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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

1

Biological roles or ubiquitous purines

Genetic codes
Energy metabolism
Enzyme co factors
Extracellular message
Intracellular message

2

Sources of purines

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

3

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

4

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

5

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
HPRT

6

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

7

Plasma urate levels

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

8

Urinary urate levels

Adult males <1.5

9

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

10

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

11

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?

12

Symptoms

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

13

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

14

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

15

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
Treatment:
Correct dehydration
Low purine diet
Alkaline urine
Allopurinol

16

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
Hypocalcaemia
Prevention-> fluids, alkalinisation, allopurinol

17

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

18

Treatment of HPRT deficiency

High fluid intake
Alkalisation
Allopurinol
No effect on neurological intake

19

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

20

Hereditary xanthinuria

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

21

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