two primary roles of NADPH in the body are 1 Reducing power for biosynthesis 2 Reducing power for detoxification of reactive oxygen species Reduces glutathione which is the body s primary protection against oxidative damage Pentose phosphate pathway activity is abundant in tissues which require either function 1 2 NADPH Protects Cells Against Oxidative Stress A downside of using oxygen for energy production oxidative phosphorylation is the production of toxic Reactive Oxygen Species ROS or free radicals and peroxides Glutathione is an antioxidant which can reduce ROS and prevent Oxidized glutathione is reduced by glutathione reductase along with oxidative damage an NADPH co factor Reduced ROS Oxidized Oxidized Reduced Pentose Phosphate Pathway There are two stages to the pentose phosphate pathway 1 The oxidative stage where the sugar is oxidized and decarboxylated yielding reduced NADPH 2 The non oxidative stage where a total of three ribulose 5 phosphate 3x 5C molecules are combined to form two molecules of fructose 6 phosphate 2x 6C and one glyceraldehyde 3 phosphate 1x 3C There are MANY entry and exits points into the pentose phosphate pathway through normal sugar metabolism Pentose Phosphate Pathway Oxidative Stage The oxidative stage converts glucose 6 carbons to the pentose ribulose 5 carbons while simultaneously producing NADPH The first step is catalyzed by glucose 6 phosphate dehydrogenase Glucose 6 Phosphate Dehydrogenase G6PDH Deficiency G6PDH deficiency is the most common human enzyme defect More than 400 million people effected X chromosome linked Major symptom Abnormal Red Blood Cell breakdown hemolysis W hy Red Blood Cells RBC carry only a single isoform of G6PDH Oxygen transport leads to an increased risk of oxidation Why is it the most common human enzyme defect Reduces NADPH production Interferes with normal oxidative reductive processes more susceptible to oxidative damage Confers resistance against malaria parasite 8 6 phosphogluconate formation can also occur spontaneously without enzyme catalysis 6 phosphogluconate is converted to ribulose 5 phosphate through oxidative decarboxylation Ribose 5 Phospate is a Precursor of Nucleotides Ribose 5 phosphate is an important substrate in the pentose phosphate pathway as well as nucleic acid biosynthesis The oxidative stage of the pentose phosphate pathway is highly active in rapidly dividing cells dNDP Synthesis Ribonucleotide reductase converts ribose NDPs to deoxyribose dNDPs using both products of pentose pathway for the eventual formation of DNA Pentose Phosphate Pathway Non Oxidative Stage extra The pentose phosphate pathway can be quite confusing and it may be helpful to think about it schematically In the oxidative phase one hexose is converted to one pentose In order to proceed through the entire non oxidative stage a total of three pentose molecules are necessary The oxidative stage must be completed three times in order to complete the FULL pathway Pentose Phosphate Pathway Non Oxidative Stage The oxidative stage must be completed three times in order to complete the FULL pathway with a final net reaction of Ribulose 5 phosphate generated in the oxidative stage is the entry point for the non oxidative stage Pentose Phosphate Pathway The non oxidative stage involves the transfer of 2 or 3 carbon units from one substrate to the next The enzyme name tells which unit is being transferred Two molecules of ribulose 5 phosphate are converted to one molecule of xylulose 5 phosphate and one molecule of ribose 5 phosphate These molecules are combined to form a 3 carbon and a 7 carbon product So far two of the three pentose sugars generated in the oxidative phase have been used The products of the transketolase reaction are further combined by a transaldolase to yield fructose 6 phosphate the first product of the pathway and erythrose 4 phosphate Pentose Phosphate Pathway In the final non oxidative step erythrose 4 phosphate combines with xylulose 5 phosphate the third pentose product from the oxidative stage through a second transketolase catalyzed reaction The final products are a second molecule of fructose 6 phosphate and glyceraldehyde 3 phosphate Notice that all products are glycolysis substrates Summary of Glucose Metabolism Book Problems Pentose phosphate pathway Problems 59 60 Need to know 1 Understand the importance of the oxidative steps of pentose phosphate pathway