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Gluconeogenesis

Gluconeogenesis is the synthesis of glucose. It is basically glycolysis run backwards; three new reactions (involving four new enzymes) make the standard free energy favorable.

  • Glycolysis: \( \Delta{G}_o’ = -74 \, \text{kcal/mol} \)
  • Gluconeogenesis: \( \Delta{G}_o' = -36 \, \text{kcal/mol} \)

Gluconeo_glyc.png

For every molecule of glucose synthesized from two molecules of pyruvate, 4 ATP, 2 GTP, and 2 NADH are used.

In the Mitochondria

Pyruvate + ATP \( \rightarrow \) Oxaloacetate + ADP + P

Oxaloacetate + NADH \( \rightarrow \) Malate + NAD+

The conversion to malate allows the molecule to be transported out of the mitochondria. Once in the cytoplasm, it is converted back to oxaloacetate.

In the Cytoplasm

Malate + NAD+ \( \rightarrow \) Oxaloacetate + NADH

Oxaloacetate + GTP \( \rightarrow \) PEP + GDP

From here, it goes through the same intermediates as glycolysis. The last reaction happens in the endoplasmic reticulum.

In the Endoplasmic Reticulum

G6P \( \rightarrow \) glucose (catalyst: glucose-6-phosphatase)

A glucose transporter shuttles the glucose out into the extracellular space.

Regulation

Regulated Reactions Glycolysis Gluconeogenesis
Glucose \( \rightleftharpoons \) G6P

Hexokinase:

G6P (-)

Glucose-6-phosphatase:

[G6P] (substrate level control)

F6P \( \rightleftharpoons \) F1,6BP

Phosphofructokinase:

F2,6BP (+); AMP (+); ATP (-); citrate (-)

Fructose-1,6-bisphosphatase:

F26BP (-); AMP (-)

PEP \( \rightleftharpoons \) Pyruvate

Pyruvate kinase:

F1,6BP (+); acetyl CoA (-); ATP (-); alanine (-); cAMP-dependent phosphorylation (-)

Pyruvate carboxylase:

Acetyl-CoA (+)

These reactions are tightly controlled so that glycolysis and gluconeogenesis are not run at the same time. If they were, the F1,6BP \( \rightleftharpoons \) F6P reaction could turn into a futile cycle, using up ATP without progressing in either direction.

Glyoxylate Cycle

Plants and bacteria can convert acetyl-CoA to glucose via the glyoxylate cycle. It is a modified version of the TCA cycle; an extra malate is produced which can be converted to glucose. Since animals lack this cycle, they cannot use acetyl-CoA to make glucose because it would stop the TCA cycle.

Starch/Glycogen Synthesis

Glucose is added to chains of glycogen for storage via starch/glycogen synthesis. Glucose is converted to G-6-P, then G-1-P. This is added to UDP, which gives glucose the free energy needed to add to the glycogen. (Plants use ADPG and ATP instead of UDPG and GTP.)

Glucose + ATP \( \rightarrow \) G-6-P + ATP

(catalyst: hexokinase)

G-6-P \( \rightarrow \) G-1-P

(catalyst: P-glucomutase)

UTP + G-1-P \( \rightarrow \) UDPG + PPi

(catalyst: UDPG pyrophosphorylase)

PPi + H2O \( \rightarrow \) 2Pi

The glucose of the UDP-glucose is added to the glycogen chain, leaving UDP.

Pentose Phosphate Pathway (PPP)

The PPP is a source of NADPH, which can be used in reductive anabolic pathways. The PPP can also produce ribose.