HEXOSE MONOPHOSPHATE SHUNT

HEXOSE MONOPHOSPHATE SHUNT

1. By DR KHALED SALEH ALGARIRI International Medicine School – MSU January 2018 HEXOSE MONOPHOSPHATE SHUNT

2. Other Names Definition : This is an alternative pathway to glycolysis and TCA cycle for the oxidation of glucose. HMP shunt is more anabolic in nature and all reactions occur in cytosol .

3. PENTOSE PHOSPHATE PATHWAY Three main functions: 1) Supply the cell with nicotinamide adenine dinucleotide phosphate (NADPH ) . 2) Convert hexoses into pentoses (which are essential components of ATP, CoA, NADP+, FAD, RNA, and DNA). 3) Enable the complete oxidative degradation of pentoses by converting them into hexoses and trioses which can then enter the glycolytic pathway

4. THE ROLES OF NADH AND NADPH IN METABOLISM There is a fundamental distinction between NADH and NADPH in most biochemical reactions. NADH is oxidized by the electron transport chain to generate ATP. In contrast, NADPH functions as an electron donor (i.e., a hydride ion donor) in biosynthetic reactions. Recall that in the oxidation of a substrate, the nicotinamide ring of NADP+ accepts a hydrogen ion and two electrons, which are equivalent to a hydride ion . NADH equivalent 2.5 ATP (TCA Cycle) , NADPH not yield ATP

5. THE PERCENTAGE OF GLUCOSE METABOLIZED BY THE PENTOSE PHOSPHATE PATHWAY VARIES FOR DIFFERENT TISSUES Since, a main purpose of this pathway is to supply NADPH for reductive synthesis , it is prominent in tissues that actively carry out the reductive synthesis of fatty acids and/or steroids from acetyl Co A Liver: 5-10% of glucose is metabolized by the pentose phosphate pathway. Adipose Tissue: 30 – 50% Erythrocytes: 10% (need NADPH to maintain reduced glutathione) Thyroid gland, kidney, and brain: 3 – 5% Muscle: activity is extremely low

6. LOCATION OF THE PATHWAY The enzymes are located in the cytosol . The tissues such as liver, adipose tissue, adrenal gland, erythrocytes, testes & lactating mammary gland , are highly active in HMP shunt. Most of these tissues are involved in biosynthesis of fatty acids and steroids which are dependent on the supply of NADPH.

7. 5 carbon atoms Regulatory enzyme

8. THE NONOXIDATIVE PHASE OF THE PENTOSE PATHWAY consists of non-oxidative reactions which link the pentose phosphate pathway with glycolysis. This stage allows: 1)excess pentoses to be converted to hexoses and trioses which can then enter glycolysis. 2)hexoses to be converted to pentoses , thereby allowing pentose production without concomitant production of NADPH. Two enzymes – transketolase and transaldolase –catalyze a series of three reactions which convert 3 pentoses into 2 hexoses and 1 triose. These reactions involve interconversions of 3, 4, 5, 6, and 7-carbon sugars . Transketolase requires the coenzyme thiamine pyrophosphate (TPP ), the transaldolase does not .

9. IMPORTANCE of NADPH NADPH is required for the bio synthesis of fatty acids, fatty acid, cholestrol and steroids. Free radical Scavenging The free radicals (super oxide, hydrogen peroxide) are continuously produced in all cells . These will destroy DNA, proteins, fatty acids & all biomolecules & in turn cells are destroyed

10. The free radicals are inactivated by the enzyme systems containing superoxide dismutase SOD, peroxidase POD & glutathione reductase . Reduced GSH is regenerated with the help of NADPH .

11. 3. Erythrocyte Membrane integrity NADPH is required by the RBC to keep the glutathione in the reduced state. In turn, reduced glutathione will detoxify the peroxides & free radicals formed within the RBC. NADPH, glutathione & glutathione reductase together will preserve the integrity of RBC membrane .

12. 4 . Prevention of Met- Hemoglobinemia NADPH is also required to keep the iron of hemoglobin in the reduced (ferrous) state & to prevent the accumulation of met-hemoglobin . Met-hemoglobin cannot carry the oxygen .

13. 5- Detoxification of Drugs Most of the drugs and other foreign substances are detoxified by the liver microsomal P450 enzymes, with the help of NADPH. 6 . Lens of Eye: Maximum concentration of NADPH is seen in lens of eye. NADPH is required for preserving the transparency of lens.

14. 7. Macrophage bactericidal activity NADPH is required for the production of reactive oxygen species (ROS) by macrophases to kill bacteria. 8. Availability of Ribose Ribose & Deoxy – ribose are required for DNA & RNA synthesis.

15. 1- Glucose 6-phosphate Dehydrogenase Deficiency Mutations present in some populations causes a deficiency in glucose 6-phosphate dehydrogenase, with consequent impairment of NADPH production . Detoxification of H 2 O 2 is inhibited, and cellular damage results - lipid peroxidation leads to erythrocyte membrane breakdown and hemolytic anemia. The deficiency is manifested only when exposed to certain drugs or toxins, e.g.intake of antimalarial drug like primaquine & ingestion of fava beans( favism ) & sulpha drugs also parecipitate the hemolysis G-6-PD deficiency results in: Heamolytic Aneamia Neonatal Jaundice Kidney failure ABNORMALITIES OF HMP SHUNT

16. Glucose 6-Phosphate Dehydrogenase deficiency is a X-linked recessive hereditary disease which is due to deficiency Of G6PD,which is require for RBC metabolism

17. It is an autosomal recessive disorder caused by an alteration genetic defect in transketolase which reduces its affinity for TPP ( thiamine deficiency) Symptoms are: Mental disorders Severe memory loss Partial paralysis 2-WERNICKE-KORSAKOFF SYNDROME

18. Results in: Liver cirrhosis Male infertility 3-DEFICIENCY OF TRANSALDOSE

19. REGULATION OF HMP SHUNT The entry of glucose 6-phosphate ( Rate-limiting step ) into the pentose phosphate pathway is controlled by the cellular concentration of NADPH NADPH is a strong inhibitor of glucose 6-phosphatedehydrogenase ( G6PD) . NADPH is used in various pathways, inhibition is relieved & the enzyme is accelerated to produce more NADPH.

20. The synthesis of glucose 6-phosphate dehydrogenase is induced by the increased insulin/glucagon ratio after a high carbohydrate meal. In contrast, the enzymes decrease in d iabetes mellitus. REGULATION OF HMP SHUNT ,, cont

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