Lecture 26

Course: BMB 3110
Lecturer: William Hacker, PhD
Chapter 26: The Pentose Phosphate Pathway
   - Pathway reactions
   - Coordinate regulation with glycolysis
   - Handling of oxidative stress
Recommended problems: 1-2, 4-6, 9. 11, and 13 from Chapter 26.
Notes are for personal, educational and noncommercial use of enrolled students.
Illustrations copyrighted from "Biochemistry, A Short Course, 5th Ed."

Definition: The pentose phosphate pathway catalyzes the exchange of intermediates between glycolysis and five-carbon sugars.
   - Generates NADPH
   - Five-carbon sugars are critical for DNA and RNA synthesis.
   - Utilizes five-carbon sugars present in food.
Alternate Names:
   - Phosphogluconate pathway
   - Hexose monophosphate shunt
   - Pentose phosphate shunt
   - Various informal names such as "Johnny Five-fingers", "Fivio P’s", "P3killa", "The Baffler".

NADPH is essential and needed in substantial amounts for various biosynthetic processes.
Table 26.1: Pathways Requiring NADPH:
   - Fatty acid biosynthesis
   - Cholesterol biosynthesis
   - Neurotransmitter biosynthesis
   - Nucleotide biosynthesis
   - Detoxification processes
   - Reduction of oxidized glutathione
   - Function of cytochrome P450 monooxygenases.

The pentose phosphate pathway serves as a critical bridge between NADPH-requiring and NADH-generating pathways.
NADPH pathways include:
   - Glycolysis (and gluconeogenesis)
   - Acetyl CoA (from pyruvate hydrogenase)
   - Citric acid cycle
   - Oxidative phosphorylation
   - Fatty acid breakdown
   - Photosynthesis (Calvin cycle)
NADH pathways includes those producing NADH.

Initial Steps:
  - Catalyzed by glucose 6-phosphate dehydrogenase, producing NADPH through the oxidation of glucose 6-phosphate at carbon 1.
  - The product, phosphogluco-δ-lactone, is hydrolyzed by lactonase, releasing CO2 while producing NADPH.
  - 6-phosphogluconate is then converted to ribulose 5-phosphate.

Following the oxidative phase:
  - Ribulose 5-phosphate is converted into ribose 5-phosphate via phosphopentose isomerase.
  - Ribose 5-phosphate is essential for nucleotide synthesis.
  - If the need for NADPH exceeds that for ribose, ribose is converted to three- and six-carbon molecules:
    - Glyceraldehyde 3-phosphate
    - Fructose 6-phosphate
Reactions are catalyzed by transketolase and transaldolase, allowing for carbon sugar interconversions.

Specific Reactions Summary:
  - Transketolase Reactions:
    - $ext{5-C} + ext{5-C} \rightarrow ext{3-C} + ext{7-C}$
    - $ext{4-C} + ext{5-C} \rightarrow ext{6-C} + ext{3-C}$
  - Transaldolase Reactions:
    - $ext{3-C} + ext{7-C} \rightarrow ext{6-C} + ext{4-C}$
Net Conversion:
  - Conversion of three 5-C sugars into two 6-C and one 3-C sugar, resulting in:
    - Input: Three 5-C sugars (two xylulose 5-P, one ribose 5-P)
    - Output: One 6-C sugar (fructose 6-P), two 3-C sugars (glyceraldehyde 3-P).

Regeneration of ribulose 5-P essential for carbon fixation to proceed.
Various enzymes necessary for transforming sugars during regeneration include transketolase and aldolase which play a role in transferring two-carbon units and joining or cleaving sugars, similar to glycolysis.

Enzymatic transformations are critical to maintain the balance of reactions:
  - Transketolase: Catalyzes conversion between pentose and triose sugars.
  - Transaldolase: Facilitates conversions among hexoses and pentoses.
  - Epimerase: Engages in the interconversion of ribulose 5-P and xylulose 5-P.

The oxidative phase is primarily regulated by concentrations of NADP+:
- Low concentrations reduce the pathway functioning, thus lowering NADPH levels.
- NADPH also acts as an inhibitor, competing at the active site of glucose 6-phosphate dehydrogenase, the committed step enzyme of the oxidative phase.

Coordination: The PPP and glycolysis share glucose 6-phosphate as a substrate; relative flux is determined by NADP+ concentrations.
Growth Conditions: During rapid growth, the demand for ribose 5-phosphate becomes greater, indicating a higher flux through the nonoxidative phase.
Balanced Needs: If both NADPH and ribose 5-P needs are equal, the PPP dominates, routing glucose through its pathway.
High Demand for NADPH: When NADPH demand rises (e.g., in fatty acid synthesis), gluconeogenesis becomes active, and the oxidative phase generates necessary NADPH.

Table 26.3: Identifies tissues heavily using the PPP:
  - Adrenal gland: Steroid synthesis
  - Liver: Fatty acid and cholesterol biosynthesis
  - Testes, Ovary: Hormonal synthesis
  - Adipose tissue, Mammary gland: Lipid synthesis
  - Red blood cells: Maintenance of reduced glutathione for cellular antioxidant defense.

Discusses cancer metabolism where specific enzymatic activity aligns with cancer cell demands, highlighting the unique metabolic needs of these cells.
Clinical Insight: Relates defects in glucose 6-phosphate dehydrogenase and their connection to malaria treatments and oxidative stress susceptibility.

Understand the phases and key reactions of the PPP, particularly regarding NADPH and ribose 5-phosphate production.
Recognize the importance of enzyme regulation and the metabolic context of the pentose phosphate pathway.
Anticipate connections to glycolysis and the broader metabolic programs of cells under varying physiological conditions.