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The hexose monophosphate shunt © Michael Palmer 2016 1 The hexose monophosphate shunt: Overview © Michael Palmer 2016 2 Reactions in the oxidative stage © Michael Palmer 2016 3 Reactions in the sugar shuffle stage © Michael Palmer 2016 4 Ketoses and aldoses in the HMS © Michael Palmer 2016 5 The mechanism of transketolase © Michael Palmer 2016 6 The mechanism of transaldolase © Michael Palmer 2016 7 Why do we need both NADH and NADPH? © Michael Palmer 2016 8 NADPH generation by malic enzyme © Michael Palmer 2016 9 NADPH generation by transhydrogenase and NADP-linked isocitrate dehydrogenase © Michael Palmer 2016 10 Uses of NADPH 1. synthesis of fatty acids and cholesterol 2. fixation of ammonia by glutamate dehydrogenase 3. oxidative metabolism of drugs and poisons by cytochrome P450 enzymes 4. generation of nitric oxide and of reactive oxygen species by phagocytes 5. scavenging of reactive oxygen species that form as byproducts of oxygen transport and of the respiratory chain © Michael Palmer 2016 11 Nitric oxide synthase requires NADPH © Michael Palmer 2016 12 Signaling effects of nitric oxide © Michael Palmer 2016 13 Phagocytes use NADPH to generate reactive oxygen species © Michael Palmer 2016 14 Scavenging of reactive oxygen species requires NADPH, too © Michael Palmer 2016 15 Glucose-6-phosphate dehydrogenase deficiency • X-chromosomally encoded—males more severely affected • most patients are healthy most of the time—hemolytic crises occur upon exposure to drugs or diet components that cause enhanced formation of ROS • manifest in red blood cells because these cells lack protein synthesis—no replacement of deficient protein molecules • affords partial protection against malaria—similar to sickle cell anemia and other hemoglobinopathias © Michael Palmer 2016 16 Vicia faba and favism © Michael Palmer 2016 17 Redox cycling of isouramil © Michael Palmer 2016 18 Malaria parasites detoxify heme by crystallization © Michael Palmer 2016 19 Primaquine and glucose-6-phosphate dehydrogenase deficiency © Michael Palmer 2016 20
