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HMP Pathway- A Quick Revision

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HMP Pathway- Steps and clinical significance

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HMP Pathway- A Quick Revision

  1. 1. HMP Pathway- A Quick Revision Namrata Chhabra SSR Medical College, Mauritius
  2. 2. HMP Pathway Phospho gluconate pathway Pentose phosphate pathway Hexose monophosphate shunt [HMP shunt] All the intermediates of this pathway are in the mono phosphate form contrary to glycolysis where bisphosphate forms of intermediates are also there. 12/22/2016Namrata Chhabra, M.D. 2
  3. 3. What is the purpose of HMP pathway ? • An alternative route for the metabolism of glucose • What is the outcome ??? o NADPH o Pentoses o Not directly meant for energy production. 12/22/2016Namrata Chhabra, M.D. 3
  4. 4. Where does this pathway take place ? Organs/Tissues Rapidly dividing cells and in tissues where there is a great requirement of NADPH such as:  Liver,  Adipose tissue,  Adrenal cortex,  Gonads  Lens,  RBCs and  Lactating mammary gland The pathway is less active in the skeletal muscle. 12/22/2016Namrata Chhabra, M.D. 4
  5. 5. HMP Pathway • All the reactions of this pathway take place in the cytoplasm 12/22/2016Namrata Chhabra, M.D. 5
  6. 6. An overview HMP Pathway Oxidative phase NADPH Pentoses Non – Oxidative Phase Glycolytic intermediates 12/22/2016Namrata Chhabra, M.D. 6
  7. 7. Oxidative phase leads to formation of Ribose-5-P by oxidative decarboxylation Non oxidative phase involves rearrangement process results in the formation of glycolytic intermediates 12/22/2016Namrata Chhabra, M.D. 7
  8. 8. Glycolysis V/S HMP pathway Characteristics Glycolysis HMP pathway Occurrence All cells of the body Active in liver, adipose tissue, adrenal cortex, thyroid, erythrocytes, testis, and lactating mammary glands. Coenzyme NAD + NADP+ CO2 production No CO2 production CO2 is produced. Pentose production Pentoses are not produced Pentoses are produced. Intermediates Intermediates can be in the mono or bisphosphate forms Intermediates are never in the bisphosphate form. Energy ATP is utilized as well as produced ATP is neither utilized nor produced. Glycolytic intermediates may enter glycolytic pathway to produce energy Biological Significance Energy production both in aerobic and anaerobic conditions NADPH is required for reductive biosynthesis and Pentoses are required for synthesis of coenzymes and nucleotides. 12/22/2016Namrata Chhabra, M.D. 8
  9. 9. Reactions of HMP pathway- Oxidative phase Reactions of oxidative phase of HMP pathway- 2 molecules of NADPH and one of CO2 are produced in the oxidative phase. 12/22/2016Namrata Chhabra, M.D. 9
  10. 10. Reactions of HMP pathway- Non- Oxidative phase • Ribulose 5-phosphate 3-epimerase (Phosphopentose epimerase) alters the configuration about carbon 3, forming the epimer Xylulose 5-phosphate, also a ketopentose. • Ribose 5-phosphate keto Isomerase (Phosphopentose isomerase) converts Ribulose 5-phosphate to the corresponding aldopentose, ribose 5-phosphate. 12/22/2016Namrata Chhabra, M.D. 10
  11. 11. Non-oxidative phase • The pathway catalyzes the interconversion of : • three, • four, • five, • six, and seven-carbon sugars in a series of nonoxidative reactions • that can result in the synthesis of o five-carbon sugars for nucleotide biosynthesis or o the degradation of excess five-carbon sugars into intermediates of the glycolytic pathway. 12/22/2016Namrata Chhabra, M.D. 11
  12. 12. Rearrangement of sugars in the Non- oxidative phase 12/22/2016Namrata Chhabra, M.D. 12
  13. 13. Step-1-Non-oxidative phase • Transketolase catalyzes the transfer of the two- carbon unit comprising carbons 1 and 2 of a ketose (from Xylulose 5-phosphate) to the aldehyde carbon of an aldose sugar (ribose 5- phosphate), producing the seven-carbon ketose sedoheptulose 7-phosphate and the aldose glyceraldehyde 3-phosphate. 12/22/2016Namrata Chhabra, M.D. 13
  14. 14. Step-1- Non-Oxidative phase • Transketolase effects the conversion of a ketose sugar into an aldose with two carbons less and an aldose sugar into a ketose with two carbons more. • The reaction requires Mg2+ and thiamine pyrophosphate (vitamin B1) as coenzyme. • Clinical significance- R.B.C Transketolase activity is measured to diagnose underlying thiamine deficiency. • In thiamine deficiency Transketolase activity is reduced. 12/22/2016Namrata Chhabra, M.D. 14
  15. 15. Step-2- Non-Oxidative phase • Transaldolase catalyzes the transfer of a three-carbon Dihydroxyacetone moiety (carbons 1–3) from the ketose sedoheptulose -7-phosphate onto the aldose glyceraldehyde 3- phosphate to form the ketose fructose 6-phosphate and the four-carbon aldose Erythrose 4- phosphate 12/22/2016Namrata Chhabra, M.D. 15
