SN2
SHORT NOTE
5M
★ High-yield
Describe the salvage pathway of purines. Add a note on Lesch–Nyhan syndrome.
Definition
Salvage pathway = the route by which preformed purine and pyrimidine bases and nucleosides, released from nucleic acid turnover or diet, are re-converted to nucleotides instead of being degraded.
The Enzymes
| Enzyme | Substrate | Product | Co-substrate |
|---|---|---|---|
| HGPRT | Hypoxanthine, guanine | IMP, GMP | PRPP |
| APRT | Adenine | Amp | PRPP |
| Adenosine kinase | Adenosine | Amp | ATP |
| Thymidine kinase | Thymidine | DTMP | ATP |
Importance
- Energetically far cheaper — de novo synthesis of one purine costs about 6 ATP; salvage costs one
- Brain, RBC, leucocytes and bone marrow depend on salvage, being unable to carry out de novo synthesis
- Consumes PRPP, which restrains de novo synthesis indirectly
- Reduces the load of uric acid that would otherwise be produced
Lesch–nyhan Syndrome
Complete deficiency of HGPRT; X-linked recessive; affects boys.
HGPRT absent → Hypoxanthine and guanine cannot be salvaged → Diverted to xanthine oxidase → ↑↑ uric acid → Meanwhile PRPP accumulates (not consumed by salvage) → PRPP drives de novo synthesis → more purines → more urate → Double mechanism of hyperuricaemia
Clinical features
- Severe hyperuricaemia — gout, urate stones, "orange sand" in the nappy
- Choreoathetosis, spasticity and dystonia
- Mental retardation
- Compulsive self-mutilation — biting of lips and fingers; the characteristic and distressing feature
- The neurological features are not caused by urate and are not improved by allopurinol — they relate to defective dopamine pathways in the basal ganglia
Comparison of HGPRT Defects
| Degree | Condition | Features |
|---|---|---|
| Complete deficiency | Lesch–Nyhan | Hyperuricaemia plus neurological and behavioural disease |
| Partial deficiency | Kelley–Seegmiller | Gout and stones only, with normal intellect |
Applied Aspects
- Allopurinol controls the urate but not the neurological disease — a clear illustration that a metabolite and a phenotype need not be causally linked
- Physical restraints and dental extraction are sometimes needed to prevent self-injury
- Prenatal diagnosis and carrier detection are possible by enzyme assay or DNA analysis
- Salvage enzymes are exploited in chemotherapy — 6-mercaptopurine must be activated by HGPRT, so tumours lacking it become resistant
All questions in Nucleotide Metabolism & Molecular Biology
- Q1Describe the de novo synthesis of purine nucleotides with its regulation. Explain the salvage pathway and the degradation of purines. ★
- Q2Describe the synthesis and degradation of pyrimidine nucleotides. Compare them with purines and add a note on orotic aciduria. ★
- Q3Describe the process of DNA replication with the enzymes involved. Add a note on telomeres and the inhibitors of replication. ★
- Q4Describe transcription and the post-transcriptional processing of mRNA. Compare it with replication. ★
- Q5Describe the process of translation. Explain the genetic code and the inhibitors of protein synthesis. ★
- SN1Define gout. Describe its biochemical basis, causes and treatment. ★
- SN2Describe the salvage pathway of purines. Add a note on Lesch–Nyhan syndrome. ★
- SN3Describe the principle, steps and applications of the polymerase chain reaction. ★
- SN4Classify mutations with examples. Add a note on DNA repair. ★
- SN5Describe the tools of recombinant DNA technology and its medical applications. ★
- SN6Describe the genetic code with its properties. Add a note on the wobble hypothesis.
- SN7Describe the structure of DNA. Add a note on its denaturation and melting temperature. ★