PURINE CATABOLISM AND ITS DISORDERS

M.Prasad Naidu
MSc Medical Biochemistry, Ph.D,.
FAD, Molybdenum,iron
Catabolism of purines :
The end product of purine catabolism is uric acid
in humans.

Uric acid is degraded into allantoic acid and finally
to ammonia in animals other than man.

Uric acid is 2,6,8 trioxy purine.

It acts as antioxidant by converting itself into
allantoin.
Uric acid
Normal serum concentration : 3 to 7 mg /dl in males
2 to 5 mg/dl in females
Miscible pool the quantity of uric acid present in
body water. It is on average of 1130mg
Daily turnover : 500 to 600 mg synthesized
400 to 600 mg/day excreted
Uric acid is cleared by both
glomerular filtration and
tubular secretion.
Hyperuricemia and gout:

Hyperuricemia increased serum uric acid levels.

Gout is a metabolic disorder of purine catabolism,
resulting in overproduction of uric acid.

At physiological pH , uric acid is more soluble than
urates.
In hyperuricemia ,serum urate levels exceed

solubility limit, leading to formation of crystals and

get deposited in joints.The deposits are called tophi.


Tophi cause inflammation of joints resulting in painful

acute gouty arthritis, that can progress to chronic

gouty arthritis leading to urolithiasis and renal damage.

Clinical features:
Manifestations are due to the low solubility of
uric acid in water.
Typical gouty arthritis affects first
metatarsophalangeal joint.(GREAT TOE).
Attacks are precipitated by alcohol intake.
Often patient have few drinks , go to sleep
symptomless , but are awakened during early
hours by severe joint pains.
Synovial fluid shows birefringent crystals under
polar microscope is diagnostic.
Types of gout :
1.Primary gout :a) metabolic b) renal
a)Metabolic Causes :
Abnormal enzyme - PRPP ---
glutamylamidotransferase is active but not
sensitive to feedback control.
Variant form of PRPP synthetase- not subject to
allosteric control.
Deficiency of enzymes of salvage pathway
HGPRT deficiency leading to Lesch-Nyhan
syndrome.
b) Renal causes: due to failure in uric acid excretion.

2. Secondary gout:

a)Overproduction of uircacid due to enhanced
turn over rate of nucleic acids

i) Increased tissue turn over due to psoriasis.

ii) rapidly growing malignant tissues-leukemias.
ii)Increased tissue break down after treatment
for large tumour masses.
(with radiation,chemotherapy)

b)Reduced excretion of uric acid
i) Increased alcohol consumption leads to lactic -
acidosis. Lactic acid inhibits uric acid excretion.
ii) Thiazide diuretics inhibits tubular secretion of uric
acid.
iii)Renal failure.
c) OTHERS
VONGIERKES DISEASE
Elevated glutathione reductase
Treatment:
Low intake of purine diet
Restrict alcohol

Drugs:

1.uricosuric drugs
probenecid,salicylates,halofenate

2. enzyme inhibitors allopurinol




Action of allopurinol:

Allopurinol alloxanthine
xanthine oxidase
inhibits
Xanthine and hypoxanthine are more soluble and
excreted easily.
Palliative treatment :
Anti-inflammatory drugs :
Colchicine is used .
Others include indomethacin , ibuprofen.
Steroids also used.
Lesch-Nyhan syndrome:
Inheritance pattern -- X-linked recessive
Enzyme defect(salvage pathway) --
hypoxanthine guanine phoshoribosyl
transferase (HGPRT)
Rate of salvage pathway decreases

Accumulation of intracellular PRPP and decrease
in GMP and IMP ,the inhibitory nucleotides

Increased production and degradation of purine
nucleotides.
Features:
Only males are affected, as structural gene for
HGPRT is on X- chromosome.
Characterised by excess formation of uric acid.
Nephrolithiasis
Selfmutilation
Neurological abnormalities like mental -
retardation, aggressive behavior , learning
disabilities occur.
Neurological symptoms may be due to
dependence of brain on the salvage pathway.
Adenosine deaminase deficiency and purine-
nucleoside phosphorylase deficeincy:
Both are Inherited as autosomal recessive.

Deficeincy

ADA purine nucleoside phosphorylase
Both T and T-cells affected ,
B-cells affected. B -cells are normal.


Immune dysfunction appear to result from

accumulation of dGTP and dATP
.
These allosterically inhibits ribonucleotide-

reductase,thereby depletes cells of DNA

precursors, particularly dCTP.

HYPOURICEMIA.
VONGIERKES DISEASE :
Glucose-6-
phophatase
Pseudogout :
Serum uric acid level normal.
Symptoms as seen in gout.
But it is characterised by deposition of calcium
pyrophosphate crystals.
Hypouricemia :
Xanthine oxidase deficiency, either genetic or due to
severe liver damage.
Patients exhibit xanthinuria and xanthine lithiasis.
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