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Glycolysis, Pentose Phosphate Pathway, & Disease

Presentation covering the basics of glycolysis, the pentose phosphate pathway, and associated diseases
by

Jay Silveira

on 21 July 2015

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Transcript of Glycolysis, Pentose Phosphate Pathway, & Disease

Fructose 1,6-Bisphosphate
Glucose
Glucose 6-Phosphate
Fructose 6-Phosphate
Dihydroxyacetone Phosphate
Glyceraldehyde
3-Phosphate
1,3-Bisphosphoglycerate
3-Phosphoglycerate
2-Phosphoglycerate
Phosphoenolpyruvate
Pyruvate
Lactate
Structure learning tip…
G-6P is easy to draw if you’ve learned glucose, simply exchange the hydroxyl at position 6 for a phosphate group.
Glycolysis = sweet dissolution (Greek origin from glyk- [sweet] and lysis [dissolution]), also known as the Embden-Meyerhof pathway.
Why are defects in glycolysis quite rare?
- Consumes glucose
- Takes place in the cytoplasm of the cell
- Does not require oxygen
- Consumes some ATP
- Generates some ATP
- Produces net ATP
- Consumes NAD+ in the absence of fermentation
Glycolysis
Hexokinase
Phosphoglucose Isomerase
Phosphofructokinase
Aldolase
Triose Phosphate Isomerase
Glyceraldehyde 3-Phosphate Dehydrogenase
Phosphogylcerate Kinase
Phosphogylcerate Mutase
Enolase
Pyruvate Kinase
Lactate Dehydrogenase
C5
C6
Glycolysis, Pentose Phosphate Pathway, & Disease - Objectives
List some of the key metabolic, chemical, and cellular properties of glycolysis.
Calculate the net ATP formation in glycolysis using knowledge of the individual steps of ATP utilization and production.
Identify the three regulatory steps of glycolysis, and which reaction represents the key regulatory step.
Determine where any of the reactions of glycolysis sit with respect to equilibrium based on the free energy change for the reaction in cells.
Know the main allosteric effectors for the regulatory glycolytic enzymes and explain the metabolic logic behind their use.
Recognize the need for lactate in anaerobic glycolysis.
Relate the formation of 2,3-BPG to glycolysis and oxygen delivery in red blood cells.
Explain the biochemical bases relating, cancer, arsenate poisoning, fluoride use, and pyruvate kinase deficiency to the glycolytic pathway and individual steps within it.
Describe the metabolic roles of the pentose phosphate pathway and the physiological effects of glucose 6-phosphate dehydrogenase deficiency.

ATP
ADP
Structure learning tip…
G-6P is easy to draw if you’ve learned glucose, simply exchange the hydroxyl at position 6 for a phosphate group.
C5
C6
ATP
ADP
Phosphoglucose Isomerase
Aldolase
Triose Phosphate Isomerase
Glyceraldehyde 3-Phosphate Dehydrogenase
Phosphogylcerate Kinase
Phosphogylcerate Mutase
Enolase
Lactate Dehydrogenase
Glycolysis is such a central and critical metabolic pathway that you can’t exist without it!
Structure learning tip…
G-6P is easy to draw if you’ve learned glucose, simply exchange the hydroxyl at position 6 for a phosphate group.
C5
C6
ADP (X2)
ATP (X2)
ADP (X2)
ATP (X2)
Structure learning tip…
G-6P is easy to draw if you’ve learned glucose, simply exchange the hydroxyl at position 6 for a phosphate group.
C5
C6
NAD+ (X2)
NADH (X2)

