Objectives After studying this unit the student should be able to: : Understand the metabolic significance of the two arms of the pentoseephosphate pathway. Illustrate the conversion of glucose into glucuronic acid and appreciate the physiological role of glucuronic acid. 1 Objectives After studying this unit the student should be able to: Pentose Phosphate Pathway (PPP) Hexose monophosphate shunt (HMP shunt): P entose P hosphate P athway ( PPP ) H exose m ono p hosphate shunt ( HMP shunt ) All reactions of this pathway occur in cytosol. Occurs mainly in liver, RBCs, adrenal cortex and tests. Overview of the Pathway : It comprises of two phases: oxidative phase . non oxidative phase . Glucose-6-P dehydrogenase: Glucose-6-P dehydrogenase 6-phosphgluconolactonase 6-P-gluconate dehydrogenase Slide 4: The oxidative phase : Glucose 6- phosphate is irreversibly oxidized to produce : one molecule of pentose phosphate (ribulose -5-phosphate) two molecules of NADPH, one molecule of CO 2 . Gl-6-ph. 2 NADP 2 NADPH 2 CO 2 Pentose phosphate The key enzyme is: gl-6-ph. dehydrogenase Slide 5: Non oxidative phase : The pentose phosphates (aldose and ketose isomers ) are interconverted with glycolytic intermediates (Fr. 6-ph.). This phase is reversible and thus provides a mean of converting hexose phosphates to pentose phosphates and vise versa. Slide 6: The Pentose Phosphate Pathway: Non-oxidative phases Regulation of HMP shunt: Regulation of HMP shunt The first reaction catalyzed by G-6-PDase is the rate limiting step . It is inhibited by increased level of NADPH . Insulin will induce G-6-PDase and therefore will increase the overall pathway. Importance of the pentose phosphate pathway: Importance of the pentose phosphate pathway It is most active in cells which : have a high rate of nucleotide synthesis (rapidly dividing tissues such as: bone marrow, skin, gastric mucosa). utilize NADPH in large amounts . Slide 9: It is the only source of pentose used for : synthesis of nucleic acid (DNA and RNA). coenzymes (as NAD + , FAD). nucleotides as ATP. Slide 10: It is the major source of NADPH used for: Biosynthesis of: fatty acids ( within liver, adipose tissue , lactating mammary gland ). cholesterol (In liver, adrenal cortex , skin , gonads) . catecholamines ( nervous system , adrenal medulla ). Slide 11: Preserving the transparency of the eye lens, by keeping crystellin (eye lens protein) in the active reduced state. Slide 12: To preserve erythrocyte membrane integrity. Glucose-6- phosphate dehydrogenase deficiency: Glucose-6- phosphate dehydrogenase deficiency Deficiency of glucose- 6- phosphate dehydrogenase (G-6-PDase) is an X -linked condition which lead to drug - induced hemolytic anemia. Slide 15: Deficiency of G-6-PDase results in decreased concentrations of NADPH required for reduction of glutathione . The deficiency is manifested only after intake of certain oxidizing agents. Oxidizing agents, in absence of reduced glutathione; may distort the surface and function of RBCs resulting in hemolysis . Jaundice is developed, the Hb content of blood drops sharply and the urine turns black. Slide 16: examples of oxidizing agents: primaquine (antimalarial drug ). acetylsalicylic acid (aspirin). fava beans, in this case the condition is called Favism . Slide 17: In some cases: massive destruction of RBCs causes death. Glucuronic acid pathway: Glucuronic acid pathway It is a quantitatively minor route of glucose metabolism. it involves the conversion of gl-6-ph . into glucuronic acid . Liver is the major tissue performing this function. The enzymes involved are located in the cytosol . Glucouronic acid is a component of glycosaminoglycans and it is used for detoxification of non polar toxic compounds (examples : bilirubin and steroid hormons). The pathways can be classified into three stages:: The pathways can be classified into three stages : Conversion of gl-6-ph. into UDP- glucose ( in a manner similar to that used for glycogenesis ) Slide 21: Conversion of UDP-glucose into UDP-glucuronate . This reaction is catalyzed by NAD-dependent UDP-glucose dehydrogenase . UDP-glucuronate is the active form . Slide 23: Unused UDP-glucuronate can be converted into pentose-phosphate which then can be connected to glycolysis through non-oxidative phase of HMP shunt. Slide 24: Some compounds markedly increase the rate of uronic acid pathway such as: barbiturates administration or bilirubin caused by hemolysis .