Gluconeogenesis / Pentose Phosphate Pathway

Pentose Phosphate Pathway / Gluconeogenesis

Pentose Phosphate Pathway:

-Source of NADPH (reductive synthesis, maintainence of glutathione in the reduced state), pentoses for nucleic acid synthesis, interconversion of pentoses with hexoses and trioses.

Oxidative Branch:

Glucose-6-phosphate ----> 6-Phosphogluconate ----> Ribulose-5-phosphate ----> Ribose-5-phosphate

Produces: 2 NADPH

Non-Oxidative Branch:

Ribose-5-phosphate ----> ----> Glyceraldehyde-3-phosphate + Fructose-6-phosphate

Produces:

Ribose-5-phosphate for nucleic acid synthesis.

Interconverts pentoses, hexoses and trioses.

Meeting Cellular Needs:

[1] When the requirement for Ribose-5-phosphate exceeds the need for NADPH

(a) Non-Oxidative Branch: reversed to produce Ribose-5-phosphate (nucleic acid precursor)

(b) Oxidative Branch: shut-down, no NADPH production

[2] When the requirement for NADPH exceeds the need for Ribose-5-phosphate

(a) Oxidative Branch: will be activated

(b) Non-Oxidative Branch: Ribose-5-phosphate will be converted to Glyceraldehyde-3- phosphate and Fructose-6-phosphate which will enter the glycolytic pathway for metabolism to pyruvate (this eliminates "feedback" inhibition by Ribose-5- phosphate which would inactivate the Oxidative Branch).

[3] When a balanced requirement for NADPH and Ribose-5-phosphate must be met

(a) Oxidative Branch: activated

(b) Non-Oxidative Branch: inactivated (Ribose-5-phosphate is not metabolized)

Glutathione: Tripeptide (Glu-Cys-Gly)

Glutathione Reduced: Glu-Cys(SH)-Gly

Glutathione Oxidized:

Glu-Cys-Gly

Glutathione Reductase:

Glutathione_oxidized + NADPH + H⁺ ----------------> 2 Glutathione_reduced + NADP⁺

Contains bound FAD which it uses to transfer electrons from NADPH to Glutathione_oxidized

Glutathione Peroxidase:

2 Glutathione_reduced + H₂O₂ ---------------------> Glutathione_oxidized + 2 H₂O

Glutathione_reduced: removes peroxides maintaining RBC membrane integrity and preventing hemolytic anemia.

Gluconeogensis:

Pyruvate Carboxylase: Pyruvate ---------> OAA

Requires biotin as a prosthetic group to carry CO₂.

Requires ATP.

Activated: by acetyl CoA in concert with the inhibition of Pyruvate DH (PDH).

Phosphoenolpyruvate Carboxykinase (PEPCK): OAA ------------> PEP

"Rate -Limiting", commited step.

Requires GTP.
Induced during starvation.

Fructose 1,6-bisphosphatase: (Fructose-1,6-bisphosphate ------> Fructose-6-phosphate + P_i)

Can form a futile cycle with phosphofructokinase-1 (PFK-1)

Fructose-6-phosphate + ATP ------> Fructose-1,6-bisphosphate + ADP

The two enzymes are reciprocally regulated or ATP would be lost without energy conservation.

Glucose-6-Phosphatase: (Glucose-6-phosphate ------> Glucose)

Can form a second futile cycle with hexokinase/glucokinase

Glucose + ATP --------> Glucose-6-phosphate + ADP

The two enzymes are reciprocally regulated or ATP would be lost without energy conservation.

Unique to tissues producing glucose, i.e. liver and kidney.

Glucose-6-phosphate produced from the gluconeogenic pathway is transported to the ER for dephosphorylation.
Glucose and P_i are returned to the cytosol.
Glucose is exported to the blood and P_i remains in the cell.

Lactate as a Precursor: ~40% contribution

Derived from RBC's or from muscle during exercise.

The Cori Cycle:

Shows an interrelationship between liver and RBC's.

This cycle provides a means for localized ATP production. However, as a consequence of gluconeogenesis there is an overall NET LOSS of ATP in the body.

Alanine as a Precursor: ~25% contribution

Alanine is converted to pyruvate via alanine aminotransferase.

The Alanine Cycle (Glucose-Alanine Cycle):

Shows an interrelationship between liver and muscle.

Again, this cycle provides a means for localized ATP production. However, as a consequence of gluconeogenesis there is an overall NET LOSS of ATP in the body.

Glycerol as a Precursor: ~10% contribution

Produced from the breakdown of triacylglycerols in adipose tissue.

Glycerol ------> -------> DHAP, involves only enzymatic reactions in the cytosol.