Pentose Phosphate Pathway (PPP)

Pentose Phosphate Pathway (PPP) Objectives:

• By the end of this lecture, you will be able to explain the role of the PPP as an alternative pathway for glucose metabolism compared to glycolysis.
• This lecture will introduce you to the key differences between the PPP and glycolysis in terms of their products and functions.
• You will gain a comprehensive understanding of the primary function of the PPP in generating essential biomolecules like ribose-5-phosphate, a precursor for nucleotides.
• This lecture will explore how the PPP contributes to the synthesis of nucleic acids (RNA and DNA) and other important cellular components.
• You will be able to differentiate between the oxidative and non-oxidative phases of the PPP, explaining their roles in generating reducing equivalents (NADPH) and sugar phosphates.
• Briefly mention the role of the PPP in generating NADPH, a crucial reducing agent for various cellular processes like fatty acid synthesis and detoxification.

Hexose Monophosphate Shunt

• The hexose monophosphate (HMP) shunt, also known as the pentose phosphate pathway (PPP) occurs in the cytoplasm of all cells.
• The HMP shunt serves two major functions, NADPH production and source of ribose 5-phosphate for nucleotide synthesis.
• The first part of the HMP shunt starts with glucose 6-phosphate and ends with ribulose 5-phosphate and is irreversible.
• This part produces NADPH and involves the rate-limiting enzyme glucose 6-phosphate dehydrogenase (G6PDH).

G6PDH Regulation and Pathway Reversibility

• G6PDH is induced by insulin, inhibited by NADPH, and activated by NADP.
• The second part of the pathway beginning with ribulose 5-phosphate represents a series of reversible reactions.
• These produce an equilibrated pool of sugars for biosynthesis, including ribose 5-phosphate for nucleotide synthesis.
• Fructose 6-phosphate and glyceraldehyde 3-phosphate, can feed back into glycolysis.
• Pentoses can be made from glycolytic intermediates without going through the G6PDH reaction.
• Transketolase, which requires thiamine, is important for these interconversions and is the only thiamine enzyme in red blood cells.

NADPH Importance in Leukocytes

• NADPH plays a crucial role in leukocytes during the respiratory burst.
• During the respiratory burst, leukocytes (neutrophils and macrophages) engulf pathogens in a phagosome.
• NADPH oxidase, a complex enzyme assembly, gets activated and uses NADPH to transfer an electron to oxygen.
• This conversion results in the production of the reactive oxygen species (ROS) called superoxide.
• Superoxide is a weak antimicrobial agent, but it serves as the starting point for more potent microbicidal agents.

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

• G6PD deficiency is an inherited disease characterized by hemolytic anemia due to the inability to detoxify oxidizing agents.
• It affects more than 400 million individuals worldwide and is the most common enzyme abnormality in humans.
• G6PD deficiency is caused by more than 400 different mutations in the gene coding for G6PD.
• Some mutations cause clinical symptoms, including hemolytic anemia and neonatal jaundice which typically appears 1-4 days after birth.
• A severe form of G6PD deficiency may shorten life span due to complications from chronic hemolysis.

G6PDH Deficiency and Hemolysis

• Mutations that partially destroy G6PDH activity may lead to acute, episodic hemolysis.
• Erythrocytes cannot synthesize proteins, hence the enzyme is gradually lost, and older red blood cells lyse.
• Certain drugs and fava beans can accelerate this process in some patients.
• The most likely cause of a hemolytic episode in these patients is overwhelming infection like pneumonia (viral and bacterial), or infectious hepatitis.
• In rare instances, a mutation can decrease G6PDH activity enough to cause chronic nonspherocytic hemolytic anemia.

Favism

• Broad beans, also known as fava beans, are common in Mediterranean diets (Greece, Italy, Spain, Portugal, and Turkey).
• Individuals with G6PDH deficiency may experience severe hemolysis upon ingestion of these beans.
• Clinically, the condition manifests as pallor, hemoglobinuria, jaundice, and severe anemia 24-48 hours after ingestion.