THE PENTOSE PHOSPHATE PATHWAY

THE PENTOSE PHOSPHATE PATHWAY

Dr Sumreena Mansoor Assistant Professor Biochemistry Shifa college of Medicine

• 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.

OBJECTIVES

• The pentose phosphate pathway is an alternate route for the oxidation of glucose

PENTOSE PHOSPHATE PATHWAY

FUNCTIONS

1- Generates(NADPH) for fat & steroid biosynthesis  2- Generates pentoses and pentose Phosphates

3- Provides catabolic path for dietary pentose metabolism

4- Generates aldose and ketose families of C3, C4, C5, and C7 carbohydrates

Two Irreversible Oxidative reactions

Reversible sugar-Phosphate Interconversion

No ATP directly consumed or produced in the cycle

NADP+ is used as hydrogen acceptor CO2

Glucose-6-Phosphate 2NADPH(OXIDATIVE PART)

PENTOSE PHOSPHATE PATHWAY

TWO PHASES OXYDATIVE

• 2 irreversible reactions

• NADPH

NON- OXYDATIVE• Series of reversible reactions

• Ribose-5-phosphate----Nucleotide Biosynthesis

• (Diet, Degradation of structural CHO HMP act as

mechanism for metabolic use of 5-Carbon sugars

IRREVERSIBLE OXIDATIVE REACTIONS

Glucose-6-Phosphate

Ribulose 5-phosphate+Co2+2NADPH

IMPORTANCE OF IRREVERSIBLE OXIDATIVE

REACTIONS• NADPH dependent Fatty acid synthesis-----liver, lactating mammary gland• NADPH-dependent biosynthesis of Steroid----- Testes, Ovaries, Placenta, Adrenal cortex• R. B. C requires------- NADPH for Glutathione

reduction

Glucose-6-phosphateNADP+

GLUCOSE-6-PHOSPHATE DEHYDROGENASE

NADPH+H+ (G6PD) (-)NADPH

(+)INSULIN C=O HC-OH HO-CH O HC-OH HC

CH2O P 6-phosphogluconate

OXIDATIVE PHASE

6-PhosphogluconateNADP+

6-PHOSPHOGLUCONATE DEHYDROGENASE

NADPH+H+= (OXIDATIVE DECARBOXYLATION FROM C-1)

CO2

CH2OH C=O HCOH HCOH CH2OP D-ribulose-5-phosphate (5C-ketose)

REVERSIBLE NON-OXIDATIVE REACTIONS

• Occur in all cell----- RNA, DNA• Interconversion of 3,4,5,6 & 7 C-sugars • Ribulose 5-phosphate Ribose 5-P Nucleotide Synthesis

Fructose 6-P

Glyceraldehyde 3-PGlycolysis Intermediates

Trans-ketolase (2-C)Trans-aldolase (3-C)

Isomerase

More NADPH demand

inreductivereactions

More

RIBOSE demand for Nucleotide synthesis

Erthrose 4-PSedoheptulose 7-PXylulose 5-P Ribulose 5_Pepimerase

RIBOSE 5-PFructose 6-P Glyceraldehyde 3-P

IsoTransGlycolysis

HMP Shunt

SUMMARYGlucose-6- P + 2 NADP+ + H2O Ribose-5- P +CO2 + 2 NADPH + 2H+

 This reductive portion of the shunt has generated

NADPH 5-carbon sugars

NADPH

• Reductive Biosynthesis• Reduction of H2O2

• Cytochrome P450• Phagocytosis by white blood

cells• Synthesis of nitric oxide

REACTIVE OXYGEN SPECIES (ROS)

Glucose 6-P

G6PD

Pentose Phosphate

NADPH

Hb Denaturation(Heinz bodies)

NADP+

Oxidant Stress•Infection•Drugs•fava beans

H2O2

Membrane Damage(Hemolytic Anemia)

HMP Shunt

O2 + H2O

R B C

O2Oxidized

GlutathioneReduced

Glutathione

If accumulates

Glutathione Peroxidase

(Se)

GlutathioneReductase

ROLE OF NADPH AND GLUTATHIONE IN PROTECTING CELLS AGAINST ROS

CYTOCHROME P450

CYTOCHROME P450

NEUTROPHIL---KILLING BACTERIA

Neutrophil granulocytes have trapped Shigella bacteria. Neutrophil Extracellular Traps (NETs) that are composed of nucleic acid and aggressive enzymes

CHRONIC GRANULOMATOUS DISEASE

SYNTHESIS OF NO

G6PD

• Rare• Hemolytic Anemia

G6PD DEFICIENCY

• ROS---- damage protein, lipid in cell

• HB----------Denature Protein Oxid of SH (Heinz Bodies)

• Lipid Peroxidation ----Hemolysis

• ACUTE EPISODIC HEMOLYSISRBC cannot synthesize new proteins, the

ENZYME is lost over time and RBC lyse

• ACCELERATED• Drugs

• Fava beans

• Infection

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

• The entry of glucose 6-phosphate into the pentose phosphate pathway is controlled by the cellular concentration of NADPH

• NADPH is a strong inhibitor of glucose 6-phosphate dehydrogenase

• As NADPH is used in various pathways, inhibition is relieved, and the enzyme is accelerated to produce more NADPH

REGULATION OF PENTOSE PHOSPHATE PATHWAY

THANKS