ChemPath: Hyperuricaemia and Gout Flashcards
What are purines?
Ubiquitous Biomolecules:
Adenosine, Guanosine and Inosine
What are the 3 important biological roles purines?
- Genetic code A & G
- Second messengers for hormone action in the form of cAMP and cGMP
- Energy transfer/stores as ATP and GTP
What is the prevalence of gout?
3% of males have gout sometime in life. Lower prevalence in females.
Describe purine catabolism.
Purine is down into urate
Urate is relatively ____ . It circulates in blood streams at a concentration close to its ______ of ______ . It is constantly on the brink of ________ out and forming ____ _________ which are the aetiology of gout.
Urate is relatively insoluble. It circulates in blood streams at a concentration close to its limit of solubility. It is constantly on the brink of precipitating out and form uric acid crystals which are the aetiology of gout.
What are the normal plasma concentrations of monosodium urate?
Men 0.12 - 0.42 mmol/l
Women 0.12 - 0.36 mmol/l
What does solubility of urate depend on?
Temperature and pH.
Solubility at 37C = 0.40 mmol/l
At 30C = 0.27 mmol/l
Lower pH - solubility decreases
Cooler temperatures - solubility decreases
This may be why the first MTP joint is the first to be affected - cooler temperature on the extremities
Describe renal urate handling.
Uric acid is reabsorbed and re-excreted at the PCT → 90% gets reabsorbed
What is the FEUA?
Fractional Excretion of Uric Acid - approximately 10%.
90% is reabsorbed which keeps the uric acid levels in circulation high and close to its limit of solubility
What are the two main ways of purine synthesis?
- De novo synthesis - this is metabolically hard work, insufficient in terms of energy use
- Salvage pathway - highly energy efficient. Recycles purines. Vast majority of purine synthesis via salvage pathway.
Which tissue does the de novo purine pathway dominate?
Bone marrow
What is the rate-limiting step in de novo purine synthesis? What are the positive and negative feedback mechanisms of this rate-limiting step?
The reaction catalysed by PPAT enzyme is the rate-limiting step.
The outputs of the enzyme PPAT are AMP and GMP which exert a negative feedback on PPAT.
If PRPP levels increase this provides positive feedback on PPAT.
What is the main enzyme in the purine salvage pathway?
HGPRT (hypoxanthine-guanine-phosphoribosyltransferase)
What does HGPRT do?
Salvages partially-catabolised purines and converts them back into subtrates for purine synthesis
What is Lesch-Nyhan syndrome? What is its pattern of inheritance?
- Complete HGPRT deficiency
- It is an X-linked disease
- No HGPRT means you cannot do the salvage pathway of purine metabolism.