Carbohydrate metabolism
Carbohydrate metabolism: glycolysis, TCA cycle, gluconeogenesis, glycogen, HMP shunt
Glucose is broken down by glycolysis and the TCA cycle for energy, stored as glycogen, made anew by gluconeogenesis in fasting, and diverted through the HMP shunt for NADPH. Exams target rate-limiting enzymes, where each pathway happens, and the diseases from missing enzymes.
Rate-limiting enzymes
| Pathway | Rate-limiting enzyme | Site |
|---|---|---|
| Glycolysis | Phosphofructokinase-1 (PFK-1) | Cytoplasm |
| Gluconeogenesis | Fructose-1,6-bisphosphatase | Cytoplasm (pyruvate carboxylase in mitochondria) |
| TCA cycle | Isocitrate dehydrogenase | Mitochondrial matrix |
| Glycogenesis | Glycogen synthase | Cytoplasm |
| Glycogenolysis | Glycogen phosphorylase | Cytoplasm |
| HMP shunt | Glucose-6-phosphate dehydrogenase | Cytoplasm |
Glycolysis
- Glucose gives 2 pyruvate; net 2 ATP and 2 NADH; occurs in all cells; the only ATP source for red cells (no mitochondria).
- Irreversible steps: hexokinase/glucokinase, PFK-1, pyruvate kinase.
- Glucokinase (liver, β cells): high Km, not inhibited by product, induced by insulin; acts as the glucose sensor (MODY 2 mutation). Hexokinase (other tissues): low Km, inhibited by glucose-6-phosphate.
- PFK-1 activated by fructose-2,6-bisphosphate and AMP; inhibited by ATP and citrate.
- Anaerobic: conversion of pyruvate to lactate (lactate dehydrogenase) regenerates NAD⁺.
- Pyruvate kinase deficiency: haemolytic anaemia (low ATP, rigid red cells); raised 2,3-BPG.
- Arsenic inhibits lipoic acid-dependent enzymes; fluoride inhibits enolase (used in blood glucose tubes).
- 2,3-BPG made by the Rapoport–Luebering shunt in red cells.
Pyruvate dehydrogenase
- Pyruvate to acetyl-CoA (mitochondria); needs five cofactors: thiamine pyrophosphate (B1), lipoic acid, CoA (B5), FAD (B2), NAD⁺ (B3).
- Thiamine deficiency (alcoholics) impairs PDH and α-ketoglutarate dehydrogenase, leading to lactic acidosis, Wernicke encephalopathy; give thiamine before glucose.
- PDH deficiency: lactic acidosis, neurological problems; ketogenic diet, more lysine and leucine.
TCA cycle
- Per acetyl-CoA: 3 NADH, 1 FADH₂, 1 GTP, 2 CO₂.
- Total ATP from one glucose with full oxidation: about 30–32 ATP.
- Succinate dehydrogenase is also complex II of the electron transport chain.
- Intermediates feed synthesis: citrate (fatty acids), succinyl-CoA (haem), α-ketoglutarate and oxaloacetate (amino acids).
Gluconeogenesis
- Mainly liver (also renal cortex in prolonged fasting); substrates: lactate (Cori cycle), alanine (glucose–alanine cycle), glycerol, propionate (odd-chain fatty acids). Even-chain fatty acids cannot make net glucose (acetyl-CoA cannot become pyruvate).
- Bypass enzymes: pyruvate carboxylase (needs biotin, activated by acetyl-CoA), PEPCK, fructose-1,6-bisphosphatase, glucose-6-phosphatase (liver and kidney only, so muscle glycogen cannot release free glucose).
- Stimulated by glucagon and cortisol; inhibited by insulin. Alcohol inhibits it (high NADH:NAD⁺), causing hypoglycaemia.
Glycogen
- Liver glycogen maintains blood glucose (lasts about 12–24 hours of fasting); muscle glycogen is for local use.
- Glycogen phosphorylase needs pyridoxal phosphate (B6); breaks α-1,4 bonds; debranching enzyme handles α-1,6 bonds.
- Glucagon (liver) and adrenaline (liver and muscle) activate phosphorylase via cAMP–PKA; insulin activates glycogen synthase.
