Red Blood Cell s Metabolism: HMP Pathway

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1 Click to edit Master title style Edit Master text styles Second level Third level Fourth level Fifth level Red Blood Cell s Metabolism: HMP Pathway Prof. Samar Kassim Prof. Reem Sallam

2 1. Recognize that there are other glucose oxidative pathways that have specific functions. 2. Identify the importance of NADPH production to RBCs. 3. Describe how glutathione can keep the integrity of RBCs membrane. 4. Explain how an enzyme deficiency can cause hemolytic anemia. Extended Modular Program 2

3 Pentose Phosphate Pathway (PPP) Also known as: Pentose shunt Hexose monophosphate shunt (HMP) Phosphogluconate pathway It occurs in the cytosol.

4 One fate of G6P is the pentose P pathway

5 It s a shunt

6 What does the pentose phosphate pathway achieve? 1. The pathway yields reducing potential in the form of NADPH to be used in reductive biosynthesis. 2. The pathway yields ribose 5-phosphate to be used in nucleotide biosynthesis. Nucleotide biosynthesis leading to the synthesis of: DNA RNA Various cofactors (CoA, FAD, SAM, NAD + /NADP + ).

7 NADPH is a phosphorylated form of NADH. In general, with some exceptions,: NADH is used to drive the phosphorylation of ADP to ATP. NADPH is used where reducing potential is required for synthetic reactions.

8 The pentose phosphate pathway can be divided into two phases. Oxidative Non-oxidative interconversion of sugars

9 The oxidative phase of the pentose P pathway H+ + (6-phosphogluconolactone Hydrolase)

10 Regulatory enzyme

11 (6-phosphogluconolactone Hydrolase)

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13 The nonoxidative phase of the pentose pathway This entails extensive carbon atom rearrangement Transketolase requires the coenzyme thiamine pyrophosphate (TPP), the transaldolase does not.

14 Transketolase (TPP dependent) and transaldolase are the link back to glycolysis by producing intermediates of the glycolysis pathway: Glyceraldehyde 3-phosphate Fructose 6-phosphate Net result: 3 C 5 2 C 6 + C 3

15 Ingested ribose can enter the glycolytic pathway through the pentose pathway

16 Regulation of the Pentose Pathway Glucose 6-phosphate dehydrogenase (G6PD) is the regulatory enzyme. NADPH is a potent competitive inhibitor of the enzyme. Usually the ratio NADPH/NADP+ is high so the enzyme is inhibited. But, with increased demand for NADPH, the ratio decreases and enzyme activity is stimulated.

17 The reactions of the non-oxidative portion of the pentose pathway are readily reversible. The concentrations of the products and reactants can shift depending on the metabolic needs of a particular cell or tissue.

18 Rapidly dividing cells require more ribose 5-phosphate than NADPH

19 The need for NADPH and ribose 5- phosphate is balanced

20 More NADPH is needed than ribose 5-phosphate; RBCs & Fatty acid synthesis in adipose cells.

21 The cell needs both NADPH and ATP

22 Glutathione and NADPH What is glutathione? Why is it important? How is it related to NADPH?

23 Glutathione is a tripeptide composed of: glutamate cysteine glycine Reduced glutathione (GSH) maintains the normal reduced state of the cell. Reduced glutathione (GSH)

24 So, what happens if glucose 6-phosphate dehydrogenase (G6PD) is defective? Insufficient production of NADPH. Which translates into insufficient glutathione. Is this a medical problem? YES

25 Glutathione and Erythrocytes GSH is extremely important particularly in the highly oxidizing environment of the red blood cell.

26 Glutathione and Erythrocytes Mature RBCs have no mitochondria and are totally dependent on NADPH from the pentose phosphate pathway to regenerate reduced glutathione (GSH) from oxidized glutathione (GSSG) via glutathione reductase.

27 Glutathione and Erythrocytes In fact, as much as 10% of glucose consumption, by erythrocytes, is mediated by the pentose phosphate pathway.

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29 G6PD deficiency G6PD deficiency is a hereditary condition, inherited as X-linked. It is a group of deficiencies caused by a number of different mutations in the gene for G6PD. It is characterized by hemolytic anemia caused by the inability to detoxify oxidizing agents. It is the most common disease-producing enzyme abnormality in humans.

30 G6PD deficiency It has the highest prevalence in : The Middle East Tropical Africa Asia Clinical manifestations: Hemolytic anemia Jaundice: Due to increased production of unconjugated bilirubin. Neonatal jaundice (in the first 1-4 days after birth) There is a survival advantage for G6PD deficiency: an increased resistance to Plasmodium falciparum malaria is noticed in G6PD deficiency

31 Conditions for hemolytic anemia related G6PD deficiency. The ingestion of oxidative agents that generate peroxides or reactive oxygen species (ROS): Antimalarial: pamaquine, premaquine fava beans (contains divicine which is an Oxidant)

32 Conditions for hemolytic anemia related G6PD deficiency. Individuals with G6PD deficiency can not produce sufficient GSH to cope with the Reactive Oxygen Species (ROS). Proteins become cross linked leading to Heinz bodies formation and cell lysis.

33 Heinz bodies

34 People with the disorder are not normally anemic and display no evidence of the disease until the red blood cells are exposed to an oxidant or stress. Drugs that can precipitate this reaction: antimalarial agents sulfonamides (antibiotic) non-steroidal anti-inflammatory drugs (NSAIDs)

35 FAVISM Individuals with G6PD deficiency must not eat Fava beans. Pythagoras???: Avoid Fava Beans Erythrocytes lyse=dark or black urine. Interesting The growth of Plasmodium falciparum (malaria parasite) fails in G6PD deficient individuals.

36 Thank you