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 broken down into hypo-xanthine.
Hypo-xanthine is sequentially oxidised to xanthine by XANTHINE OXIDASE. Then oxidised to urate.
What is the difference between human and cow purine metabolism?
Cows (and other animals) have enzyme Uricase which converts urate to allantoin which is highly soluble and freely excreted in the urine.
Homosapiens have an inactive mutation of uricase.
Urate is relatively insoluble.
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 it 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 37oC = 0.40 mmol/l At 30oC = 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.
Tubular urate handling leads to high concentration of urate.
Uric acid is reabsorbed and re-excreted at the PCT → 90% gets reabsorbed
What is the FEUA?
Fractional Excretion of Uric Acid is about 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 PAT enzyme is the rate-limiting step.
The outputs of the enzyme PAT are AMP and GMP which exert a negative feedback on PAT.
If PRPP levels increase this provides positive feedback on PAT.
What is the main enzyme in the purine salvage pathway?
HGPRT
What does HGPRT do?
It scoops up partially catabolised purines and brings them back to the metabolic pathways of IMP and GMP.