The Pentose Phosphate Pathway

Al-Sham Private UniversityFaculty Of Pharmacy

Lecturer Prof. Abboud Al-Saleh

•BIOMEDICAL IMPORTANCE

• The pentose phosphate pathway is an alternative route for the metabolism of glucose. It does not generate ATP but has two major functions:

• (1) The formation of NADPH for synthesis of fatty acids and steroidsand

• (2) the synthesis of ribose for nucleotide and nucleic acid formation.

• Glucose, fructose, and galactose are the main hexoses absorbed from the gastrointestinal tract, derived principally from dietary starch, sucrose, and lactose, respectively.

• Fructose and galactose are converted to glucose, mainly in the liver.

• Genetic deficiency of glucose 6-phosphate dehydrogenase, the first enzyme of the pentose phosphate pathway, is a major cause of hemolysis of red blood cells, resulting in hemolytic anemia and affecting approximately 100 million people worldwide.

• Glucuronic acid is synthesized from glucose via the Uronic acid pathway, of major significance for the excretion of metabolites and foreign chemicals (xenobiotics) as glucuronides.

• A deficiency in the pathway leads to essential pentosuria.

• Deficiencies in the enzymes of fructose and galactose metabolism lead to essential fructosuria and the galactosemias.

Importance of pentose phosphate pathway

PPP is divided into two phasesOxidative non-reversible phase

-generates NADPH

-Glucose 6-p undergoes dehydrogenation and decarboxylation to give a pentose, ribulose 5-p, which is converted to its isomer, D-ribose 5-p.

-Overall equation of 1st phase:

Glucose 6-p + 2 NADP++ H2O ribose 5-p + CO2 + 2 NADPH + 2 H+

Non-oxidative reversible phase

-ribose 5‐P is converted back to Glucose 6-p by a series of reactions involving especially two enzymes

1.Transketolase :Transfer of the 2‐C fragment

2.Transaldolase :Transfer of the 3‐C fragment

SUMMARY

Importance of PPP in RBC

When erythrocytes are exposed to chemicals thatgenerate high levels of superoxide radicals, GSH (ReducedGlutathione) is required to reduce these damagingcompounds

Glutathione Peroxidase catalyzes degradation of organichydroperoxides by reduction, as two glutathionemolecules are oxidized to a disulfide GSSG

The PPP is responsible for maintaining high levels ofNADPH in red blood cells for use as a reductant in theglutathione reductase reaction.

Glucose-6-phosphate dehydrogenase deficiency causes hemolytic anemia

Mutations present in some populations causes a deficiency in glucose 6‐phosphate dehydrogenase, with consequent impairment of NADPH production

Detoxification of H2O2 is inhibited, and cellular damage results ‐ lipid peroxidation leads to erythrocyte membrane breakdown and hemolytic anemia.

Most G6PD‐deficient individuals are asymptomatic ‐ only in combination with certain environmental factors (sulfa antibiotics, herbicides, antimalarials, *divicine) do clinical manifestations occur.

*toxic ingredient of fava beans