4. Description of Pentose Phospahe Pathway.pptx

Description of the pentose pathway

1. Fate of cellular glucose- Pentose Phosphate Pathway (PPP) E. A. Tagoe 2019

2. Specific objectives: To let students appreciate the various pathways that cellular glucose can take. To let students know the role of glucose in synthesis of cell genetic materials (Pentose Phosphate Pathway-PPP). To let students understand the relationship between PPP and glycolysis To let students know the importance of the pentose phosphate pathway in reduction of oxidative stress and synthesis of fatty acids Fate of cellular glucose

3. Glucose Pyruvate Ribose-5-phosphate Glycogen Pentose Phosphate Pathway (PPP) Glycolysis in cytosol Triglyceride Liver Adipose Tissue C ytosol Fate of cellular glucose

4. Fate of cellular glucose Synthesis Ribose-5-phosphate (Pentose Phosphate pathway) Glucose enters skeletal muscle cells and is phosphorylated by Hexokinase into glucose-6-phosphate. After phosphorylation, glucose can either be used for energy production or stored in the form of glycogen. A small percentage of glucose can either be channeled to hexose biosynthesis or pentose phosphate pathways for a variety of metabolic functions.  

5. Also known as: Pentose shunt Hexose monophosphate shunt Phosphogluconate pathway It occurs in the cytosol. Pentose Phosphate Pathway - PPP Fate of cellular glucose

6. Pentose Phosphate Pathway - PPP Fate of cellular glucose

7. NADPH is needed for synthesis of fatty acids Fate of cellular glucose Fatty acids are a highly reduced energy store. Palmitate is the primary fatty acid, made to 16Cs by the serial addition of 2Cs from Acetyl-S-CoA Acetyl-S-CoA Just attaching Acetyls together would yield this, which is NOT found This is palmitate the primary product of the following reaction

8. 8 Acetyl-CoA +7ATP +7H + + H 2 0 + 14 NADPH 8 CoA + 7Pi + 7ADP + Palmitate + 14 NADP+ So Palmitate and all other reduced fatty acids require the oxidation of NADPH to NADP+. Oxidation is the opposite of reduction. If something is reduced then something else must be oxidized. NADP+ is reduced to NADPH in the pentose phosphate pathway Fatty acid synthesis and NADPH continued Fate of cellular glucose

9. NADPH: Is derived from Vitamin B 3 Fate of cellular glucose Dietary Deficiency of Niacin results in pellagra ( rough skin)

10. The pentose phosphate pathway.

11. The Oxidative Steps of the Pentose Phosphate Pathway Glucose G6P HK F6P PGI G6PDH 6PGL NADPH NADP + lactonase 6PG FA/cholesterol synthesis RBC ox stress CO 2 6PGDH Ru5P NADPH NADP + HK : hexokinase G6P : glucose-6-phosphate G6PDH : glucose-6-phosphate dehydrogenase NADP + /NADPH : nicotinamide adenine dinucleotide phosphate FA : fatty acid 6PG: 6phosphogluconate RBC : red blood cell PGI : phosphoglucose isomerase 6PGL : 6-phosphoglucono-δ-lactone Ru5P : ribulose-5 phosphate F6P : fructose-6-phosphate 6PGDH : 6-phosphogluconate dehydrogenase

12. The Nonoxidative Steps of the Pentose Phosphate Pathway The transketolase reaction of step 8 in the pentose phosphate pathway. This is another two-carbon transfer, and it also requires TPP as a coenzyme (Last Spep )

13. Utilization of Glucose-6-P Depends on the Cell’s Need for ATP, NADPH, and Rib-5-P Glucose can be a substrate either for glycolysis or for the pentose phosphate pathway The choice depends on the relative needs of the cell for biosynthesis and for energy from metabolism ATP can be made if G-6-P is sent to glycolysis Or, if NADPH or ribose-5-P are needed for biosynthesis, G-6-P can be directed to the pentose phosphate pathway Depending on these relative needs, the reactions of glycolysis and the pentose phosphate pathway can be combined in four principal ways

14. Four Ways to Combine the Reactions of Glycolysis and Pentose Phosphate 1) Both Ribose-5-P and NADPH are needed by the cell In this case, the first four reactions of the pentose phosphate pathway predominate NADPH is produced and ribose-5-P is the principal product of carbon metabolism 2) More Ribose-5-P than NADPH is needed by the cell Synthesis of ribose-5-P can be accomplished without making NADPH, by bypassing the oxidative reactions of the pentose phosphate pathway

15. Four Ways to Combine the Reactions of Glycolysis and Pentose Phosphate Case 1: Both ribose-5-P and NADPH are needed When biosynthetic demands dictate, the first four reactions of the pentose phosphate pathway predominate and the principal products are ribose-5-P and NADPH.

