Pentose Phosphate Pathway: An Overview

Pentose Phosphate Pathway Overview

• This pathway is also known as the hexose monophosphate shunt or the phosphogluconate pathway
• It provides NADPH for biosynthetic processes
• It also produces ribose-5-phosphate, a key component for nucleic acid synthesis
• Metabolites of the pentose phosphate pathway (PPP) can be shuttled into glycolysis

Fate of G6P

• One possible outcome for Glucose-6-Phosphate (G6P) is entry into the pentose phosphate pathway

PPP as a Shunt

• The pentose phosphate pathway works as a shunt.
• During moderate glucose flux, glycolysis is the preferred route of metabolism.
• During large glucose flux through the pathway, the PPP provides an alternative route for glucose processing

Phases of the Pentose Phosphate Pathway

• Consists of an oxidative phase that generates NADPH
• Consists of a nonoxidative phase that interconverts phosphorylated sugars

NADPH Production

• Two molecules of NADPH are produced when glucose 6-phosphate is converted into ribulose 5-phosphate

Isomerization of Ribulose 5-Phosphate

• Ribulose 5-phosphate is converted into ribose 5-phosphate by phosphopentose isomerase

Epimerization

• Ribulose 5-P is converted into an epimer by phosphopentose epimerase for the transketolase reaction

Linking PPP and Glycolysis

• The pentose phosphate pathway and glycolysis are linked by the enzymes transketolase and transaldolase
• Net reaction: 3 C5 converts to 2 C6 + C3

Reactions Linking PPP and Glycolysis

• Formation of glyceraldehyde 3-P and sedoheptulose 7-P from two pentoses is the first reaction linking the pentose phosphate pathway and glycolysis
• Glyceraldehyde 3-P and sedoheptulose 7-P produced by transketolase then react to form fructose 6-phosphate and erythrose 4-P
• Transketolase catalyzes the synthesis of fructose 6-phosphate and glyceraldehyde 3-P from erythrose 4-P and xylulose 5-P

Interconnected Pathways

• The glycolytic and pentose phosphate pathways feature interconnectivity

Control of Pentose Phosphate Pathway: Mode 1

• In mode 1, more ribose 5-phosphate than NADPH is needed
• Glucose 6-phosphate converts to Fructose 6-phosphate and Fructose 1,6-bisphosphate, and then to Dihydroxyacetone phosphate and Glyceraldehyde 3-phosphate, resulting in Ribose 5-phosphate

Control of Pentose Phosphate Pathway: Mode 2

• In mode 2, NADPH and ribose 5-phosphate needs are balanced
• Glucose 6-phosphate is converted to Ribulose 5-phosphate (producing NADPH in the process)
• The Ribulose 5-phosphate then converts to Ribose 5-phosphate

Control of Pentose Phosphate Pathway: Mode 3

• In mode 3, there is more NADPH needed than ribose 5-phosphate
• Glucose 6-phosphate converts to ribulose 5-phosphate producing NADPH
• The Ribose 5-phosphate converts to Fructose 6-phosphate and back into Glucose 6-phosphate
• The Fructose 6-phosphate converts to Fructose 1,6-bisphosphate the Dihydroxyacetone phosphate and Glyceraldehyde 3-phosphate

Control of Pentose Phosphate Pathway: Mode 4

• In mode 4, NADPH and ATP are both required
• Glucose 6-phosphate is converted to ribulose 5-phosphate producing NADPH, then Ribose 5-phosphate
• The Ribose 5-phosphate converts to Fructose 6-phosphate and back into Glucose 6-phosphate
• The Fructose 6-phosphate converts to Fructose 1,6-bisphosphate, Dihydroxyacetone phosphate and Glyceraldehyde 3-phosphate then Pyruvate (producing ATP)

Hemolytic Anemia

• Glutathione is an important molecule in cells lacking mitochondria
• Reduced glutathione (GSH) maintains a normal reduced state in the cell

Role of Sulfhydryl and GSH

• The sulfhydryl of GSH is used to reduce peroxides (ROS) formed during oxygen transport
• Oxidized form of GSH is two molecules linked by a disulfide bridge (GSSG).

Peroxide Elimination

• Peroxides are usually eliminated by the enzyme glutathione peroxidase
• The enzyme uses reduced glutathione as a reducing agent

Glutathione Reductase and NADPH

• The enzyme glutathione reductase uses NADPH as a cofactor
• The NADPH reduces GSSG back to two moles of GSH

Glutathione's Role in Maintaining Sulfhydryl Groups

• Glutathione’s role is maintaining the reduced form of sulfhydryl groups in protein amino acid residues

Hemolytic Anemia and Enzyme Deficiency

• In hemolytic anemia, the enzyme glucose-6-phosphate dehydrogenase is deficient or defective
• Defective glucose 6-phosphate DH leads to insufficient production of NADPH
• Insufficient NADPH results in insufficient levels of glutathione; this is a medical problem

Hemoglobin and Glucose 6-Phosphate

• Hemoglobin molecules cross-link and form aggregates called Heinz bodies on cell membranes
• Glucose 6-phosphate dehydrogenase is required to maintain reduced glutathione levels to protect against oxidative stress

Favism

• Individuals with G6PD deficiency must not eat Fava beans
• A Greek philosopher and mathematician, Pythagoras prohibited his followers from dining on fava beans
• When erythrocytes lyse, urine turns dark or black

Favism and Glutathione

• Reduced glutathione (GSH) protects the cell by destroying hydrogen peroxide and hydroxyl free radicals
• Regeneration of GSH from oxidized form (GSSG) requires NADPH
• The NADPH is produced in the glucose 6-phosphate dehydrogenase reaction

The pentose phosphate pathway (PPP), also known as the hexose monophosphate shunt, provides NADPH for biosynthesis and ribose-5-phosphate for nucleic acid synthesis. PPP metabolites can be shuttled into glycolysis. It consists of oxidative and nonoxidative phases.