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THE PENTOSE PHOSPHATE PATHWAY. Dr Sumreena Mansoor Assistant Professor Biochemistry Shifa college of Medicine. OBJECTIVES. - PowerPoint PPT Presentation
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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