Pentose Phosphate Pathway 2024-1 PDF

Pentose Phosphate pathway Also called Hexose monophosphate shunt (HMP shunt) What is it? Additional CHO metabolic pathway: Scenic bypass around the first stage of glycolysis Where does it take place? In the cytosol of the cell – and of all cells What are its functions? Pro...

Pentose Phosphate pathway Also called Hexose monophosphate shunt (HMP shunt) What is it? Additional CHO metabolic pathway: Scenic bypass around the first stage of glycolysis Where does it take place? In the cytosol of the cell – and of all cells What are its functions? Produces reducing power in the form of NADPH Produces ribose 5-phosphate for nucleotides  Overview Occurs in the cytosol of the cell Includes 2 irreversible oxidative reactions Followed by a series of reversible sugar- phosphate interconversions 2 branches i) Irreversible Oxidative branch ii) Reversible Non-oxidative branch 3 reactions 1. Dehydration of glucose 6- phosphate to 6- Rate limiting rxn phosphogluconolactone - By glucose 6-phosphate dehydrogenase - Specific for NADP as coenzyme - NADPH is a potent inhibitor of the enzyme - Insulin upregulates the expression of the gene for G6PD 2. Formation of ribulose 5-phosphate 6-phosphogluconolactone hydrolase hydrolyzes 6-phospholactone to 6- phosphogluconate. This undergoes Yield from oxidative rxns oxidative decarboxylation by 6- Ribulose 5-phosphate phosphogluconate dehydrogenase to Co2 yield ribulose 5-phosphate 2 molecules of NADPH for each molecule of G 6-P oxidized Main Advantages of the this portion of the pathway Liver, mammary glands and adipose tissue All active in NADPH-dependent biosynthesis of Fatty acids Testes, ovaries, placenta and adrenal cortex – all active in the NADPH-dependent biosynthesis of steroid hormones Red blood cells – require NADPH to keep glutathione reduced  Reversible nonoxidative reactions Occurs in cell types synthesizing nucleotides and nucleic acids Catalyze the interconversion of sugars containing 3-7 carbons These reversible rxns permit ribulose 5- phosphate to be converted either to A) ribose 5-phospate (for nucleotide synthesis) B) intermediates of glycolysis (F 6-P and glyceraldehyde 3-P)  Main enzymes of nonoxidative reactions – transaldolase and transketolases The flux through any cell of one set of reactions is determined by the needs of the cell NOTE: transketolases are Thiamine pyrophosphate requiring enzymes (remember PDH and KGDH also TPP requiring enzymes)  If cell needs NADPH, not ribose 5P (R5P) -R5P is converted to glyceraldehyde 3 P and F6P and enter glycolysis If cell needs more R5P than NADPH F6P and glyceraldehyde 3P converted to R5P  Most important products 1. NADPH - for reductive biosynthetic reactions e.g synthesis of FAs 2. Ribose 5-P For RNA, DNA, NAD+, FAD, ATP, coenzyme A synthesis  Uses of NADPH 1. Reductive biosynthesis: FAs, Cholesterol, steroid hormones, bile salts 2. Reduction of hydrogen peroxide Enzymes that catalyze antioxidant reactions Antioxidant chemicals-antioxidant properties in lab? 3. Cytochrome P450 monooxygenase Mitochondrial System Microsomal System 4. Phagocytosis by white blood cells Oxygen-independent mechanism Oxygen-dependent mechanism 5. Synthesis of nitric oxide Actions of NO on vascular endothelium Role of NO in mediating macrophage bactericidal activity Other functions of NO 1. Reductive biosynthesis: FAs, Cholesterol, steroid hormones, bile salts NADPH – high energy molecule In PPP part of the energy of G 6-P is conserved in NADPH (has a negative reduction potential) Therefore can be used in reactions requiring an electron donor  2. Reduction of hydrogen peroxide (H2O2) H2O2 one of a family of reactive oxygen species (ROS) Formed from the partial reduction of molecular oxygen Formed continuously during aerobic metabolism/rxns with drugs and environmental toxins/when cellular level of antioxidant is low ROS cause serious damage to DNA, proteins, unsaturated lipids – can lead to cell death ROS implicated in Reperfusion injury Cancer Inflammatory disease aging  Enzymes can catalyze antioxidant reactions Reduced glutathione (G-SH) can detoxify H2O2 The oxidized glutathione formed during the rxn (G-S-S-H) can be converted back to G-SH by glutathione reductase NADPH is used in this reaction as a source of electrons Note : RBC are totally dependent on PPP for supply of NADPH - 3. Cytochrome P450 monooxygenase System Cytochrome P450 (CYP) enzymes are a superfamily of related , heme-containing monooxygenases Participate in variety of reactions R-H + O2 + NADPH + H+ R-OH + H2O Common substrates – steroids /drugs Mitochondria system – for biosynthesis of steroid hormone/bile acid synthesis Microsomal system – detoxification of xenobiotics 4. Phagocytosis by white blood cells -Important defence system particularly in bacterial infections Neutrophils and monocytes have both O2 – dependent and independent means of destroying pathogens O2 –independent: use pH changes and lysosomal enzymes O2 –dependent use enzymes NADPH oxidase and myeloperoxidase (MPO). Note: Rare genetic deficiencies in NADPH oxidase cause chronic granulomatous disease characterised by severe, persistent infections and formations of granulomas of sequestered bacteria 5. Synthesis of Nitric oxide (NO) NO is an endothelial –derived relaxing factor Functions: (i) causes vasodilation by relaxing smooth muscle (ii) Acts as a neurotransmitter (iii) Prevents platelet aggregation (iv) Essential for macrophage function Synthesized by Nitric Acid Synthase – an NADPH requiring enzyme  Glucose 6-phosphate Dehydrogenase (G6PD) deficiency G6PD deficiency is the most common disease- producing enzyme abnormality in humans G6PD deficiency – characterised by hemolytic anemia caused by the inability to detoxify oxidizing agents - Family of deficiencies – a no of different mutations in the gene coding for G6PD  Silence of the Lambs "Liver, fava beans and a nice chianti