Glycolysis and Gluconeogenesis
Direct answer
Glycolysis is the cytoplasmic pathway that splits one glucose into two pyruvate, yielding a net two ATP and two NADH, and it is the only energy pathway that works without oxygen. Gluconeogenesis synthesises glucose from non-carbohydrate precursors — lactate, glycerol and glucogenic amino acids — mainly in the liver, and in the kidney during prolonged fasting. The two are reciprocally regulated: insulin promotes glycolysis, while glucagon and fasting promote gluconeogenesis.
What you must remember
- Three irreversible steps in glycolysis: hexokinase or glucokinase, phosphofructokinase-1 (the rate-limiting, committed step) and pyruvate kinase; two ATP are spent and four produced, for a net two ATP and two NADH per glucose.
- Phosphofructokinase-1 regulation: inhibited by ATP and citrate, activated by AMP and — most powerfully — fructose-2,6-bisphosphate, whose level is raised by insulin and lowered by glucagon.
- Anaerobic glycolysis: lactate dehydrogenase reduces pyruvate to lactate, regenerating NAD+; the Cori cycle returns muscle and red cell lactate to the liver for rebuilding into glucose.
- Pyruvate dehydrogenase converts pyruvate to acetyl CoA irreversibly in mitochondria and needs five cofactors — thiamine pyrophosphate, lipoic acid, coenzyme A, FAD and NAD — hence its failure in thiamine deficiency and arsenic poisoning.
- Gluconeogenic substrates: lactate, glycerol and glucogenic amino acids (all except leucine and lysine, which are purely ketogenic); acetyl CoA and even-chain fatty acids cannot yield net glucose.
- Four bypass enzymes: pyruvate carboxylase (biotin, mitochondrial), phosphoenolpyruvate carboxykinase (GTP-driven), fructose-1,6-bisphosphatase (inhibited by AMP and fructose-2,6-bisphosphate) and glucose-6-phosphatase — present only in liver and kidney, so muscle glycogen cannot replenish blood glucose; its deficiency causes von Gierke disease.
- Physiological role: gluconeogenesis sustains blood glucose in fasting and prevents hypoglycaemia; ethanol, by raising NADH, suppresses it and precipitates fasting hypoglycaemia.
Common confusion
The classic mistake is treating gluconeogenesis as glycolysis reversed; the three irreversible steps must instead be bypassed by four different enzymes. Students also state that fats make glucose — true only of odd-chain fatty acids via propionyl CoA — and confuse glucokinase (liver, high Km, insulin-induced) with hexokinase (all tissues, low Km, inhibited by glucose-6-phosphate).
Exam-focused takeaway
In theory, draw both pathways as one flow chart, mark the three irreversible steps and four bypass enzymes, and show fructose-2,6-bisphosphate as the reciprocal switch. In viva, be ready with the rate-limiting enzymes, the ATP yield, the five pyruvate dehydrogenase cofactors, and why acetyl CoA cannot become glucose. In practicals, link the topic to fasting plasma glucose and glucose tolerance test exercises.
Practise MCQs and previous-year questions on carbohydrate metabolism in the PrepElephant app. Free notes continue on this website.
Frequently asked questions
What is the net ATP yield of glycolysis?
Two ATP per glucose (four produced, two invested) plus two NADH; anaerobically the NADH is consumed in reducing pyruvate to lactate.
Which enzyme is rate-limiting in glycolysis?
Phosphofructokinase-1, the committed step — inhibited by ATP and citrate, activated by AMP and fructose-2,6-bisphosphate.
Which four enzymes bypass the irreversible steps of glycolysis?
Pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase.
Why cannot fatty acids be converted into glucose?
Even-chain fatty acids yield acetyl CoA, whose carbons are lost as carbon dioxide in the citric acid cycle; only propionyl CoA from odd-chain fats is gluconeogenic.
What is the Cori cycle?
Muscle and red cell lactate travels to the liver, is rebuilt into glucose by gluconeogenesis, and returns to the tissues — at an energy cost to the liver.
Where does gluconeogenesis occur?
Chiefly in the liver, which exports the glucose formed; the kidney contributes importantly during prolonged fasting and acidosis, using glutamine as a substrate.
Practise this in the PrepElephant app
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