Pentose phosphate pathway

1. Pentose phosphate pathway Pentose phosphate pathway has two phases

2. The main product of PPP is ribose 5-phosphate and NADPH • PPP oxidizes glucose 6-phosphate, producing ribose 5-phosphate (precursor for nucleotides) and NADPH (reducing agent for lipid biosynthesis).

3. What type of tissues require PPP? • Rapid dividing cells (bone marrow, skin, intestinal mucosa….) • Tissues that carry out extensive fatty acid synthesis (liver, adipose, lactating mammary gland) or very active synthesis of cholesterol and steroid hormones (liver, adrenal glands, gonads). • Erythrocytes, lens and cornea cells.

4. PPP is highly active in fatty acid- and steroid- synthesizing tissues

5. The oxidative phase of PPP Products of this phase are ribose 5-phosphate and NADPH

6. 1. Glucose 6-phosphate dehydrogenase (G6PD) produces NADPH and 6-phosphoglucono-d-lactone • G6PD oxidize glucose 6-phosphate, producing NADPH and 6-phosphoglucono-d-lactone. • Deficiency of G6PD causes favism. G 6-P NADP+ 6-phospho- glucono-d-lactone Glucose 6-phosphate dehydrogenase NADPH

7. 2. Conversion of 6-phosphoglucono-d-lactone to 6-phosphogluconate 6-phospho- glucono-d-lactone • Lactonase hydrolyzes 6-phosphoglucono-d-lactone, producing 6-phosphogluconate. H2O 6-phospho- gluconate lactonase

8. 3. Oxidation and decarboxylation of 6-phosphogluconate • Oxidation and decarboxylation of 6-phosphogluconate is catalyzed by 6-phosphogluconate dehydrogenase. This reaction also produces NADPH. 6-phosphogluconate NADP+ 6-phosphogluconate dehydrogenase D-ribulose 5-phosphate NADPH CO2

9. 4. Conversion of ribulose 5-phosphate to ribose 5-phosphate D-ribulose 5-phosphate • Ribulose 5-phosphate is converted to ribose 5-phosphate by phosphopentose isomerase. • In some tissues, the PPP ends at this point. Phosphopentose isomerase D-ribose 5-phosphate

10. The nonoxidative phase of PPP Nonoxidative phase of PPP is very important for tissues that only require NADPH but not ribose 5-phosphate

11. Nonoxidative phase is important for recycling ribose 5-phosphate • For cells carrying out extensive fatty acid, cholesterol, or steroid hormone synthesis, only NADPH is required from PPP but not ribose 5-phosphate. • In addition, erythrocytes, lens and cornea cells also do not need ribose 5-phosphate. • In these tissues, ribose 5-phosphate produced by PPP must be recycled.

12. Nonoxidative phase starts with epimerization of ribulose 5-phosphate • Ribulose 5-phosphate is epimerized to xylulose 5-phosphate by ribose 5-phosphate epimerase, which starts the nonoxidative phase of PPP. Ribose 5-phosphate epimerase CH2OH I C=O I OH - H- -OH -H C I H-C-OH I CH2OPO32- Ribulose 5-phosphate Xylulose 5-phosphate

13. Transketolase and transaldolase rearrange the carbon skeleton, producing 5 fructose 6-phosphate from 6 ribose 5-phosphate Sedoheptulose 7-phosphate Fructose 6-phosphate Ribose 5-phosphate Ribose 5-phosphate Phosphohexose isomerase G 6-P G 6-P G 6-P G 6-P Phosphohexose isomerase Sedoheptulose 7-phosphate Erythrose 4-phosphate Fructose 6-phosphate Xylulose 5-phosphate G 3-P transaldolase epimerase transketolase Erythrose 4-phosphate F 6-P F 6-P Xylulose 5-phosphate G 3-P FBPase-1 Aldolase Triose phosphate isomerase transketolase G 3-P F 6-P F 6-P Xylulose 5-phosphate G 3-P

14. Transketolase • Transketolase catalyzes the transfer of a two-carbon fragment from a ketose donor to an aldose acceptor. • Transketolase need the coenzyme TPP. A mutation resulting in 1/10 affinity for TPP causes genetic disorder Wernicke-Korsakoff syndrome (p. 554): severe memory loss, mental confusion, and partial paralysis.

15. Transaldolase • Transaldolase cleaves the ketose and transfer one of the fragment to a aldose. • Both enzymes catalyze similar reaction.

16. Nonoxidative phase of PPP provides a means of converting hexose phosphates to pentose phosphates • Nonoxidative phase of PPP is reversible and happens in cytosol. • During photosynthetic assimilation of CO2, nonoxidative phase of PPP is very important in converting hexose phosphates to pentose phosphates.

17. Glucose 6-phosphate is partitioned between glycolysis and PPP by [NADP+] Glucose • NADP+ stimulate G6PD. When [NADP+] is high (meaning more NADPH is consumed), G6PD is stimulated and G-6-P is flowing toward PPP. G 6-P G 6-P glycolysis ATP G6PD G6PD NADPH NADPH 6-phospho- gluconate 6-phospho- gluconate NADPH NADPH Pentose phosphates Pentose phosphates

18. Favism is a deficiency of G6PD • Deficiency of G6PD block the first step of PPP. • However, because cells have other pathway to synthesize ribose 5-phosphate, G6PD deficiency is generally nonfatal and asymptomatic.

19. Glutathione peroxidase G SH G HS NADP+ NADP+ NADPH Glutathione reductase Glutathione reductase Glutathione reductase Glutathione peroxidase Glutathione peroxidase NADPH Glutathione reductase G SH G HS GS SG O2 Mitochondrial respiration, ionizing radiation, sulfa drugs, herbicides, antimalarials, divicine O2- Superoxide radical O2- 2H+ e- H2O2 H2O2 H2O Hydrogen peroxide Glucose 6-phosphate dehydrogenase NADPH NADPH NADP+ 6-phospho-glucono-d-lactone G6P

20. Glutathione peroxidase GS SG Glutathione peroxidase G SH G HS NADP+ NADP+ Glutathione reductase Glutathione reductase Glutathione peroxidase Glutathione peroxidase NADPH Glutathione reductase G SH G HS GS SG O2 Mitochondrial respiration, ionizing radiation, sulfa drugs, herbicides, antimalarials, divicine O2- Superoxide radical O2- 2H+ e- H2O2 H2O2 H2O2 H2O2 H2O Hydrogen peroxide H+ e-  OH H2O Hydroxyl free radical