Pyruvate carboxylase, PEP carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase
Expansion
Gluconeogenesis is not simply glycolysis reversed. Three glycolytic steps are irreversible, so four enzymes bypass them:
- Pyruvate carboxylase (mitochondrial, requires biotin and ATP): pyruvate to oxaloacetate
- PEP carboxykinase: oxaloacetate to phosphoenolpyruvate. Induced by glucagon and cortisol
- Fructose-1,6-bisphosphatase: the rate-limiting step, inhibited by AMP and fructose-2,6-bisphosphate
- Glucose-6-phosphatase: present only in liver and kidney
Substrates: lactate (Cori cycle), glycerol from triglyceride, and glucogenic amino acids, chiefly alanine.
Fatty acids cannot be used, because acetyl-CoA cannot be converted to pyruvate. This is the single most important consequence of the pathway’s design, and it explains why prolonged fasting must break down muscle protein.
The absence of glucose-6-phosphatase in muscle means muscle glycogen serves only local needs. Its deficiency causes von Gierke disease (glycogen storage disease type I), with severe fasting hypoglycaemia, lactic acidosis, hyperuricaemia and hepatomegaly.