  16. 16. Step-3 Non-Oxidative phase • In this reaction catalyzed by transketolase, Xylulose 5- phosphate again serves as a donor of glycoaldehyde. • In this case Erythrose 4-phosphate is the acceptor, and the products of the reaction are fructose 6-phosphate and glyceraldehyde 3-phosphate. 12/22/2016Namrata Chhabra, M.D. 16
  17. 17. Biological advantage of reversible reactions • Since the reactions of non oxidative phase are irreversible, the glycolytic intermediates can also rearrange to form pentoses. • The sum of these reactions is: 12/22/2016Namrata Chhabra, M.D. 17
  18. 18. Degradation of excess Pentoses through HMP pathway • Xylulose 5-phosphate can be formed from ribose 5-phosphate, or vice versa, by the sequential action of phosphopentose isomerase and phosphopentose Epimerase, therefore: o Thus, excess ribose 5-phosphate formed by the pentose phosphate pathway can be completely converted into glycolytic intermediates. o Moreover, any ribose ingested in the diet can be processed into glycolytic intermediates by this pathway. o The carbon skeletons of sugars can be extensively rearranged to meet physiologic needs. 12/22/2016Namrata Chhabra, M.D. 18
  19. 19. Summary 12/22/2016Namrata Chhabra, M.D. 19
  20. 20. Complete oxidation of glucose • 3 molecules of Glucose-6-P enter simultaneously in this pathway to produce 3 molecules of CO2, 6 NADPH , 2 fructose-6-P and one molecule of glyceraldehyde- 3-P. • 2 molecule of Fructose-6-P are converted to 2 molecule of Glucose-6-P while Glyceraldehyde-3-P is presumed to be equivalent to half a molecule of Glucose-6-P. • Three carbons less are presumed to be lost as CO2. • If 6 molecules enter at the same time then it would represent loss of 6 molecules of CO2 equivalent to complete oxidation of one molecule of glucose. 12/22/2016Namrata Chhabra, M.D. 20
  21. 21. Significance of HMP Pathway Major outcomes: • NADPH • Pentoses • Glycolytic intermediates • CO2 12/22/2016Namrata Chhabra, M.D. 21
  22. 22. Significance of NADPH NADPH is mainly used for reductive biosynthesis. Additionally it is used for maintenance of membrane integrity of red blood cell and lens, detoxification and macrophageal functions. 12/22/2016Namrata Chhabra, M.D. 22
  23. 23. Significance of Pentoses Pentoses Nucleic acids ATP Glycoproteins Coenzymes 12/22/2016Namrata Chhabra, M.D. 23
  24. 24. Utilization of Pentoses Pentoses Degradation of coenzymes Dietary Degradation of Nucleic acids Non-oxidative phase-HMP Pathway 12/22/2016Namrata Chhabra, M.D. 24
  25. 25. Significance of Glycolytic intermediates • Glyceraldehyde-3-P and fructose-6-Pformed from 5‐C sugar phosphates may enter Glycolysis for ATP synthesis or may be used as intermediates of pathway of gluconeogenesis. • The Pentose Phosphate Pathway thus serves as an entry into Glycolysis for both 5‐carbon & 6‐carbon sugars. 12/22/2016Namrata Chhabra, M.D. 25
  26. 26. Significance of CO2 • CO2 produced from this pathway can be utilized for CO2 fixation reactions, Such as: • Pyruvate to Oxaloacetate • Acetyl co A to Malonyl co A • Propionyl co A to Methyl malonyl co A • Gamma carboxylation of glutamic acid residues etc. 12/22/2016Namrata Chhabra, M.D. 26
  27. 27. Clinical significance • Glucose-6-phosphate dehydrogenase (G6PD) deficiency • An X-linked disorder • Asymptomatic or Hemolytic anemia • Anemia may be associated with hemogobinemia and hemoglobinuria • Acute HA can develop as a result of three types of triggers: (i) fava beans, (ii) infections, and (iii) drugs like- Antimalarial, antibiotics, Antipyretics/ analgesics, sulfonamides etc. 12/22/2016Namrata Chhabra, M.D. 27
  28. 28. Pathophysiology Of Hemolytic Anemia • Reduced glutathione (GSH), a tripeptide with a free sulfhydryl group, is required to combat oxidative stress and maintain the normal reduced state in the cell. • Oxidized glutathione (GSSG) is reduced by NADPH generated by glucose 6-phosphate dehydrogenase in the pentose phosphate pathway. • Cells with reduced levels of glucose 6- phosphate dehydrogenase are especially sensitive to oxidative stress. 12/22/2016Namrata Chhabra, M.D. 28
  29. 29. Treatment of Hemolytic Anemia in G6PD deficiency • Identification and discontinuation of the precipitating agent is critical in cases of glucose-6- phosphatase dehydrogenase (G6PD) deficiency. • Affected individuals are treated with oxygen and bed rest, which may afford symptomatic relief. • Prevention of drug-induced hemolysis is possible in most cases by choosing alternative drugs. 12/22/2016Namrata Chhabra, M.D. 29
  30. 30. Thank you 1) Further reading 2) 3) 4) 3/ 5)