Pentose Phosphate Pathway Notes

Pentose Phosphate Pathway

Overview

The pentose phosphate pathway is crucial for growth, providing:

• NADPH: Biochemical reducing power.
• Ribose sugars: Precursors for RNA, DNA, and nucleotide coenzymes.

Learning Objectives

• Understand the oxidative phase.
• Understand the non-oxidative phase.
• Understand the different modes based on cellular needs.
• Understand reduced glutathione.

Key Products and Equation

The pentose phosphate pathway yields five-carbon sugars and NADPH.

• Overall Reaction:
  $glucose \text{ } 6\text{-phosphate} + 2NADP^+ + H<em>2O \rightarrow ribulose \text{ } 5\text{-phosphate} + 2NADPH + 2H^+ + CO</em>2$

• Two NADPH molecules are generated during the conversion of glucose 6-phosphate into ribulose 5-phosphate.

• NADPH is the primary source of biosynthetic reducing power in organisms.

Two Phases of the Pathway

1. Oxidative Generation of NADPH: Produces NADPH.
2. Nonoxidative Interconversion of Sugars: Interconverts different sugars.

Phase 1: Oxidative Generation of NADPH

• Initiated by glucose 6-phosphate dehydrogenase.

• Reaction: Glucose 6-phosphate is converted into 6-phosphoglucono-δ-lactone, reducing $NADP^+$ to NADPH.

• A second NADPH is generated when 6-phosphogluconate is converted into ribulose 5-phosphate and $CO_2$. This reaction is catalyzed by 6-phosphogluconate dehydrogenase, which decarboxylates 6-phosphogluconate and oxidizes the 3C hydroxyl to a ketone.

Phase 2: Nonoxidative Interconversion of Sugars

• This phase involves the interconversion of various sugars:

  • Ribulose 5-phosphate
  • Ribose 5-phosphate (R5P)
  • Xylulose 5-phosphate (Xu5P)
  • Sedoheptulose-7-phosphate (S7P)
  • Glyceraldehyde-3-phosphate (GAP)
  • Erythrose-4-phosphate (E4P)
  • Fructose-6-phosphate (F6P)

• Isomerization: Ribulose 5-phosphate, generated in the oxidative phase, is isomerized into ribose 5-phosphate.

• Importance of Ribose 5-phosphate: Ribose 5-phosphate is a precursor for DNA, RNA, ATP, NADH, and FAD.

Interconnection with Glycolysis

• Cells often need more NADPH than ribose 5-phosphate.
• Ribose 5-phosphate can be converted into glyceraldehyde 3-phosphate and fructose-6-phosphate.
• Transketolase and transaldolase provide a reversible link between the pentose phosphate pathway (phase 2) and glycolysis.

Reactions Catalyzed by Transketolase and Transaldolase

• Transketolase:

  • Converts two five-carbon sugars into a three-carbon and a seven-carbon sugar.
  • Xylulose 5-phosphate reacts with ribose 5-phosphate to produce glyceraldehyde 3-phosphate and sedoheptulose 7-phosphate.

  $Xylulose \text{ } 5\text{-phosphate} + Ribose \text{ } 5\text{-phosphate} \rightleftharpoons Glyceraldehyde \text{ } 3\text{-phosphate} + Sedoheptulose \text{ } 7\text{-phosphate}$

• Xylulose 5-phosphate is formed from ribulose 5-phosphate via an epimerization reaction.

• Transaldolase:

  • Forms a six-carbon and a four-carbon sugar from a three-carbon and a seven-carbon sugar.

• Transketolase:

  • Converts a four-carbon sugar and a five-carbon sugar into a six-carbon sugar and a three-carbon sugar.

Modes of Operation

The pentose phosphate pathway can operate in four distinct modes, combining the oxidative phase, nonoxidative phase, glycolysis, and gluconeogenesis.

• Mode 1: Ribose 5-phosphate needs exceed NADPH needs.

  • Rapidly dividing cells require ribose 5-phosphate for nucleotide precursor synthesis.
  • $5 \text{ } glucose \text{ } 6\text{-phosphate} + ATP \rightarrow 6 \text{ } ribose \text{ } 5\text{-phosphate} + ADP + H^+$

• Mode 2: NADPH and ribose 5-phosphate needs are balanced.

  • $glucose \text{ } 6\text{-phosphate} + 2 \text{ } NADP^+ + H<em>2O \rightarrow ribose \text{ } 5\text{-phosphate} + 2 \text{ } NADPH + 2H^+ + CO</em>2$

• Mode 3: More NADPH is needed than ribose 5-phosphate.

  • The equivalent of glucose 6-phosphate can be completely oxidized to $CO_2$ to generate NADPH.
  • Fatty acid synthesis requires NADPH.
  • $glucose \text{ } 6\text{-phosphate} + 12 \text{ } NADP^+ + 7 \text{ } H<em>2O \rightarrow 6 \text{ } CO</em>2 + 12 \text{ } NADPH + 12H^+$

• Mode 4: NADPH and ATP are both required.

  • $3 \text{ } glucose \text{ } 6\text{-phosphate} + 6 \text{ } NADP^+ + 5 \text{ } NAD^+ + 5Pi + 8 \text{ } ADP \rightarrow 5 \text{ } pyruvate + 3 \text{ } CO<em>2 + 6 \text{ } NADPH + 5 \text{ } NADH + 8 \text{ } ATP + 2 \text{ } H</em>2O + 8H^+$

Oxidative Stress

• Pathological conditions are associated with oxidative cell damage.
• Reactive oxygen species (ROS) are generated during oxidative metabolism and can damage macromolecules, leading to cell death.

Reduced Glutathione

• Protects against oxidative stress.
• Peroxides can cause damage to red blood cells, leading to hemolytic anemia.
• Reduced glutathione (GSH) is a tripeptide with a free sulfhydryl group.
• GSH combats oxidative stress by reducing ROS to harmless forms.
• GSH is oxidized to GSSG, forming a disulfide bond between two GSH molecules.

Role of Glucose 6-Phosphate Dehydrogenase

• Plays a key role in protection against ROS.
• Oxidized glutathione (GSSG) is converted into reduced glutathione by NADPH, a reaction catalyzed by glutathione reductase.
• The reducing power is supplied by glucose 6-phosphate dehydrogenase in the pentose phosphate pathway.
• Compromised glucose 6-phosphate dehydrogenase activity can lead to inadequate NADPH production, affecting GSH levels.