Biochemistry - Lesson 13: Pentose Phosphate Pathway and Other Carbohydrate Pathways

The pentose phosphate pathway (PPP) provides NADPH for biosynthesis and ribose-5-phosphate for nucleotide synthesis, branching off from glycolysis at glucose-6-phosphate. It can reconnect to glycolysis via intermediates, allowing cells to balance energy production with reductive biosynthesis and DNA/RNA precursor supply. Additionally, alternative sugar metabolism routes (for fructose, galactose, and other carbohydrates) feed into or out of glycolysis, illustrating the metabolic flexibility cells possess for handling diverse dietary inputs.

Pentose Phosphate Pathway Overview

The PPP is divided into two phases:

• Oxidative Phase: Irreversibly generates NADPH through the oxidation of glucose-6-phosphate and subsequent decarboxylation of 6-phosphogluconate, producing ribulose-5-phosphate.
• Non-oxidative Phase: Reversibly interconverts sugar phosphates (ribose-5-phosphate, xylulose-5-phosphate, sedoheptulose-7-phosphate, glyceraldehyde-3-phosphate, fructose-6-phosphate), allowing the pathway to produce ribose for nucleotides or re-enter glycolysis as needed.

NADPH is essential for reductive biosynthesis (fatty acids, cholesterol) and for combating oxidative stress (e.g., glutathione regeneration). Ribose-5-phosphate underpins nucleotide and nucleic acid synthesis.

Cells can increase or decrease PPP flux based on NADPH needs or ribose demands. For instance, rapidly dividing cells often elevate the non-oxidative phase to supply ribose for nucleotides, while cells engaged in fatty acid synthesis run the oxidative phase to generate NADPH.

Regulation of the PPP

• Glucose-6-phosphate dehydrogenase is the major regulatory enzyme; high NADPH inhibits it.
• Transketolase activity can be diagnostic for thiamine deficiency when measured in RBCs, reflecting TPP availability.

Other Carbohydrate Pathways

Beyond glucose, other dietary sugars integrate into carbohydrate metabolism:

Fructose Metabolism

Fructose enters glycolysis at fructose-6-phosphate (muscle/adipose) or glyceraldehyde-3-phosphate/dihydroxyacetone phosphate (liver). Excessive fructose intake can bypass major regulatory steps (e.g., phosphofructokinase-1), contributing to imbalances in lipid synthesis.

flowchart LR A["Fructose (Diet)"] --> B["Fructokinase: Fructose → Fructose-1-phosphate (Liver)"] B --> C["Aldolase B: Fructose-1P → DHAP + Glyceraldehyde"] C --> D["Glyceraldehyde → Glyceraldehyde-3P"] D --> E["Enters Glycolysis / Lipogenesis"]

Galactose Metabolism

Galactose from dairy products is phosphorylated (galactokinase) and then converted to glucose-1-phosphate via the galactose-1-phosphate uridyltransferase system, eventually entering glycolysis or glycogenesis. Defects in these enzymes underlie classic galactosemia (leading to cataracts, liver damage) or other milder disorders.

Summary

The pentose phosphate pathway supplies NADPH for reductive biosynthesis and ribose-5-phosphate for nucleotide synthesis. Its oxidative phase generates NADPH and CO₂, while the non-oxidative phase interconverts sugar phosphates to meet cellular demands for ribose or glycolytic intermediates. Fructose and galactose pathways illustrate how diverse dietary sugars feed into central metabolism. By balancing energy needs, biosynthetic demands, and redox status, these pathways underscore the integrated nature of carbohydrate metabolism.

Suggested Reading:
Lehninger Principles of Biochemistry (chapters on the pentose phosphate pathway and sugar metabolism)
Biochemistry by Berg, Tymoczko, and Stryer (sections detailing PPP regulation, fructose/galactose integration)