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
Figure 18.1 The Glycolysis Pathway
Figure 18.1 The Glycolysis Pathway
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
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.
The pyruvate carboxylase reaction.
First Reaction of Gluconeogenesis
- recall that pyruvate is the final product of glycolysis.
(Simplified)
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.
ATP
Carbonyl phosphate
oxaloacetate
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
The PEP carboxykinase reaction.
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)
Fig. 18-26, p. 595
Enolase Reaction
gluconeogenesis
glycolysis
Fig. 18-23, p. 594
The Phosphoglycerate Mutase Reaction
gluconeogenesis
glycolysis
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.
Fig. 18-20, p. 593
Phospoglycerate kinase
glycolysis
gluconeogenesis
The glyceraldehyde-3-phosphate dehydrogenase reaction
glycolysis
gluconeogenesis
Fig. 18-14, p. 589
Triose phosphate isomerase
glycolysis
gluconeogenesis
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
Fig. 18-4, p. 584
- enzyme unique to liver and kidney allowing them to supply glucose to other tissues. Found in ER
Glucose-6-phosphatase
The Cori Cycle
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.
A potent allosteric regulatory molecule.
- activates phosphofructokinase.
- inhibits fructose-1,6-bisphosphatase.
- its synthesis and degradation are catalyzed by the same bifunctional enzyme.
Fructose-2,6-bisphosphate activates glycolysis and inhibits gluconeogenesis, so its level is very important.
F2,6 BP
ATPADP
Pi
F2,6 BPPFK-1
PFK-2
INHIBITS
F2,6 BP
STIMULATES
6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
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
Substrates for gluconeogenesis:
Not substrates for gluconeogenesis:
PyruvateLactateTCA cycle intermediatesMost amino acids
Acetyl-CoAFatty acidsLysineLeucine
Plants and bacteria can make glucose from acetate.