PENTOSE PHOSPHATE SHUNT or HEXOSE MONOPHOSPHATE PATHWAY This pathway consists of two parts:

1. Ferchmin 2012 • Pentose phosphate pathway or shunt (PPP). • 2) Oxidative and isomerization parts. • 3) Regulation • 4) Metabolic roles of PPP • 5) Reduction of glutathione. In glycolysis there was no net oxidation/reduction only “reshuffling” of the redox state of the carbons PENTOSE PHOSPHATE SHUNT or HEXOSE MONOPHOSPHATE PATHWAY This pathway consists of two parts: 1) Glucose-6-P undergoes two oxidations by NADP+, the second is an oxidative decarboxylation that forms a pentose-P. 2) The P-pentoses that are formed during the first part are transformed into glucose-6-P.

2. GPDH deficiency is relatively common in persons with roots from regions with endemic malaria. In glycolysis followed by TCA (Kreb’s) cycle the first Cs to be converted to CO2 are # 3 and 4. In PPP is C #1.

3. See Puerto Rico is in the map! We have a risk of getting malaria. Are you infected? Plasmodium falciparum

4. Glucose-6-Phosphate Dehydrogenase Deficiency Glucose-6-phosphate dehydrogenase deficiency is an inherited condition caused by a defect or defects in the gene that codes for the enzyme, glucose-6-phosphate dehydrogenase (G6PD). It can cause hemolytic anemia, varying in severity from life-long anemia, to rare bouts of anemia to total unawareness of the condition. The episodes of hemolytic anemia can be triggered by common medicines, oxidants, infection, or by eating fava beans. G6PD deficiency is the most common enzyme deficiency in the world, with about 400 million people living with it. It is most prevalent in people of African, Mediterranean, and Asian ancestry. The incidence in different populations varies from zero in South American Indians to less than 0.1% of Northern Europeans to about 50% of Kurdish males. In the United States, it is most common among African American males; about 11 to 14% are G6PD-deficient. G6PD deficiency is a recessive sex-linked trait. Thus, males have only one copy of the G6PD gene, but females have two copies. Recessive genes are masked in the presence of a gene that encodes normal G6PD. Accordingly, females with one copy of the gene for G6PD deficiency are usually normal, while males with one copy have the trait. G6PD is present in all human cells but is particularly important to red blood cells. It is required to make NADPH in red blood cells and maintain the RBC reduced. It is also required to make glutathione. Glutathione and NADPH both help protect red blood cells against oxidative damage. Thus, when G6PD is defective and the demand for NADPH is too high oxidative damage to red blood cells readily occurs causing hemolysis and hemolytic anemia. As of 1998, there are almost 100 different known forms of G6PD enzyme molecules encoded by defective G6PD genes, yet not one of them is completely inactive. This suggests that G6PD is indispensable. Many G6PD defective enzymes are deficient in their stability rather than their initial ability to function. Since red blood cells lack nuclei, they, unlike other cells, cannot synthesize new enzyme molecules to replace defective ones. Hence, we expect young red blood cells to have new, functional G6PD and older cells to have non-functioning G6PD. This explains why episodes of hemolytic anemia are frequently self-limiting; new red blood cells are generated with enzymes able to afford protection from oxidation.

5. 2) Nonoxidative steps of pentose phosphate shunt transketolase requires thiamine pyrophosphate (vitamin B1) transketolase requires thiamine pyrophosphate (vitamin B1) Positive regulator of lipid synthesis

6. Do you? If you don’t study this. The NBE boys want you to know the sequences: 1) vitamin, 2) coenzyme, 3) enzyme involved, 4) name of disease caused by vitamin deficiency and symptoms.

8. GSSG is oxidized and GSH reduced glutathione which will be discussed in next page

9. Glutathione synthesis is not ribosomal and glutathione is not directly encoded in DNA. Notice the unusual bonds between cysteine and glutamate. Unusual “peptide” bond.

11. Link between hexose monophosphate pathway and reduction of peroxides

12. Proposed mechanism of glutathione peroxidase Glutathione peroxidase has selenocysteine a rare amino acid that contains selenium. The story of selenocysteine incorporation into proteins is unusual. There are many antioxidants that neutralize the oxygen reactive species (ROS). Among them are: vitamins C and E and recently the tomato red pigment, lycopene. Lycopene, became notorious for reportedly preventing prostate cancer and retinal macula degeneration.