16. Four Ways to Combine the Reactions of Glycolysis and Pentose Phosphate 3) More NADPH than ribose-5-P is needed by the cell This can be accomplished if ribose-5-P produced in the pentose phosphate pathway is recycled to produce glycolytic intermediates 4) Both NADPH and ATP are needed by the cell, but ribose-5-P is not This can be done by recycling ribose-5-P, as in case 3 above, if fructose-6-P and glyceraldehyde-3-P made in this way proceed through glycolysis to produce ATP and pyruvate, and pyruvate continues through the TCA cycle to make more ATP

17. Xylulose-5-Phosphate is a Metabolic Regulator In addition to its role in the pentose phosphate pathway, xylulose-5-P is also a signaling molecule When blood glucose rises, glycolysis and the pentose phosphate pathways are activated in the liver The PPP makes xylulose-5-P, which stimulates protein phosphatase 2A (PP2A) to maintain g lycolysis and activate lipid biosynthesis.

18. Aldose Reductase and Diabetic Cataract Formation The complications of diabetes include a high propensity for cataract formation in later life Hyperglycemia is the cause, but why? Evidence points to the polyol pathway , in which glucose and other simple sugars are reduced in NADPH-dependent reactions Glucose is reduced by aldose reductase to sorbitol , which accumulates in lens fiber cells, increasing pressure and eventually rupturing the cells Aldose reductase inhibitors such as tolrestat and epalrestat suppress cataract formation

19. Aldose Reductase and Diabetic Cataract Formation Glucose is reduced by aldose reductase to sorbitol , which accumulates in lens fiber cells, increasing pressure and eventually rupturing the cells Aldose reductase inhibitors such as tolrestat and epalrestat suppress cataract formation

20. Glucose 6-Phosphate Dehydrogenase Deficiency affects more than 400 million people in the world. - most common enzyme abnormality ( enzymopathy ) in people. the disease results in acute hemolytic anemia. NADPH is important for maintaining adequate levels of reduced glutathione ( GSH ) in the cell. The GSH is critical for destroying hydrogen peroxide and maintaining the cysteine residues in hemoglobin and other rbc proteins in the reduced state as well as the iron in hemoglobin in the ferrous state.

21. Glycolysis and Pentose Phosphate Pathways PPP NADPH 6PG 3-7 C metabolites (R5P, F6P, G3P) G6PDH lactonase 6PGDH CO 2 NADP + + H + GSH GSSG GR GP H 2 O 2 H 2 O Glc Pyr G6P 1,3-BPG 3PG HK PGI PK F6P DHAP + G3P PFK aldolase F16BP 2PG PEP PGK PGM enolase G3PDH Glycolysis Glc: glucose, HK : hexokinase, G6P: glucose-6-phosphate, G6PDH : glucose-6-phosphate dehydrogenase, PGI : phosphoglucose isomerase, PFK : phosphofructokinase, DHAP : dihydroxyacetonephosphate , BPG : bisphophoglycerate , PEP : phosphoenolpyruvate , Pyr : pyruvate, PK : pyruvate kinase (2 genes, 4 isozymes ), NADP +/NADPH: nicotinamide adenine dinucleotide,R5P : ribose-5-phosphate,F6P : fructose-6-phosphate,G3P : glyceraldehyde-3-phosphate,GSH : reduced glutathione ( GSH = Glu-Cys-Gly ), GSSG : oxidized glutathione, PPP : pentose phosphate pathway, 6PGDH: 6-phosphogluconate dehydrogenase, GR: glutathione reductase, GP: glutathione peroxidase, 3PG : 3-phosphoglycerate, 6PG: 6-phosphogluconate.

22. More than 400 variants of G6PD deficiency . Most of the mutations are single-base changes that result in an amino acid substitution. The G6PD gene is on the X chromosome so males are primarily affected ( X-linked recessive disorder) . Most female carriers (heterozygotes) are asymptomatic. G-6-PD deficiency affects all races. The highest prevalence is among persons of African, Asian, or Mediterranean descent. Severity varies significantly between racial groups because of different variants of the enzyme . Glucose 6-Phosphate Dehydrogenase Deficiency

23. About 11% of African-American males are affected by the so-called A-type . In Africa, female carriers of the mutation were found to have an increased resistance to malaria . People originating in the Mediterranean region may have another, more serious variant, called the Mediterranean type . People are usually asymptomatic but certain drugs can trigger a severe episode of hemolytic anemia within hours of exposure. Glucose 6-Phosphate Dehydrogenase Deficiency

24. Drugs that can bring on an acute reaction include: • antimalarial agents • sulfonamides (antibiotic) • aspirin • nonsteroidal anti-inflammatory drugs • nitrofurantoin • quinidine • quinine • others Glucose 6-Phosphate Dehydrogenase Deficiency N.B : Bacterial and viral infections can also trigger episodes.

25. What are the main functions of the pentose phosphate pathway? Which enzymes produce NADPH? Which intermediates can feed back into the glycolytic pathway? Review Questions

26. Clinical correlation A 10-year old boy was found very weak and pale. Laboratory investigation revealed that the boy has malaria infection and very low haemoglobin. The boy was transfused and treated with antimalarial agents. The boy responded well to treatment until the fourth month where the boy’s condition begun to degenerate. The Physician requested for G6PDH deficiency test and the report was positive. Questions: 5. Suggest management plan for the child. What accounted for the child’s condition before admission? 2. Explain why the boy recovered after the transfusion? 3. What could be the underlying cause of the re-occurring of the episode after 4 months? 4. If both parents of the boy are asymptomatic of the G6PDH deficiency, explain why the boy showed symptoms .