Al-Sham Private University Faculty Of Pharmacy

The Pentose Phosphate Pathway

Lecturer Prof. Abboud Al-Saleh • BIOMEDICAL IMPORTANCE • The pentose phosphate pathway is an alternative route for the metabolism of . It does not generate ATP but has two major functions: • (1) The formation of NADPH for synthesis of fatty acids and steroids and • (2) the synthesis of ribose for nucleotide and nucleic acid formation. • Glucose, , and are the main absorbed from the gastrointestinal tract, derived principally from dietary starch, , 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 . Importance of pentose phosphate pathway

PPP is divided into two phases Oxidative 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 that generate high levels of superoxide radicals, GSH (Reduced Glutathione) is required to reduce these damaging compounds Glutathione Peroxidase catalyzes degradation of organic hydroperoxides by reduction, as two glutathione molecules are oxidized to a disulfide GSSG The PPP is responsible for maintaining high levels of NADPH in red blood cells for use as a reductant in the glutathione 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