Purine Metabolism 5k13q

PURINE CATABOLISM AND ITS DISORDERS

M.Prasad Naidu MSc Medical Biochemistry, Ph.D,.

Catabolism of purines :

FAD, Molybdenum,iron

•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 ts.The deposits are called tophi. •Tophi cause inflammation of ts 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 t.(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 t 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 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 VONGIERKE’S 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 purinenucleoside phosphorylase deficeincy: Both are Inherited as autosomal recessive.

Deficeincy

ADA Both T and B-cells affected.

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

•Immune dysfunction appear to result from accumulation of dGTP and dATP . •These allosterically inhibits ribonucleotidereductase,thereby depletes cells of DNA precursors, particularly dCTP.

HYPOURICEMIA.

VONGIERKE’S DISEASE : Glucose-6phophatase

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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