7 min readPathway sheetOften a 10-mark answer; the Cori cycle comes as a 5-mark note

Gluconeogenesis

Making new glucose from non-carbohydrate sources like lactate, glycerol and amino acids, mainly in the liver, to keep blood sugar up during fasting.

WhereLiver mainly; also kidney

SubstratesLactate, glycerol, glucogenic amino acids, propionate

Energy cost4 ATP + 2 GTP (6 high-energy bonds) + 2 NADH per glucose

Bypass enzymesPyruvate carboxylase, PEP carboxykinase, fructose-1,6-bisphosphatase, glucose-6-phosphatase

Pyruvate to glucose: the key steps

Most glycolysis steps simply run backwards. Its three one-way steps are bypassed by four different enzymes (starred). Pyruvate carboxylase works in the mitochondria and glucose-6-phosphatase in the endoplasmic reticulum; the rest run in the cytoplasm.

1★
Pyruvate → Oxaloacetate
Pyruvate carboxylase · in mitochondria · uses ATP · needs biotin
2★
Oxaloacetate → Phosphoenolpyruvate (PEP)
PEP carboxykinase (PEPCK) · uses GTP · oxaloacetate leaves mitochondria as malate
3
PEP → … → Fructose-1,6-bisP
Glycolysis enzymes in reverse (enolase back to aldolase) · uses 1 ATP + 1 NADH per 3-carbon unit
4★
Fructose-1,6-bisP → Fructose-6-P
Fructose-1,6-bisphosphatase · main control point
5
Fructose-6-P → Glucose-6-P
Phosphohexose isomerase
6★
Glucose-6-P → Glucose
Glucose-6-phosphatase · in liver and kidney; absent in muscle

★ one-way, controls the pace

Substrates and where they enter

Substrate	Comes from	Enters as
Lactate	Working muscle, red blood cells	Pyruvate (lactate dehydrogenase)
Glycerol	Fat breakdown in adipose tissue	Glycerol-3-P → DHAP (glycerol kinase is in liver, not adipose tissue)
Glucogenic amino acids (those that can form glucose, e.g. alanine)	Muscle protein broken down in fasting	Pyruvate or TCA intermediates (alanine → pyruvate)
Propionate	Odd-chain fatty acids; a major source in cattle	Propionyl-CoA → succinyl-CoA (needs biotin and vitamin B12)

Cori cycle (lactate cycle)

Working muscle and red blood cells turn glucose into lactate (glycolysis without oxygen). Lactate travels in the blood to the liver, which turns it back into glucose by gluconeogenesis. The glucose returns to the muscle. Muscle gains 2 ATP per glucose but the liver spends 6, so the cycle costs the body 4 ATP. It recycles lactate and prevents lactic acidosis.

Energy cost (2 pyruvate → 1 glucose)

Pyruvate carboxylase (×2)2 ATP

PEP carboxykinase (×2)2 GTP

Phosphoglycerate kinase, in reverse (×2)2 ATP

Glyceraldehyde-3-P dehydrogenase, in reverse (×2)2 NADH

Total per glucose6 high-energy bonds (4 ATP + 2 GTP) + 2 NADH

Nutrition link

During fasting, starvation or very low-carbohydrate diets, gluconeogenesis keeps blood glucose up for the brain and red blood cells, partly by breaking down muscle protein. Biotin is needed by pyruvate carboxylase. In diabetes, too much gluconeogenesis in the liver raises fasting blood sugar; the drug metformin works mainly by reducing it. Heavy alcohol blocks gluconeogenesis and can cause low blood sugar.

Exam angle

10 marks: “Describe gluconeogenesis and its significance.” Define it, list the substrates, show the three bypass reactions with enzymes, give the energy cost, then add the Cori cycle and significance.

5 marks: “Write a note on the Cori cycle.” Muscle lactate goes to the liver, becomes glucose by gluconeogenesis and returns to muscle; net cost 4 ATP per turn.

2 marks: “Why can't muscle glycogen supply blood glucose?” Muscle lacks glucose-6-phosphatase, so it cannot release free glucose into the blood.

Remember it

Four enzymes bypass three one-way steps. Two 'carbox' enzymes (pyruvate carboxylase, PEP carboxykinase) undo pyruvate kinase; two phosphatases undo PFK-1 and hexokinase.