Pentose Phosphate Pathway (PPP) - PDF

Pentose phosphate pathway (PPP) Objectives:- After studying this topic, you should be able to:- 1. Describe the pentose phosphate pathway and its roles as a source of NADPH and of ribose for nucleotide synthesis. 2. Understand the reactions of the pentose phosphate pathway and its cellul...

Pentose phosphate pathway (PPP) Objectives:- After studying this topic, you should be able to:- 1. Describe the pentose phosphate pathway and its roles as a source of NADPH and of ribose for nucleotide synthesis. 2. Understand the reactions of the pentose phosphate pathway and its cellular location 3. Appreciate how PPP& glutathione peroxidase protect RBCs against hemolysis.  The pentose phosphate pathway - (hexose monophosphate Shunt) is an alternative route for the metabolism of glucose.  It has two major functions: (1).Formation of NADPH for: synthesis of fatty acids and steroids and maintaining reduced glutathione for antioxidant activity(RBCs preventing hemolysis) (2).Synthesis of ribose for nucleic acid formation. Three molecules of glucose-6-phosphate give rise to:  Three molecules of CO2 and  Three 5-carbon sugars, which are rearranged to regenerate two molecules of glucose-6-phosphate and one molecule of glyceraldehyde-3-phosphate.  The G6P can be recycled into the pathway generating more NADPH. Tissues with active PPP 1. Liver, 2. Adipose tissue, 3. Adrenal cortex, 4. Testis 5. Lactating mammary gland 6. Erythrocytes  Reactions of the pentose phosphate pathway occur in the cytosol Two phases: 1. Irreversible oxidative phase:  Glucose- 6-phosphate undergoes dehydrogenation and decarboxylation to yield a pentose, ribulose-5- phosphate. 2. Reversible nonoxidative phase:  Ribulose-5-phosphate is converted back to glucose- 6-phosphate by a series of reactions involving mainly two enzymes: transketolase and transaldolase Transketolase;  Transfers 2 carbon groups from a ketose to aldose, thus, the ketose which donates the 2 carbons becomes aldose and the aldose which accepts the two carbons becomes ketose.  Transketolase requires (TPP) as a co-factor in the transfer reaction. Transaldolase  Transaldolase transfers 3 carbon groups in the same way done by transketolase…. Both enzymes catalyse a reversible reaction The Oxidative Phase ; Generates NADPH The Non-oxidative Phase ;Generates Ribose Precursors The Nonoxidative Phase ; Generates Ribose Precursors  Ribose can be synthesized in virtually all tissues  It is not necessary to have a completely functioning pentose phosphate pathway for a tissue to synthesize ribose 5-phosphate.  Most tissues (Muscle), it is capable of synthesizing ribose- 5-phosphate by reversal of the nonoxidative phase of the pentose phosphate pathway utilizing fructose-6-phosphate.  Regulation 1. Glucose-6-P dehydrogenase First step ,Rate limiting 2. Allosteric Regulation Feedback inhibited by NADPH 3. Inducible enzyme Induced by insulin PPP& glutathione peroxidase protect RBCs against hemolysis; Glutathione :  GSH (γ-glutamylcysteinylglycine), is a tripeptide composed of g-glutamate, cysteine and glycine.  The -SH of the cysteine residues of two glutathione molecules form a disulfide bond (GS-SG) during the course of being oxidized by various oxides and peroxides in cells.  Reduction of GSSG to two moles of GSH is the function of glutathione reductase, an enzyme that requires coupled oxidation of NADPH.  In RBCs, the PPP is the sole source of NADPH for the reduction of oxidized glutathione.  The reaction is important since accumulation of H2O2 may decrease the life span of the erythrocyte by causing oxidative damage to the cell membrane, leading to hemolysis.  CLINICAL ASPECTS  Impairment of the pentose phosphate pathway leads to erythrocyte hemolysis:  Genetic defects of glucose-6-phosphate dehydrogenase (G6PD),with consequent impairment of the generation of NADPH, are common in populations of Mediterranean and Afro-Caribbean origin.  The gene is on the X chromosome, so it is mainly males who are affected.  400 million people carry a mutated gene for glucose-6- phosphate dehydrogenase, (the most common genetic defect), but most are asymptomatic. G6PD Deficiency;  Hemolytic anemia when susceptible individuals are subjected to oxidative stress:  Exposure to anti-malarial drugs (Primaquine) results in increased cellular production of superoxide and hydrogen peroxide (Primaquine sensitivity)  Other chemicals known to increase oxidant stress: Sulfonamides (antibiotic). Asprin and NSAIDs. Quinadine and quinine. Fava beans (favism). THANK YOU