Glycogen storage diseases
| Type | Enzyme | Features |
|---|---|---|
| I (von Gierke) | Glucose-6-phosphatase | Severe fasting hypoglycaemia, lactic acidosis, hyperuricaemia, hyperlipidaemia, hepatomegaly |
| II (Pompe) | Lysosomal acid α-glucosidase (acid maltase) | Cardiomegaly, hypotonia; early death in infancy; enzyme replacement |
| III (Cori) | Debranching enzyme | Milder type I; normal lactate |
| V (McArdle) | Muscle glycogen phosphorylase | Exercise cramps, myoglobinuria, no rise in lactate with exercise; second-wind phenomenon |
HMP shunt (pentose phosphate pathway)
- Produces NADPH (fatty acid and steroid synthesis, glutathione reduction, respiratory burst) and ribose-5-phosphate (nucleotides); no ATP.
- Active in liver, adrenal cortex, lactating breast, red cells.
- G6PD deficiency (X-linked): low NADPH, so oxidised glutathione, so oxidant haemolysis with primaquine, dapsone, sulphonamides, nitrofurantoin, fava beans, infection; Heinz bodies and bite cells; protects against falciparum malaria.
- Transketolase needs thiamine (red cell transketolase activity measures B1 status).
Fructose and galactose
- Hereditary fructose intolerance: aldolase B deficiency, so fructose-1-phosphate accumulates, leading to hypoglycaemia, vomiting, liver failure after fruit or sucrose.
- Essential fructosuria: fructokinase deficiency; benign.
- Classic galactosaemia: galactose-1-phosphate uridyltransferase deficiency leads to jaundice, hepatomegaly, cataracts, *E. coli* sepsis in neonates; remove lactose.
- Galactokinase deficiency: cataracts only.
- Sorbitol (aldose reductase) accumulates in lens, nerves and retina in diabetes.
- Lactase deficiency: osmotic diarrhoea, bloating; positive hydrogen breath test.
How FCPS asks it
Recalls test: rate-limiting enzymes; ATP yield; glucokinase versus hexokinase; PDH cofactors and thiamine; biotin and pyruvate carboxylase; why fatty acids cannot make glucose; glucose-6-phosphatase location; glycogen storage disease features; G6PD deficiency triggers; aldolase B and galactosaemia enzymes; fluoride and enolase.
Exam trap PFK-1 limits glycolysis; isocitrate dehydrogenase limits the TCA cycle.
Exam trap Muscle lacks glucose-6-phosphatase, so muscle glycogen cannot raise blood glucose.
Exam trap McArdle disease: no lactate rise on exercise.
Test yourself on this topic
5 of the 55 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
Complete aerobic oxidation of one glucose molecule to CO₂ and water yields about how many ATP by current estimates?
Answer: About 30–32
Glycolysis gives 2 ATP (net) and 2 NADH, pyruvate dehydrogenase 2 NADH, and the TCA cycle 2 GTP, 6 NADH and 2 FADH₂. Using about 2.5 ATP per NADH and 1.5 per FADH₂ gives about 30–32 ATP. Older textbooks quote 36–38 using whole-number ratios (3 and 2), so exam keys may show 38. Anaerobic glycolysis gives only 2. Palmitate gives about 106.
ATP from glucose
- Anaerobic: 2 ATP
- Full oxidation: 30–32 ATP
- Old figure: 36–38
- NADH ~2.5; FADH₂ ~1.5
Remember Modern 32, old books 38.
Exam trap If the options give 38 but not 30–32, choose 38 (older ratio).
Why the other options are wrong
- 2 Anaerobic glycolysis only.
- About 8 Glycolysis with NADH, not the full pathway.
- About 15 Too low.
- About 106 Palmitate oxidation.
Thiamine pyrophosphate is the cofactor for which group of enzymes?
Answer: PDH, α-KGDH, transketolase
Thiamine (B1), as thiamine pyrophosphate, is needed for oxidative decarboxylation of α-keto acids—pyruvate dehydrogenase (pyruvate to acetyl-CoA), α-ketoglutarate dehydrogenase (TCA cycle), branched-chain α-keto acid dehydrogenase—and for transketolase in the pentose phosphate pathway. Deficiency impairs glucose-derived energy, especially in brain and heart: dry beriberi (neuropathy), wet beriberi (high-output heart failure), Wernicke-Korsakoff syndrome, and lactic acidosis. Red cell transketolase activity is used to assess thiamine status.
