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OBJECTIVES

OBJECTIVES. To understand the function of the pentose phosphate pathway in production of NADPH and ribose precursors for nucleic acid synthesis. To examine the importance of NADPH in protection of cells against highly reactive oxygen species.

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OBJECTIVES

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  1. OBJECTIVES • To understand the function of the pentose phosphate pathway in production of NADPH and ribose precursors for nucleic acid synthesis. • To examine the importance of NADPH in protection of cells against highly reactive oxygen species. • To relate defects in the pentose phosphate pathway to disease conditions.

  2. HMP Shunt Hexose Mono Phosphate Shunt = Pentose Phosphate Pathway = Complete Glucose Oxidation Function : Production of • For NADPH • Ribose 5P Site : • In the cytoplasm of all cells except muscle, and nonlactating mammary gland (low activity)

  3. Generation of NADPH - mainly used for reductive syntheses of fatty acids, steroids, amino acids via glutamate dehydrogenase; and production of reduced glutathione in erythrocytes and other cells. - active in liver, adipose tissue, adrenal cortex, thyroid, erythrocytes, testes, and lactating mammary gland - not active in non-lactating mammary gland and has low activity in skeletal muscle. • Production of ribose residues for nucleotide and nucleic acid synthesis.

  4. NADPH for H2O2 elimination • In the Erythrocytes, Pulmonary Cells, and Liver Cells : H2O2 + GSH  GS-SG + H2O (1) GS-SG + 2 NADPH  2 GSH + 2 NADP (2) Enzyme 1.Glutathione peroxidase Enzyme 2.Glutathione reductase

  5. Glucose-6-phosphate dehydrogenase (G6PD) 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

  6. NADPH + H+ is formed from two separate reactions. The glucose 6-phosphate DH (G6PD) reaction is the rate limiting step and is essentially irreversible. Cells have a greater need for NADPH than ribose 5-phosphate.

  7. Regulatory enzyme The enzyme is highly specific for NADP+; the Km for NAD+ is 1000 greater than for NADP+.

  8. The nonoxidative phase of the pentose pathway This entails extensive carbon atom rearrangement. Transketolase requires the coenzyme thiamine pyrophosphate (TPP), the transaldolase does not.

  9. Transketolase (TPP) and transaldolase are the link back to glycolysis. • Glyceraldehyde 3-phosphate • Fructose 6-phosphate • Net result: • 3C5 2C6 + C3

  10. (4) (5) (3) (6)

  11. In the muscle • HMP Shunt inactive because G 6P Dehydrogenase and 6 P Gluconate Dehydrogenase deficient • Ribose 5 P synthesized in the way of reverse HMP Shunt or through Transketolase path.

  12. Synthesis Ribose 5P in the muscle G  G 6P  F 6P  F 1,6 BP Glyceraldehyde 3P DHAP (Gld 3P) Gld 3P + F 6P  Xylulose 5P + Erythrose 4P Xylulose 5P  Riboluse5 P  Ribose 5P

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