Uric acid metabolism Flashcards
what are the 3 roles of purines?
○ Genetic code (A & G)
○ Second messengers for hormone action (e.g. cAMP)
○ Energy transfer (e.g. ATP)
precursors for urate
outline the process of purine catabolism?
list the eznyme involved
Purine** -> Hypo Xanthine ->* Xanthine ->* Urate
- eznyme = xanthine oxidase
** note; adenine and guanine both undergo DIFFERENT reaction pathways where they are converted into the common INOSINE which is then converted to hypoxanthine
why is it that animals dont get gout?
list the eznyme involved
this reaction occurs:
Urate -> Allantoin
enzyme: uricase
allantoin, is more easily excreted by the kidney because of its water-soluble compound.
In humans, a mutation during evolution resulted in an inactivated gene encoding uricase
what causes formation of gout?
whihc is most common joint ?why at certain locations?
crystalisation of urate:
- cooler temperature
- higher concentration of urate
- acidic pH
(there are limits of solubility)
first metatarsophalangeal joint - periphery so cooler.
what is the Fractional Excretion of Uric Acid (FEUA)?
why
10%
urat = antioxidant to protect us against oxidative stress
where us urate excreted?
kidneys/nephrons
outline the process of renla urate handling
urate is reabsorbeed AND excreeted in the Prxomial Convoluted tubule PCT
only 10% excreted 90% reabsorbs
what are the 2 pathways involved in purine synthesis/metabolism?
what are their charcateristics, which area in body uses them?
- De novo synthesis pathway
- make purines from scratch
- Bone marrow uses this to make purines
- inefficient, meetabolically demanding
- BM has high demand for purines so no.2 not enough - Salvage pathway
- used by most cells in body
- energy efficient
- Recycles partially catabolised purines to make purines
how does the salvage pathway make purines?
main enzyme?
Recycles partially catabolised purines to make purines
main reactions:
§ Hypoxanthine –> IMP (inosinic acid)
§ Guanine –> GMP - guanylic acid
Main enzyme:
• HPRT (aka HGPRT)
○ Hypoxanthine-guanine phosphoribosyltransferase
how does the de novo s pathway make purines?
uses atp and other compounds to make IMP - inosinic acid
Uses IMP to make AMP and GMP
enzyme: PAT (pprp amido transferase)
what is the rate-limiting step in the de novo s pathway?
what are the outputs of this reaction?
5 phosphoribosyl-1 pyrophosphate (PRPP) -> 5 phosphoribosyl-1 amine (PRA)
catalysed by PAT enzyme :phosphoribosyl-1 aminotransferase
outputs: IMP AMP GMP
what is the output of the:
A. de novo pathway
B. salvage pathway
de novo pathway: IMP, AMP, GMP
salvage pathway: IMP, GMP
what is the feedback inhibition in de novo pathway?
AMP and GMP exert Negative feeback to PAT to slow down rate of purine output
PPRP (5-phosphorybosil…) exerts Positive feedback to increase reaction rate
what is the pathology of Lesch nyhan diseasee?
This is an X-linked disease (almost exclusively affects boys)
• It is caused by absolute deficiency of HPRT
- this means there is no/less negative feedback inhibition on PAT, so the DE NOVO pathway goes into overdrive, makes lots of IMP
- also PPRP builds up to = more IMP
which means salvage pathway makes lots of urate
wahta are the clinical features of Lesch nyhan disease?
○ Normal at birth ○ Developmental delay at 6 months ○ Hyperuricaemia (rarer in children) ○ Choreiform movements (at 1 year) ○ Spasticity and mental retardation ○ KEY FEATURE: Self-mutilation in 85% of patients at ages 1-16 (e.g. biting lips very hard)
