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Ubiquitous purines

Nucleobases-> adenine, guanine
Nucleosides-> Nucleobase and ribose/deoxyribose -> 'osides'
Nucleotides-> nucleoside and phosphate-> AMP,ADP,ATP,cAMP etc
Nuclei acids-> nucleotide polymers-> RNA and DNA


Biological roles or ubiquitous purines

Genetic codes
Energy metabolism
Enzyme co factors
Extracellular message
Intracellular message


Sources of purines

Endogenous synthesis-> energetically expensive-> tissues with high cellular turnover
Dietary intake-> very limited
Purine salvage/recycling-> main source


Purine biosynthesis

Precursors-> amino acids
Produces nucleotides
Majority in liver, also brain
Ribose 5-phosphate-> ATP/PRPP synthase-> PRPP
PRPP+glut amine-> phosphoribosylamine first committed step
Phosphoribosylamine is converted to inosine monophosphate->
Adenosine/guanine mono-phosphate-> phosphorylated with 5NT-> adenosine/guanosine
Adenosine -> phosphorylated with PNP-> adenine
Or with ADA-> inosine
Guanosine-> phosphorylated with 5HT-> guanine
Inosine-> PNP-> hydroxyxanthine
Hydroxyxanthine/guanine-> XO-> xanthine1-> XO-> uric acid


Purine salvage

Using hypoxanthine phosphoribosyltransferase HPRT
Recovers nucleotides from nucleobases
eg adenine to adenosine monophosphate
Hypoxanthine-> inosine monophosphate and phosphorinosyl pyrophosphat
Guanine-> guanine 5 monophosphate and pyro phosphate
In between stages require PRPP


Key enzymes

5NT-> 5'nucleotidase-> hydrolysed nucleotides to nucleosides
ADA-> adenosine deaminase-> produces inosine from adenosine
PNP-> purine nucleoside phosphorylase-> hydrolysed nucleosides into nucleobases
XO-> xanthine oxidase-> produces uric acid from purines


Uric acid

End product of purine catabolism via XO
>70% excreted by kidney, remainder metabolised by commensal bacteria in the GI tract
Non primates have uricase-> uric acid to allantoin
Water soluble anti oxidant-> preferential binding of hydroxyl and hypochlorus acid radicals
Net production is by coronary vasculature and lungs
Body levels effected by-> diet, age, sex


Plasma urate levels

Adult male-> 281+-41mmol/l
Adult female-> 222+- 42
Children-> 1 dayr up to 310
-> 7 days up to 140


Urinary urate levels

Adult males <1.5


Causes of hyperuricaemia

Excessive production -> idiopathic gout, myeloproliferative disease, malignancy, tumour lysis, alcohol, genetic defects
Excessive intake
Defective excretion-> idiopathic gout, renal failure, drugs, organic acids, low urine volume, genetic defects


Pathophysiology of gout

Precipitation of crystals of mono sodium urate mono hydrate
Joints-> acute arthritis
Subcutaneously-> tophi-> bulges under skin
Don't know the cause
Local inflammation-> cytokines and lysosomal enzymes
Male to female 7:1
3 per 100 75% male over 65
The higher your uric acid levels the higher the prevelance of gout


Clinical features of gout

Age of onset-> 45-50 most common
More common in males
Joints most commonly effected-> 1st metatarsal, ankle, knee
Acute attack-> pre existing crystals
Age of onset-> slow crystal growth?



Exquisite pain and tenderness
Sudden onset, often at night
Redness, desquamation
Naturally resolves in 1-3 weeks
Isolated attack in 5-10%
Unpredictable time between attacks
Many progress to chronic tophaceous gout


Treatment of gout

Most people with hyperuricaemia remain asymptomatic
Conservative treatment-> weight reduction, low purine diet, alcohol reduction
Consider drug treatment if:
Serum urate >700mmol/l
>2 attacks per year
Radiological evidence of joint damage
Tophi are present
Renal dysfunction


Anti hyperuricaemia drugs

Xanthine oxidase inhibitors -> allopurinol, febuxostat
-> may precipitate an acute attack-> give anti inflams to cover this
Uricosuric drugs-> probeneciol, contraindicated in impaired renal function
Anti- inflams-> idomethacin, colchicine


Urate nephrolithiasis

Indicaters-> radiolucant calculi, persistantly acid urine, uric acid crystals in urine, family history of gout
10-20% of gout suffers
Hyperuricaemia can cause renal parenchyma
Increased risk with acidic urine or dehydration
Correct dehydration
Low purine diet
Alkaline urine


Tumour lysis syndrome

Massive destruction of tumour tissue-> chemo
Usually lymphoma or leukaemia
Patients with renal insufficiency at highest risk
-> hyperuricaemia, urate nephropathy, acute renal failure-> most common
Hyperkalaemia and hyperphosphataemia
Prevention-> fluids, alkalinisation, allopurinol


HPRT deficiency

Decreased recycling of purines
Lack of feed back control-> increased purine synthesis
Increased purine degradation-> hyperuricaemia
X linked recessive
Presents 1st year to early adult life
-> crystalluria, acute renal failure, gout
-> neurological defects-> leech nyhan syndrome 2/3
-> spasticity, self mutilation, choreoathesis
-> mental retardation
-> growth failure, lack of pubertal development


Treatment of HPRT deficiency

High fluid intake
No effect on neurological intake


Diagnosis of HPRT defect

Serum urate increase
Urinary uric acid/creatine ratio increased
Crystal nephropathy on ultrasound
Uric acid stones
Low HPRT activity in lysed RBCs
Pre natal-> cvs or fetal blood enzyme assays


Hereditary xanthinuria

Rare autosomal recessive disease
XO deficiency
Perverse tail excretion of xanthine-> Low solubility-> crystal nephropathy, renal stones
Increased plasma xanthine >25 mmol/l
Crystal nephropathy
Iatrogenic hyoerxanthinuria-> caused by allopurinol


ADA/PNP deficiency

Defective purine metabolism associated with immunodeficiency
Cause of types of SCID
-> unexplained neurological defects
-> renal stones and crystalluria
-> renal failure
-> persistent urinary tract infections
-> family history of gout or renal failure
-> immune deficiency
-> adverse reaction to drugs which are purine analogues