synthesis of "new glucose" from common metabolites humans use ~160 g of glucose per day...
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Synthesis of "new glucose" from common metabolites
• Humans use ~160 g of glucose per day
• 75% is used by the brain
• Body fluids contain only 20 g of glucose
• Glycogen stores yield 180-200 g of glucose
• So the body must be able to make its own glucose
• 90% of gluconeogenesis occurs in the liver and kidneys
Gluconeogenesis
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Figure 18.1 The Glycolysis Pathway
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Figure 18.1 The Glycolysis Pathway
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Why is gluconeogenesis not just the reverse of glycolysis?
The reverse of glycolysis is
2 Pyruvate + 2ATP + 2 NADH + 2H+ + 2H20 a glucose +2ADP +2Pi + 2 NAD + (DG = +74 kJ/mol)
This is thermodynamically unfavorable, so energetically unfavorable steps in the reverse glyolysis reaction are replaced and energy is added in the form of GTP and ATP to give:
The actual equation for gluconeogenesis of
2Pyruvate + 4ATP +2GTP+ 2NADH + 2H+ + 6H20 a glucose +4ADP +2GDP +6Pi + 2 NAD + (DG = -38 kJ/mol)
Notice the extra ATPs and GTPs drive the process
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Glycolysis vs Gluconeogenesis
GlycolosisGlucose (6C) to 2 pyruvates (3C)
Creates energy 2ATP
Reduces 2 NAD+ to 2 NADH
Active when energy in cell low
10 steps from glucose to pyruvate
Pyruvate to AcCoA before Krebs
Gluconeogenesis2 pyruvates (3C) to Glucose (6C)
Consumes energy 4ATP+2GTP
Oxidizes 2NADH to 2 NAD+
Active when energy in cell high
11 steps from pyruvate to glucose
AcCoA isn’t used in gluconeogenesis
Gluconeogenesis uses 7 of the 10 enzymatic reactions of glycolysis but in the reverse direction. The 3 not used are the ones requiring ATP in glycolysis.
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The pyruvate carboxylase reaction.
First Reaction of Gluconeogenesis
- recall that pyruvate is the final product of glycolysis.
(Simplified)
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Biotin is an essential cofactor in most carboxylation reactions.
It is an essential vitamin in the human diet, but deficiencies are rare.
Avidin, a protein found in egg white binds tightly to biotin and excessive consumption of raw egg white can lead to biotin deficiency.
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ATP
Carbonyl phosphate
oxaloacetate
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Oxaloacetate cannot be transported directly across the mitochondrial membrane so it is converted to malate, then transported, then oxidized back to oxaloacetate.
Pyruvate is converted to oxaloacetate in the mitochondria
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The PEP carboxykinase reaction.
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Nucleotide diphosphate kinases
Both glycolysis and Oxidative phosphorylation produce ATP with its high energy phoshoanhydride bonds: How does GTP get made from GDP?
Directly from a single step in the Krebs cycle AND from the following reaction
GDP + ATP → GTP + ADP
This is carried out in the cell by an enzyme called
Nucleotide diphosphate kinase which carries out the general reaction
NDP + ATP → NTP + ADP (where N is T, G, or C)
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Fig. 18-26, p. 595
Enolase Reaction
gluconeogenesis
glycolysis
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Fig. 18-23, p. 594
The Phosphoglycerate Mutase Reaction
gluconeogenesis
glycolysis
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Isomerase: An enzyme that catalyzes the transformation of compounds into their positional isomers. In the case of sugars this usually involves the interconversion of an aldose into a ketose, or vice versa.
Kinase: An enzyme that catalyzes the phosphorylation (or dephosphorylation) of a molecule using ATP (or ADP).
Mutase: An enzyme that catalyzes the transposition of functional groups, such as phosphates, sulfates, etc.
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Fig. 18-20, p. 593
Phospoglycerate kinase
glycolysis
gluconeogenesis
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The glyceraldehyde-3-phosphate dehydrogenase reaction
glycolysis
gluconeogenesis
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Fig. 18-14, p. 589
Triose phosphate isomerase
glycolysis
gluconeogenesis
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Aldolase4th reaction of glycolysis (7th reaction of gluconeogenesis).
Reversible reaction also used in gluconeogenesis.
An aldol cleavage reaction (the reverse of an aldol condensation).
glycolysis
gluconeogenesis
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Fig. 18-4, p. 584
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- enzyme unique to liver and kidney allowing them to supply glucose to other tissues. Found in ER
Glucose-6-phosphatase
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The Cori Cycle
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Regulation of Gluconeogenesis
Glucose-6-phosphatase is subject to substrate level control.
- at higher G6P concentrations reaction rate increases
- recall, this happens in the liver. Other tissues do not hydrolyze their G6P, thereby trapping it in the cells.
Glycolysis and gluconeogenesis are reciprocally regulated.
- regulatory molecules that inhibit gluconeogenesis often activate glycolysis, and vise versa.
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A potent allosteric regulatory molecule.
- activates phosphofructokinase.
- inhibits fructose-1,6-bisphosphatase.
- its synthesis and degradation are catalyzed by the same bifunctional enzyme.
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Fructose-2,6-bisphosphate activates glycolysis and inhibits gluconeogenesis, so its level is very important.
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F2,6 BP
ATPADP
Pi
F2,6 BPPFK-1
PFK-2
INHIBITS
F2,6 BP
STIMULATES
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6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
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6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
P
High glucagon
Increased phosphorylation
Phosphorylation of the enzyme results in the inactivation of the phosphofructokinase-2 activity and activation of the fructose-2,6-bisphosphatase activity. This results in a down regulation of glycolysis and increased gluconeogenesis.
Low glucose
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Substrates for gluconeogenesis:
Not substrates for gluconeogenesis:
PyruvateLactateTCA cycle intermediatesMost amino acids
Acetyl-CoAFatty acidsLysineLeucine
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Plants and bacteria can make glucose from acetate.
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