Gluconeogenesis

Category: biosynthesis

Overview

Hepatic (+ renal cortex) synthesis of glucose from non-carb precursors (lactate, glycerol, glucogenic amino acids). Reverses 7 of 10 glycolytic steps via the same enzymes; 4 irreversible glycolytic steps are bypassed by 4 unique gluconeogenic enzymes: pyruvate carboxylase (mitochondrial; pyruvate → OAA, biotin-dependent), PEPCK (cytosolic; OAA → PEP), fructose-1,6-bisphosphatase (RATE-LIMITING; opposes PFK-1), glucose-6-phosphatase (microsomal lumen; only expressed in liver/kidney/intestine — hence those are the only gluconeogenic tissues). Cortisol + glucagon upregulate; insulin downregulates; metformin's primary action is to suppress hepatic gluconeogenesis.

Organ Systems

Pathway Steps

  1. pyruvate → oxaloacetate — via pyruvate carboxylase (biotin). Pyruvate carboxylase (mitochondrial, biotin-dependent) is allosterically activated by acetyl-CoA — high acetyl-CoA from fat oxidation signals fasting and diverts pyruvate toward glucose. The step also replenishes TCA oxaloacetate (anaplerosis).
  2. oxaloacetate → phosphoenolpyruvate — via PEPCK (cytosolic). PEPCK (cytosolic) is transcriptionally induced by glucagon/cortisol and suppressed by insulin. Oxaloacetate must first leave the mitochondrion as malate or aspartate, since the inner membrane has no OAA transporter.
  3. phosphoenolpyruvate → fructose-1-6-bisphosphate — via glycolysis-reversed (7 reversible steps). The seven near-equilibrium glycolytic enzymes simply run in reverse here; only the three irreversible glycolytic steps need dedicated gluconeogenic bypasses (this PEP step, FBPase, and glucose-6-phosphatase).
  4. fructose-1-6-bisphosphate → fructose-6-phosphate — via fructose-1,6-bisphosphatase — RATE-LIMITING. Fructose-1,6-bisphosphatase is the rate-limiting control point and the direct counter to PFK-1: inhibited by AMP and by fructose-2,6-bisphosphate — the same insulin/glucagon signal that activates PFK-1 — so the two are reciprocally regulated to avoid a futile cycle.
  5. glucose-6-phosphate → glucose — via glucose-6-phosphatase — liver/kidney/intestine ONLY. Glucose-6-phosphatase (ER lumen) releases free glucose to the blood and is expressed only in liver, kidney, and intestine — so muscle, lacking it, cannot export glucose. Deficiency causes von Gierke disease (glycogen storage disease type I).

Known Modulators

References