Pentose Phosphate Pathway

Pentose Phosphate Pathway Learning Goals: 1. The pentose phosphate pathway provides reducing equivalents in the form of NADPH to drive biochemical processes within cells. 2. The PPP is composed of 2 stages: an oxidative stage generating NADPH and a non-oxidative stage generating various sugars. 3. Defects in this pathway  common medical syndromes (hemolytic anemia) I. II.

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The BIG Picture a. NADPH is involved in biosynthetic reactions and in maintaining a reducing environment in cells. b. Pentose Phosphate Pathway reduces NADP to NADPH. Overview of the Pathway a. The PPP particularly active in liver, mammary gland and adipose tissue (continuous supply of NADPH required for fatty acid biosynthesis) b. PPP generates NADPH required to combat the deleterious effects of oxidants i. Maintenance of reduced glutathione (reduces protein disulfides, hydrogen peroxide and peroxides via glutathione peroxidase)  glutathione disulfide  converted back to glutathione by glutathione reductase which uses NADPH Details of the Pathway a. First stage: glucose-6-phosphate oxidized in three steps to ribulose-5-phosphate  2 NADPH and CO2 i. First step: glucose-6-P oxidized by G-6-P dehydrogenase to yield NADPH and 6phosphogluconolactone ii. Entry into pathway controlled by substrate availability of NADP and competitive inhibition by NADPH (product) iii. 6-phosphogluconolactone hydrolase hydrolyzes 6-phosphogluconolactone to 6-phosphogluconate iv. Decarboxylation of 6-phosphogluconate by 6-phosphogluconate dehydrogenase yields NADPH, CO2 and ribulose-5-phosphate v. Generation of ribose-5-phosphate and xylulose-5-phosphate yields the substrates required for subsequent non-oxidative sugar interconversions 1. Ribulose-5-phosphate converted to ribose-5-phosphate by phosphopentose isomerase 2. Ribulose-5-phosphate and xylulose-5-phosphate are interconverted by phosphopentose epimerase b. Second stage: series of molecular interconversions combine sugars to form products that can reenter glycolysis i. Transketolase (cofactor = thiamine pyrophosphate) transfers 2-C keto fragments from a ketose donor to an aldose acceptor (Xylulose-5-P + Ribose-5-P  glyceraldehydes-3-P and Sedoheptulose-7-P) ii. Transaldolase (no cofactor required) transfers 3C keto fragments between a ketose donor and an aldose acceptor (Glyceraldehyde-3-P + Sedoheptulose-7-P  Fructose-6-P + Erythrose-4-P) 1. Enzyme contains an active site lysine  Schiff base intermediate with keto carbonyl group to be transferred Function of the Pentose Phosphate Pathway a. Cell needs NADPH for synthetic reactions or for GSSG reduction (most common) b. Cell needs ribose-5-P to make nucleotides (less common) i. Cells usually have enough need for NADPH to reduce GSSG that they make plenty of ribose-5-P through the oxidative branch Medical implications a. G-6-P dehydrogenase deficiency  hemolytic anemia (mild forms may not show clinical manifestations except under oxidative stress: AAA)