Purine metabolism

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Purine Catabolism and its disorders

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

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Catabolism of purines
FAD, Molybdenum,iron
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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• Types of gout
• 1.Primary gout a) metabolic
  b) renal
• Metabolic Causes
• Abnormal enzyme - PRPP --- glutamylamidotransfe
  rase 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.

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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)
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• b)Reduced excretion of uric acid
• Increased alcohol consumption leads to lactic
  -acidosis. Lactic acid inhibits uric acid
  excretion.
• Thiazide diuretics inhibits tubular secretion of
  uric acid.
• Renal failure.
• c) OTHERS
• VONGIERKES DISEASE
• Elevated glutathione reductase

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• Treatment
• Low intake of purine diet
• Restrict alcohol
• Drugs
• 1.uricosuric drugs probenecid,salicylates,hal
  ofenate
• 2. enzyme inhibitors allopurinol

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Action of allopurinol Allopurinol
alloxanthine
xanthine oxidase
inhibits Xanthine and hypoxanthine are more
soluble and excreted easily.
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• Palliative treatment
• Anti-inflammatory drugs
• Colchicine is used .
• Others include indomethacin , ibuprofen.
• Steroids also used.

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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.
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• 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.

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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.
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• 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.

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VONGIERKES DISEASE
Glucose-6-phophatase
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• Pseudogout
• Serum uric acid level normal.
• Symptoms as seen in gout.
• But it is characterised by deposition of calcium
  
• pyrophosphate crystals.

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• Hypouricemia
• Xanthine oxidase deficiency, either genetic or
  due to
• severe liver damage.
• Patients exhibit xanthinuria and xanthine
  lithiasis.

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Thank you