introduction to metabolism regulation of …...introduction to metabolism regulation of metabolism...
TRANSCRIPT
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GlycolysisIntroduction to MetabolismRegulation of Metabolism
Overview of GlycolysisReactions of Glycolysis
Suggested Reading:
Lippincot’s Ilustrated reviews: Biochemistry
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Glycolysis, an example of metabolic pathway
The product of one reaction is the substrate of the next reaction
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Metabolic pathways
intersect to form network
of chemical reactions
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Regulation of Metabolism
• Signals from within the cell
– Substrate availability, product inhibition, allosteric
– Rapid response, moment to moment
• Communication between cells (intercellular)
– Slower response, longer range integration
• Second messenger
– Ca2+ / phosphatidylinositol system
– Adenyl cyclase system
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Communication between cells;
Commonly used mechanisms
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INTRACELLULAR EFEECTSActivated enzymesInhibited Enzymescell’s ion channels bind to promoter
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GLYCOLYSIS
Universal Pathway: In all cell types
Generation of ATP
With or without O2
Anabolics Pathway:
biosynthetic precursors
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The Two Phases of the glycolytic Pathway
1 Glucose (C6)
1 ATP
1 ATP
1 Fructose 1,6 bisphosphate (C6)
2 Triose Phosphate (C3)
2 NADH
2 ATP
2 ATP
2 Pyruvate (C3)
Preparative Phase
ATP-generatingPhase
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Glycolysis occurs in all human cells
Glucose Pyruvate acetyl CoA
Lactate CO2
CO2
TCA
No O2 requirement for glycolytic anaerobic fermentation
O2 requirement for PDH & TCA activities
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Tissues with an Absolute or high Requirement for Glucose
• Brain
• Red Blood Cells
• Cornea lens and retina
• Kidney Medulla,
• Testis
• Leukocytes
• White muscle fibers
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Hexokinase Glucokinase
Occurance In all tissues In liver
Km < 0.02 mM 10-20 mM
Specificity Glc., Fruc, Man, Gal Glc.
induction Not induced ↑ insulin, Glc
Function At any glucose level Only > 100 mg/dl
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Mechanism of the reaction:
E and S form covalent linkage
S is oxidized and NADH is formed
NADH is released
Pi attacks the thioester bond releasing the
product
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-ATP-ATP
2 NADH2 ATP
2ATP
Is Oxygen needed?
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Synthesis of 2,3 bisphosphoglycerate
in RBC
Oxygen delivery to tissues
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Pyruvate + NADH Lactate + NAD+
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Lactate Production
• Cells with low energy demand
• To cope with increased energy demand in rigorously exercising muscle
lactate level is increased 5 to 10 folds
• Hypoxia
to survive brief episodes of hypoxia
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Lactic Acidosis • ↓ pH of the plasma
• The most common cause of metabolic acidosis
– ↑ Production of lactic acid
– ↓ utilization of lactic acid
Pyruvate + NADH Lactate + NAD+
• Most common cause: Impairment of oxidative metabolism due to collapse of circulatory system.
– Impaired O2 transport
– Respiratory failure
– Uncontrolled hemorrhage
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Lactic Acidosis
• Direct inhibition of oxidative phosphorylation
• Hypoxia in any tissue
• Alcohol intoxication ( high NADH/ NAD+ )
• ↓ Gluconeogenesis
• ↓ Pyruvate Dehydorgenase
• ↓ TCA cycle activity
• ↓ Pyruvate carboxylase
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Inorganic Inhibitors of GlycolysisFluoride
• Fluoride inhibits Enolase
•
Fluoridated water bacterial enolase
Prevention of Dental Carries
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Inorganic Inhibitors of GlycolysisArsenic Poisoning
– Pentavalent Arsenic (Arsenate)
competes with phosphate as
as a substrate for GA3PDH
ATP synthesis
– Trivalent Arsenic (Arsenite)
Forms stable complex with -SH
of lipoic acid
Pyruvate Dehydrogenase
α ketoglutarate Dehydrogenase
Neurological dissturbances…….DEATH
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Pyruvate Kinase Deficiency• The most common among glycolytic enzyme
deficiencies ( 95% of cases PK ; 4% PGI )
• RBC’s are affected
• Mild to severe chronic hemolytic anemia
• ATP is needed for Na+/K+ pumpmaintain the flexible shape of the cell
• Low ATP premature death of RBC
• Abnormal enzyme; mostly altered kinetic properties
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Alterations observed with various mutant forms of pyruvate kinase
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Regulation of PFK by
Fructose 2,6-bisphosphate
Fruc. 6-phosphate + ATP Fruc. 2,6 bisphosphate + ADP PFK-2
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Regulation by ATP and AMP;
why AMP
ADP + ADP ATP + AMP
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Next topic: Gluconeogenesis
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CATABO
LI
M
ANABOLISM
Energy-poor end products
Energy-yielding nutrients Complex molecules
Precursor molecules