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Gluconeogenesis. 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

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Presentation Transcript
slide1

Gluconeogenesis

  • 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
why is gluconeogenesis not just the reverse of glycolysis
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
Glycolosis

Glucose (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

Gluconeogenesis

2 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

Glycolysis vs 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.

slide7

First Reaction of Gluconeogenesis

- recall that pyruvate is the final product of glycolysis.

The pyruvate carboxylase reaction.

(Simplified)

slide8

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.

slide9

ATP

Carbonyl phosphate

oxaloacetate

slide10

Pyruvate is converted to oxaloacetate in the mitochondria

Oxaloacetate cannot be transported directly across the mitochondrial membrane so it is converted to malate, then transported, then oxidized back to oxaloacetate.

nucleotide diphosphate kinases
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)
slide15

Enolase Reaction

glycolysis

gluconeogenesis

Fig. 18-26, p. 595

slide17

The Phosphoglycerate Mutase Reaction

glycolysis

gluconeogenesis

Fig. 18-23, p. 594

slide18

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.

slide20

glycolysis

gluconeogenesis

Phospoglycerate kinase

Fig. 18-20, p. 593

slide24

glycolysis

gluconeogenesis

Triose phosphate isomerase

Fig. 18-14, p. 589

slide26

Aldolase

4th 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

slide32

Glucose-6-phosphatase

  • enzyme unique to liver and kidney allowing them to supply glucose to other tissues. Found in ER
slide34

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.

slide35

A potent allosteric regulatory molecule.

- activates phosphofructokinase.

- inhibits fructose-1,6-bisphosphatase.

- its synthesis and degradation are catalyzed by the same bifunctional enzyme.

slide36

Fructose-2,6-bisphosphate activates glycolysis and inhibits gluconeogenesis, so its level is very important.

slide37

INHIBITS

F2,6 BP

STIMULATES

PFK-1

F2,6 BP

ATP

ADP

Pi

PFK-2

F2,6 BP

slide39

6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase

Low glucose

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.
slide41

Substrates for gluconeogenesis:

Pyruvate

Lactate

TCA cycle intermediates

Most amino acids

Not substrates for gluconeogenesis:

Acetyl-CoA

Fatty acids

Lysine

Leucine