SN7
SHORT NOTE
5M
Describe the uronic acid pathway and its significance.
Definition
Uronic acid pathway (glucuronic acid pathway) = a minor route of glucose metabolism, small in bulk but important in function, producing glucuronic acid, pentoses and, in most animals, ascorbic acid.
- Site — cytosol of the liver
- Produces no ATP; it is a synthetic rather than an energy-yielding pathway
The Pathway
Glucose-6-phosphate → Glucose-1-phosphate → UDP-glucose → UDP-glucose dehydrogenase (NAD+) → UDP-glucuronic acid — the active donor → L-Gulonate → In most animals → ascorbic acid → In man → L-xylulose → xylitol → D-xylulose → HMP shunt
CLINICAL PEARL
Man, other primates and the guinea pig lack L-gulonolactone oxidase, so the pathway stops short of ascorbic acid. This single missing enzyme is why vitamin C is a vitamin for us but not for a dog or a rat.
Functions
- Conjugation and detoxification — UDP-glucuronic acid is the donor in glucuronidation, the commonest phase II reaction
- Bilirubin conjugation — by UDP-glucuronyl transferase, converting insoluble unconjugated bilirubin to the water-soluble diglucuronide
- Drug and hormone conjugation — morphine, paracetamol, chloramphenicol, steroids, thyroxine
- Synthesis of glycosaminoglycans — glucuronic acid is a component of hyaluronic acid, heparin and chondroitin sulphate
- Ascorbic acid synthesis in species that possess the final enzyme
Disorders
| Disorder | Defect | Features |
|---|---|---|
| Essential pentosuria | Xylitol dehydrogenase (L-xylulose reductase) | L-xylulose in urine; benign — but gives a positive Benedict test and may be mistaken for diabetes |
| Crigler–Najjar type I | Complete absence of UDP-glucuronyl transferase | Severe unconjugated hyperbilirubinaemia, kernicterus; fatal without transplantation |
| Crigler–Najjar type II | Partial deficiency | Milder; responds to phenobarbitone (enzyme induction) |
| Gilbert syndrome | Reduced enzyme activity (about 30%) | Mild intermittent jaundice on fasting, stress or illness; entirely benign; affects 5–10% of people |
| Neonatal physiological jaundice | Immature enzyme | Transient; matures within 1–2 weeks |
Applied Aspects
- Phenobarbitone induces UDP-glucuronyl transferase and was formerly used to treat neonatal jaundice and Crigler–Najjar type II
- Chloramphenicol in neonates causes grey baby syndrome — the immature glucuronyl transferase cannot conjugate it, so the drug accumulates
- Gilbert syndrome must be recognised as harmless — it is a common cause of unexplained mild jaundice in young adults and needs no treatment, only reassurance
- Essential pentosuria illustrates why urine sugar tests must be specific — a benign condition mistaken for diabetes on a Benedict test
- Irinotecan toxicity is greater in people with the Gilbert genotype, since the drug is cleared by the same enzyme — genotyping is used before treatment
All questions in Carbohydrate Metabolism II: Glycogen, HMP & Diabetes
- Q1Describe glycogenesis and glycogenolysis with their regulation. Compare liver and muscle glycogen. ★
- Q2Describe the HMP shunt with its reactions and significance. Explain the importance of NADPH and add a note on G6PD deficiency. ★
- Q3Classify diabetes mellitus. Describe the metabolic changes and the biochemical basis of its complications. ★
- Q4Describe the metabolism of fructose and galactose. Discuss the disorders arising from blocks in these pathways. ★
- Q5Describe the structure, synthesis, secretion and metabolic actions of insulin. Add a note on insulin resistance. ★
- SN1Describe the biochemical basis, precipitating factors and features of G6PD deficiency. ★
- SN2Describe the formation, significance and limitations of HbA1c. ★
- SN3Define metabolic syndrome. Give its diagnostic criteria and biochemical basis. ★
- SN4Define glycosuria. Classify its causes and describe the methods of detection. ★
- SN5Write a short note on galactosaemia. ★
- SN6Classify glycosaminoglycans with their functions. Add a note on the mucopolysaccharidoses.
- SN7Describe the uronic acid pathway and its significance.