4/6/2017

Objectives
• Discuss how glucose can be synthesized from
non-carbohydrate precursors
• Discuss the enzymes unique to gluconeogenesis,
co-factors involved and cell localization
• Discuss the regulation and physiological
significance of gluconeogenesis

CHEM 160
GLUCONEOGENESIS

Glucose Gluconeogenesis
• Primary fuel of the brain and red blood cells  Synthesis of glucose from
non-carbohydrate
• An average human requires 160 g of glucose precursors:
a day.
 Pyruvate, lactate,
• 75% of this daily requirement is consumed glycerol, some amino
by the brain acids, TCA cycle
• During prolonged starvation/fasting, glucose intermediates
must be synthesized from non-carbohydrate  Occurs when glycogen
precursors. reserves are already
depleted.

Gluconeogenesis 1a. Pyruvate to OAA

 NOT the exact reverse of • Occurs in the mitochondrial matrix
glycolysis
• Differs in the
irreversible steps
• Enzymes that catalyze
the reversible steps
are the same

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1b. OAA to Malate 1c. OAA to PEP

• Once formed, malate is then transported across
the mitochondrial membrane to the cytosol

mitochondrial matrix cytosol

Oxaloacetate Oxaloacetate
mitochondrial cytosolic
malate dh malate dh

Malate Malate

2. Frc-1,6-bP to Frc-6-P 3. Glc-6-P to Glucose

Overall Reaction
2 pyruvate + 4 ATP + 2 GTP +
2 NADH,H+ + 6 H2O
REGULATION OF
⬇ GLUCONEOGENESIS
Glucose + 4 ADP + 2 GDP +
6 Pi + 2 NAD+

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Futile Cycle Reciprocal Regulation

Glycolysis & Gluconeogenesis are both spontaneous.

If both pathways were simultaneously active in a cell, it would

constitute a "futile cycle" that would waste energy.

Glycolysis:
glucose + 2 NAD+ + 2 ADP + 2 Pi 
2 pyruvate + 2 NADH + 2 ATP
Gluconeogenesis:
2 pyruvate + 2 NADH + 4 ATP + 2 GTP 
glucose + 2 NAD+ + 4 ADP + 2 GDP + 6 Pi

GNG inhibition by alcohols GNG inhibition by alcohols

Alcohol Metabolism: • NADH promotes reduction of oxaloacetate back
to malate
• No OAA becomes available for gluconeogenesis

Ethanol consumption leads to an accumulation of NADH

inhibits gluconeogenesis by preventing the oxidation
of lactate to pyruvate.

consequences may be hypoglycemia and lactic acidosis.

GNG and Hypoglycemia GNG and Glycolysis in tandem

• After a night’s plenty of alcoholic drink, an
individual feels very hungry.
• Physiological conditions:
• GNG is inhibited when alcohol is
metabolized.
• Glycogen reserves are depleted.
• Blood glucose levels are significantly low:
HYPOGLYCEMIA
• Brain is in the danger of being deprived of
glucose.
• During a strenuous exercise:
• ATP requirements shoot up to a level that
cellular respiration cannot compensate.
• O2 supply in the muscle becomes depleted.
• ETC and Krebs cycle stop.
• Conditions become anaerobic that pyruvate
is diverted for lactate production.

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GNG and Glycolysis in tandem

• Lactate accumulation in the muscle is later on
suppressed by the Cori Cycle.