Hexose Monophosphate

Pentose Monophosphates
NADP+ (X2)
NADPH (X2)
2,3-Bisphosphoglycerate
Regulation of Glycolysis
Hexokinase
Phosphofructokinase*
Pyruvate Kinase
Takes place at three critical sites:
NADH (X2)
NAD+ (X2)
G6P
AMP
ATP
F-1,6BP
What do the three key regulatory reactions of glycolysis have in common with respect to the associated change in free energy?
Glycolytic enzymes
Low KM (high affinity) glucose transporters involved in basal glucose uptake.
The arsenate ion (AsO43-) can actually be used by GAPDH (which normally primes the G3P molecule with a second phosphate). However, the arsenate is lost in the next step with no ATP production and the net yield of ATP in anaerobic glycolysis drops to zero.
Arsenic and GAPDH
Hydroxyapatite crystal
Dental Caries: (noun) cavity formation in teeth caused by bacteria that attach to teeth and form acids in the presence of sucrose, other sugars, and refined starches; tooth decay.
http://www.health-res.com/EX/07-28-20/IMAGEL84.jpg
In addition to its ability to inhibit glycolysis, fluoride is also used to prevent tooth decay. When fluoride is combined hydroxyapatite (a naturally occurring mineral with the formula Ca5(PO4)3OH) fluoroapatite (Ca5(PO4)3F) is created, which is more resistant to demineralization.
Enolase and Fluoride
Pyruvate Kinase Deficiency
Autosomal recessive disorder
1/10,000 people world wide
Most common hemolytic anemia caused by a glycolytic enzyme,
RBC break down w/o sufficient ATP to keep the cell healthy.
Severe cases require transfusions.
Afflicted individuals can accumulate 2,3-BPG, affecting oxygen delivery.
Thermal lability of the enzyme
Increased Km for PEP
Decreased activation by fructose-1,6-bisphosphate
Common Causes
Glucose-6-Phosphate Dehydrogenase Deficiency
Although persons who experience hemolysis after the ingestion of fava beans can be presumed to have G6PD deficiency, not all of them will exhibit hemolysis. Fava beans are presumed to cause oxidative damage by an unknown component, possibly vicine, convicine, or isouramil.
Synonyms for Fava Beans
Bell beans
Broad beans
Fever beans
Haba beans
Horse beans
Pigeon beans
Silkworm beans
Tick beans
English dwarf beans
Most common enzyme deficiency worldwide.
Typically, the enzyme is unstable, or subject to enhanced inhibition.
X-linked inherited disorder
Most commonly affects persons of African, Asian, Mediterranean, or Middle-Eastern descent.
Approximately 400 million people are affected worldwide.
The result is decreased production of NADPH, leading to the inability to replenish the supply of reduced glutathione.
Heinz Bodies (disulfide crosslinked aggregates of hemoglobin) can be found in blood smears.
Without glutathione to protect red blood cells from oxidative stress, they are subject to lysis (hemolysis), resulting in hemolytic anemia. Red blood cells are especially sensitive to oxidative stress because they cannot replenish enzymes.
If the hemolysis is severe, hemoglobin will appear in the urine, coloring it dark. The breakdown of heme also produces excess bilirubin, which accumulates in plasma and tissues.
Usually asymptomatic unless the level of oxidative challenge in the blood is high, such as with certain drugs, severe infections, or consuming fava beans.
Glucose-6-Phosphate Dehydrogenase Deficiency
Reduced glutathione (the structure on the left without the disulfide bond) must be regenerated to serve as an antioxidant, the reducing power of NADPH is required for this regeneration.
GSH is the coenzyme for glutathione peroxidase which detoxifies hydrogen peroxide and organic (lipid) hydroperoxides.
Hydrogen peroxide and lipid peroxides are formed spontaneously in the red cell, catalyzed by side reactions of heme iron during oxygen transport on hemoglobin.
Structure of reduced glutathione (GSH) and oxidized glutathione (GSSG).
Glutathione
Glycogen
Phosphofructokinase is the primary site of regulation in glycolysis because it is the COMMITTED STEP of the pathway
Pi
Pi
2
O
Unique to RBCs
Promotes O delivery to tissues
Loss of an ATP generating step in glycolysis
Bishosphogylcerate Mutase
2
Pentose Phosphate Pathway
For NADPH and pentose production
What mechanism of regulation is accomplished through G6P, AMP, ATP, F-1,6BP, and other metabolites?
What do the actual delta G values for these reaction in the body tell you about where they sit with respect to equilibrium?
With an appropriate understanding of the material in this presentation, one should be able to…
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