3 1 15 Biochemistry 401 Lecture 25 The Pentose Phosphate Pathway PPP Overview of the pathway NADH NADPH The PPP in depth Reactions Function Pentose Phosphate Pathway Cytosolic pathway many purposes Two Phases Oxidative Non oxidative Oxidative NADPH production Non oxidative Inter conversion of sugars Products of the PPP NADPH for reductions Ribose for nucleotide synthesis Glycolytic intermediates NAD H NADP Cellular NADH NAD ratios favor NAD Cellular NADPH NADP ratios favor NADPH NAD oxidizes substrates in catabolic pathways NADPH reduces substrates in reductive synthetic reactions in anabolic pathways NADH powers ATP synthesis Reactivates glutathione 1 3 1 15 Mitochondrial Matrix NAD oxidizes substrates to produce reducing equivalents NADH Citric acid cycle Fatty Acid Oxidation NADH reduces electron carriers to power ATP synthesis Electron Transport Chain Cytoplasm NADPH reduces substrates in reductive synthetic reactions Fatty Acid Synthesis Cholesterol Synthesis Nucleotide Synthesis Neurotransmitter Synthesis NADPH serves many purposes Reducing equivalents for biosynthesis Combats infection In neutrophils used in synthesis of reactive oxygen species superoxides peroxide from O2 to kill microbes Synthesis of nitric oxide NO Short range hormone Vasodilator Used in synthesis of reactive nitrogen species to kill bacteria Reduces and thereby reactivates glutathione which is a potent antioxidant Glutathione in its reduced state is an important tripeptide that protects against oxidative stress Oxidized Glutathione is rereduced ultimately by NADPH thus sufficient levels of NADPH are important to keep our cells safe from reactive oxygen species 2 3 1 15 Red blood cells are especially sensitive to Heinz bodies clumps of denatured oxidative stress because hemoglobin adhere to membranes they rely on pentose phosphate pathway for most of their reducing power Glutathione is important as a sulfhydryl buffer to keep important cysteine residues in Hb and other red cell molecules reduced Glutathione is also important for reducing peroxides and other ROS species that can damage membranes and other cellular structures Oxidative Pentose Phosphate Pathway 3 3 1 15 Oxidative Pentose Phosphate Pathway 1 Oxidation 2 Hydration 3 Oxidation Reaction 1 is committed step G6PD is regulated G6PD 1 2 3 G6PD Regulated by NADPH NADP High NADPH NADP inhibits G6PD Low NADPH NADP activates G6PD Unstable Hydration 4 3 1 15 Second oxidation Decarboxylation To make a 5C Sugar Pentose Ketose Ketose You are here Isomerization Epimerization Ketose Aldose Aldose Two reactions at this point Ketose Nucleic acid synthesis Ketose C3 Epimer 5 3 1 15 Three main reactions generate glycolytic intermediates from excess ribose 5 P either from the oxidative reactions of the PPP or from dietary nucleic acid Reaction 1 Transketolase C5 C5 C3 C7 Reaction 2 Transaldolase C3 C7 C6 C4 Reaction 3 Transketolase C4 C5 C6 C3 C6 C3 that we generate in the end are Fructose 6 P Glyceraldehyde 3 P respectively 3 Ribose 5 phosphate 2 F6P 1 GAP Reaction 1 Transketolase C5 C5 C3 C7 Substrate only if C3 OH has configuration of Xylose reason for the epimerization of Ribulose 5 P 6 3 1 15 Reaction 2 Transaldolase C3 C7 C6 C4 Reaction 3 Transketolase C4 C5 C6 C3 Aldose Ketose 3 Ribose 5 phosphate Here we have two products that can enter glycolytic pathway 2 F6P 1 GAP 7 3 1 15 Much more Ribose 5 P much less NADPH Rapidly dividing cells need ribose 5 P for nucleotide synthesis Products from glycolysis used to make ribose 5 P 8 3 1 15 Drive Non OPPP backwards NADPH and Ribose 5 P In roughly equal amounts Oxidative PPP used Much more NADPH than Ribose 5 P Use both OPPP and Non OPPP then send products through Gluconeogenesis pathway to make more G6P for PPP OPPP Gluconeogenesis Non OPPP 9 3 1 15 Both OPPP and Non OPPP are used Products are sent to Glycolytic pathway Both NADPH and ATP needed Glycolysis TCA Cycle ATP Regulation of PPP NADP NADPH ratio The reaction catalyzed by Glucose 6 P Dehydrogenase is essentially irreversible and is rate limiting This is the point of regulation in the PPP pathway Glucose 6 P Dehydrogenase is regulated by levels of NADP NADPH in the cell Low levels of NADP are slow rxn 1 1 NADP is necessary for redox 2 NADPH is a competitive inhibitor The reactions of the non oxidative phase are regulated at the level of substrate availability 10 3 1 15 Deficiency of glucose 6 P Dehydrogenase Most common enzyme deficiency X linked Usually subclinical Increased susceptibility to oxidative injury Hemolytic anemia especially in response to oxidative challenge In RBCs PPP only source of NADPH Cannot keep important molecules in a reduced state Oxidative challenge Oxidative Drugs Some antibiotics anitmalarials fever reducers Favism Hemolytic anemia precipitated by fava bean ingestion Infection Peroxides are made in neutrophils mobilized in response to infection Prolonged Neonatal Jaundice may result from G6PDH deficiency usually seen in first four days after birth Favism Fava beans broad beans contain active oxidants vicine convicine Main staple in Mediterranean diet Can induce symptoms in persons with a certain type of mutation in G6PDH called Favism Genetic Mutations Resulting in G6PDH Deficiency High prevalence in areas where malaria is endemic May afford some protection from death from malarial infection This marks the end of Lecture 25 Have a great day 11
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