Pentose phosphate pathway Pentose phosphate pathway has two phases

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).

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.

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

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

Deficiency of G6PD causes favism. 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+ Glucose 6-phosphate dehydrogenase 6-phospho- glucono-d-lactone NADPH

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

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

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

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

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.

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- C -H -OH I H-C-OH I CH2OPO32- Xylulose 5-phosphate Ribulose 5-phosphate

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

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.

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

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.

Glucose 6-phosphate is partitioned between glycolysis and PPP by [NADP+] 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

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.

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

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