• Synthesis of glucose from non-carbohydrate precursors
• Occurs mostly in the liver and minor process in kidney
• Kidney produces 10% total glucose during overnight fast

THREE KEY SUBSTRATES

1. Lactate: enters pathway via pyruvate

• Produced by exercising muscle and red blood cells
• Reconverted to pyruvate in liver

2. Glycerol: enters via DHAP

• TAG hydrolyzes to glycerol in adipose tissue
• Liver converts glycerol to DHAP in 2 step reaction

3. Amino acids: enter via pyruvate or citric acid cycle intermediates

• Major source of glucose during extended fast
• Muscle tissue hydrolysis releases glucogenic AA during fast
• AA produce alpha-ketoacids in the liver: enter CAC or gluconeogenesis

ESSENTIAL FUNCTIONS OF GLUCONEOGENESIS

• Clears blood lactate from red blood cells and exercising muscle
• Maintains blood glucose during high fat diet or fast

ENZYMES UNIQUE TO GLUCONEOGENESIS

1. Pyruvate carboxylase (mitochondrial matrix)

• converts pyruvate to oxaloacetate
• Requires 1 ATP, biotin and 1 CO2

2. Phosphoenol carboxykinase (cytosol)

• Preceded by malate shuttle (1 NADH consumed and 1 NADH produced)
• Converts oxaloacetate to phosphoenolpyruvate (PEP)
• Consumes 1 GTP and releases 1 CO2

PEP converted to glyceraldehyde 3-phosphate in 4 reversible reactions: 1 ATP and 1 NADH consumed (double energy inputs, substrates and products)

Glyceraldehyde 3-phosphate reversibly combines w/ DHAP to form fructose 1,6-bisphosphate

3. Fructose 1,6-bisphosphatase (cytosol)

• Produces fructose 6-phosphate
• Consumes 1 H20 and releases 1 Pi

Fructose 6-phosphate reversibly converts to glucose 6-phosphate

4. Glucose 6-phosphatase (ER membrane-bound)

• Translocates glucose 6-phosphate to the ER lumen and removes Pi
• Consumes 1 H2O

ENERGY REQUIREMENTS:
(1 ATP + 1 GTP + 1 NADH + 1 ATP) x 2 = 4 ATP + 2 GTP + 2NADH