26-Pentose Phosphate Pathway

BCH 361 Principles of Biochemistry - Chapter 26: Pentose Phosphate Pathway

Introduction to Pentose Phosphate Pathway

  • NADPH: Essential for the biosynthetic reducing power, particularly in fatty acid synthesis.

  • Pentose Phosphates: Vital component of nucleic acids, crucial during cell replication.

  • Main Products: The pathway primarily generates:

    • NADPH

    • Pentose phosphates from glucose 6-phosphate (G6P)

  • For non-photosynthetic organisms, this is the sole pathway for NADPH generation.

Reactions and Products

Oxidative Phase

  • Generates 2 NADPH per glucose for anabolic reactions, specific to nucleotide biosynthesis (AMP/GMP/UMP/CMP).

  • Key Enzymes:

    • Glucose 6-phosphate dehydrogenase:

      • Converts G6P to 6-phosphoglucono-δ-lactone, reducing NADP+ to NADPH.

    • 6-phosphogluconate dehydrogenase:

      • Converts 6-phosphogluconate to ribulose 5-phosphate and CO2, facilitating the reduction of another NADP+ to NADPH.

      • Reaction analogous to isocitrate dehydrogenase in the TCA cycle.

Rate-limiting Step

  • The conversion of G6P to Ribulose 5P yields 2 NADPH and represents a critical regulatory point.

Non-Oxidative Phase

Transformations of Ribulose 5-Phosphate

  • Isomerization:

    • Ribulose 5-phosphate is converted into ribose 5-phosphate and its epimer, xylulose 5-phosphate.

  • Rearrangement Reactions:

    • Involves fragmentation and transfer between aldoses (ribose) and ketoses (xylulose) activating interconversion of sugars.

    • The net product is the conversion of 3 pentoses into 2 hexoses and 1 triose.

Pathway Summary

Conversion Processes

  • Two primary modes for generating pentose phosphate:

    1. Oxidation of G6P to yield NADPH.

    2. Conversion from glycolysis intermediates (F6P and GAP).

Distinct Modes of Operation

  1. Ribose 5-phosphate Demand > NADPH Demand:

    • Only oxidative phase is active and ribulose-5P is converted to ribose-5P.

  2. Balanced Needs for NADPH and Ribose 5-Phosphate:

    • Slower oxidative phase in cell replication.

  3. NADPH Demand > Ribose 5-phosphate Demand:

    • Pentose phosphate pathway's intermediates are used for NADPH and glycolytic reactions.

  4. Simultaneous Requirement for NADPH and ATP.

Importance of NADPH in Tissues

Role of Reduced Glutathione (GSH)

  • NADPH is critical for converting oxidized glutathione (GSSG) to its reduced form (GSH).

  • GSH is crucial for:

    • Eliminating reactive oxygen species (ROS) produced by mitochondria.

    • Maintaining the integrity of hemoglobin structure.

  • Without adequate GSH, hemoglobin aggregates form Heinz bodies, potentially leading to red blood cell lysis.

Clinical Significance

  • Glucose 6-Phosphate Dehydrogenase Deficiency:

    • Results in drug-induced hemolytic anemia.

    • Provides protection against malaria by limiting NADPH availability which is essential for malaria parasite growth.

  • Other hereditary conditions like sickle cell anemia also confer similar protective effects against malaria.