PENTOSE PHOSPHATE PATHWAY

The pentose phosphate pathway (PPP; also called the phosphogluconate pathway and the hexose monophosphate shunt) is a process that breaks down glucose-6-phosphate into NADPH and pentoses (5-carbon sugars) for use in downstream biological processes. There are two distinct phases in the pathway: the oxidative phase and the non-oxidative phase.

1. CARBOHYDRATE METABOLISM PENTOSE PHOSPHATE PATHWAY Course Title: Biochemistry III Prepared By : Rabia Khan Baber

2.   Outline the two major phases of the Pentose Phosphate Pathway: oxidative and non-oxidative phases   KEY POINTS:   There are two distinct phases in the pathway: the oxidative phase and the non-oxidative phase. In the oxidative phase, two molecules of NADP +  are reduced to NADPH, utilizing the energy from the conversion of glucose-6-phosphate into ribulose-5-phosphate. These NADPH molecules can then be used as an energy source in elsewhere in the cell. The non-oxidative phase generates 5-carbon sugars, which can be used in the synthesis of nucleotides, nucleic acids, and amino acids. The pentose phosphate pathway is an alternative to glycolysis . LEARNING OBJECTIVES

3.   Glycolysis : The cellular degradation of the simple sugar glucose to yield pyruvic acid and ATP as an energy source. NADPH : Nicotinamide adenine dinucleotide phosphate (NADP) carrying electrons and bonded with a hydrogen (H) ion; the reduced form of NADP+. KEY TERMS

4. The pentose phosphate pathway (PPP; also called the phosphogluconate pathway and the hexose monophosphate shunt) is a process that breaks down glucose-6-phosphate into NADPH and pentoses (5-carbon sugars) for use in downstream biological processes. There are two distinct phases in the pathway: the oxidative phase and the non-oxidative phase. THE PENTOSE PHOSPHATE PATHWAY

5. The  Hexose Monophosphate Shunt Pathway is present in all cells. Mainly the liver, lactating mammary glands, adipose tissue, adrenal cortex, and red blood cells (RBCs). Occurs in cell cytoplasm. LOCATION:

6. GLYCOGEN FATE

7. The first is the oxidative phase in which glucose-6-phosphate is converted to ribulose-5-phosphate. During this process two molecules of NADP + are reduced to NADPH. 6-Phosphogluconolactone is hydrolyzed by 6-phosphogluconolactone hydrolase . The oxidative decarboxylation of the product, 6-phosphogluconate is catalyzed by 6-phosphogluconate dehydrogenase . Pentose sugar–phosphate ( ribulose 5-phosphate), CO 2  (from carbon 1 of glucose), and a second molecule of NADPH are produced. Oxidative phase is irreversible phases in pentose phosphate pathway OXIDATIVE PHASE

8. Non-oxidative phase is reversible pathway . These reactions catalyze the interconversion of three-, four-, five-, six-, and seven-carbon sugars. The second phase of this pathway is the non-oxidative synthesis of 5-carbon sugars. Ribulose-5-phosphate can reversibly isomerize to ribose-5-phosphate. Ribulose-5-phosphate can alternatively undergo a series of isomerizations as well as transaldolations and transketolations that result in the production of other pentose phosphates including fructose-6-phosphate, erythrose-4-phosphate, and glyceraldehyde-3-phosphate (both intermediates in glycolysis ). These compounds are used in a variety of different biological processes including production of nucleotides and nucleic acids (ribose-5-phosphate), as well as synthesis of aromatic amino acids (erythrose-4-phosphate). NON-OXIDATIVE PHASE

9. EPIMERIZATION AND ISOMERIZATION Epimerase inter-converts stereoisomers ribulose-5-P into xylulose-5-P. Isomerase converts the ketose ribulose-5-P to the aldose ribose

10. High Activity:  Liver, adipose tissue, adrenal cortex, thyroid, erythrocytes, testis, and lactating mammary gland. These tissues use NADPH in reductive synthesis, eg , of fatty acids, steroids, amino acids. Low Activity:  Skeletal muscle, non-lactating mammary gland. TISSUES  IN WHICH PENTOSE PHOSPHATE PATHWAY IS ACTIVE

11. The Hexose Monophosphate Shunt Pathway provides a means by which glucose can be oxidized to generate NADPH and is the source of much of the NADPH that is needed for the biosynthesis of many biomolecules , most notably fats. The  Hexose Monophosphate Shunt Pathway can also be used for the catabolism of pentose sugars from the diet, the synthesis of pentose sugars for nucleotide biosynthesis, and the catabolism and synthesis of less common four- and seven-carbon sugars. IMPORTANCE OF HMP SHUNT

12. NADPH produced in the shunt is used for biosynthesis of several important compounds in various organs. In the liver, NADPH is used for fatty acid synthesis, cholesterol synthesis, bile acid synthesis, glutamate synthesis and cytochrome P450-hydroxylase system. In the adrenal cortex and gonads, NADPH is used for cholesterol and hormone synthesis. In the adipose tissue, NADPH is used for fatty acid synthesis. NADPH is used for the formation of deoxyribonucleotides and pyrimidine nucleotides. BIOLOGICAL IMPORTANCE OF HMP SHUNT

13. In RBC, NADPH produced is used for the formation of reduced glutathione from oxidized glutathione. Glutathione reductase catalyzes this reaction. Reduced glutathione is required for the removal of H2O2 by glutathione peroxidase for the conversion of methemoglobin to normal hemoglobin and for maintenance of –SH groups of erythrocyte proteins. So, reduced glutathione is essential for the integrity of normal red cell structure. Usually cells with reduced glutathione levels are more prone to hemolysis . Cont…

14. Pentoses produced in this pathway are used for nucleic acid synthesis and nucleotide coenzymes like NAD+, FAD and FMN synthesis. A non-oxidative phase of the pathway converts pentoses of endogenous or dietary nucleic acids into intermediates of glycolysis where they are, further oxidized to generate energy. Interconversion of three, four, five, six and seven carbon sugars in the non-oxidative phase metabolically connects these sugars to glycolysis Cont..

15. Glucose-6-phosphate dehydrogenase is the rate-controlling enzyme in this pathway. It is allosterically stimulated by NADP + . NADPH-utilizing pathways, such as fatty acid synthesis, generate NADP + , which stimulates glucose-6-phosphate dehydrogenase to produce more NADPH. In mammals, the PPP occurs exclusively in the cytoplasm; it is found to be most active in the liver, mammary gland, and adrenal cortex. REGULATION OF HMP SHUNT

16. Textbook of Biochemistry-U Satyanarayana Champe , PC, Harvey, RA. 2007. Biochemistry. Lippincott’s Illustrated Review. 4th Edition. Lippincott Williams & Wilkins. Murray, RK, Bender, DA, Botham , KM, Kennelly, PJ, Rodwell , VW, Weil, PA. 2006. Harper’s Illustrated Biochemistry, 28e. Lange, McGraw Hill. REFERENCES