Thiamine
- Cofactor: PDH, α-KG DH, transketolase, BCKDH
- Deficiency: beriberi, Wernicke-Korsakoff, lactic acidosis
- Test: RBC transketolase
Remember ATP needs thiamine: Alpha-ketoglutarate, Transketolase, Pyruvate.
Why the other options are wrong
- Transaminases Use pyridoxal phosphate (B6).
- Pyruvate carboxylase Use biotin.
- Methylmalonyl-CoA mutase Uses vitamin B12.
- Prolyl hydroxylases Use vitamin C.
An otherwise well infant has bilateral cataracts but no liver disease, vomiting or developmental delay. Galactose is found in the urine. Which enzyme is most likely deficient?
Answer: Galactokinase
Galactokinase deficiency is mild: galactose builds up and is reduced by aldose reductase to galactitol in the lens, which draws in water and causes cataracts, but there is no toxic galactose-1-phosphate, so the liver, kidneys and brain are spared. Classic galactosaemia (uridyltransferase deficiency) also causes vomiting, jaundice, liver failure, E. coli sepsis and developmental delay. Both are treated by removing galactose and lactose.
Galactose disorders
- Galactokinase: cataracts only
- Transferase: classic severe disease
- Lens: galactitol via aldose reductase
- Remove lactose from diet
Remember Cataracts alone: galactokinase.
Exam trap Classic galactosaemia predisposes to E. coli sepsis in newborns.
Why the other options are wrong
- Galactose-1-phosphate uridyltransferase Classic galactosaemia: severe, multisystem.
- Aldolase B Hereditary fructose intolerance.
- Glucose-6-phosphatase Von Gierke disease.
- Lactase Lactose intolerance: diarrhoea, no cataracts.
During an overnight fast, which process mainly keeps blood glucose normal for the first 12–24 hours?
Answer: Hepatic glycogenolysis
After a meal, insulin promotes glycogen storage. In early fasting, glucagon stimulates hepatic glycogenolysis; liver has glucose-6-phosphatase, so it can release free glucose. Liver glycogen lasts about 12–24 hours. Gluconeogenesis (from lactate, glycerol and amino acids, mainly alanine) then becomes dominant. Muscle lacks glucose-6-phosphatase, so its glycogen fuels only the muscle itself. Even-chain fatty acids cannot produce net glucose. In prolonged starvation, ketone bodies supply much of the brain's energy, sparing protein.
Fasting fuel
- 0–24 h: liver glycogenolysis
- After: gluconeogenesis (lactate, glycerol, alanine)
- Days: ketones for the brain
- Muscle lacks glucose-6-phosphatase
Remember Liver glycogen bridges the night.
Why the other options are wrong
- Muscle glycogenolysis releasing free glucose Muscle cannot release free glucose (no glucose-6-phosphatase).
- Ketone body production Becomes important after days.
- Gluconeogenesis from fatty acids Fatty acids give no net glucose; glycerol can.
- Absorption from the gut Not during fasting.
In McArdle disease, what happens to blood lactate during an ischaemic forearm exercise test, and why?
Answer: Fails to rise: no glycogen breakdown
McArdle disease (glycogen storage disease V) is deficiency of muscle glycogen phosphorylase. Exercising muscle cannot release glucose from glycogen, so lactate does not rise, while ammonia rises normally. Patients get pain, cramps and myoglobinuria with intense exercise, and a 'second wind' after a few minutes as blood glucose and fatty acids supply energy. CK is often raised.
McArdle disease
- Muscle phosphorylase deficiency
- Forearm test: no lactate rise
- Cramps, myoglobinuria
- Second wind phenomenon
Remember No glycogen breakdown, no lactate.
Exam trap Blood glucose is normal; only muscle is affected.
Why the other options are wrong
- Rises sharply from excess glycolysis Glycolysis from glycogen is blocked.
- Falls as the liver reuses lactate Not the finding.
- Rises only after 24 hours Not the finding.
- Rises normally, but ammonia falls Ammonia rises normally.
Where this sits in the CPSP syllabus
- Paper 1: Biomolecules and metabolism, Carbohydrate metabolism: glycolysis, TCA, gluconeogenesis, glycogen, HMP shunt
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