M.Prasad NaiduMSc 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

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 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.

VONGIERKE’S 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.