Purine Nucleotide Degradation and Uric Acid Synthesis

Degradation of Purine Nucleotides + 50. Synthesis of Uric Acid and Its Secretion. Hyperuricaemia (Gout) - p.298

Digestion of dietary NA (dietary nucleotides):

• Small intestine: Pancreatic enzymes hydrolyze the NAs to nucleotides
• Inside mucosal cells: Degradation of purine nucleotides to nucleosides, free bases, and uric acid as end product

Degradation of de novo nucleotides:

• In liver
• Free bases are sent out from the liver and sent to peripheral tissues for salvage

Degradation of Dietary Nucleic Acids in the Small Intestine:

a) Ribonucleases and deoxyribonucleases (secreted by pancreas) hydrolyze dietary RNA and DNA to oligonucleotides

b) Pancreatic Phosphodiesterases produce a mixture of mononucleotides

c) Intestinal mucosal cells: Nucleotidases remove phosphate groups hydrolytically

d) Nucleosides are further degraded to free bases

Purine bases are not often used for de novo synthesis of tissue nucleic acids; instead, they are converted to uric acid, which enters the bloodstream and is released in urine

Formation of Uric Acid

a) Amino group is removed from AMP to produce IMP by AMP deaminase or from adenosine to produce Inosine (hypoxanthine ribose) by adenosine deaminase

b) 5'nucleotidase converts IMP and GMP to inosine and guanosine (nucleoside form)

c) Purine nucleoside phosphorylase converts inosine and guanosine into their purine bases (Hypoxanthine and guanine)

d) Guanine is deaminated to form xanthine

e) Hypoxanthine is oxidized by xanthine oxidase (XO) to xanthine, which is further converted by XO to uric acid

Uric Acid is the Final Product of Human Purine Degradation!

Excreted primarily by urine (fig.22.15)

Gout

A disease associated with purine degradation

Characterized by high levels of uric acid in blood (hyperuricaemia)

Caused by either overproduction or underexcretion of uric acid

May result in:

• Chronic gouty arthritis (deposition of monosodium urate crystals in the joints)
• Chronic tophaceous gout (monosodium urate crystals in soft tissues)
• Urolithiasis: formation of uric stones in the kidney

Underexcretion of Uric Acid:

- Either by inherent excretory defects

- Or by how the kidney handles urate (lactate and urate compete for the same renal transporter in lactic acidosis)

- Thiazide diuretics

- Exposure to lead (saturnine gout)

Overproduction of Uric Acid

- Less common cause

- Primary hyperuricaemia is idiopathic (no known cause)

- Mutations in the gene for X-linked PRPP synthetase result in increased purine production and elevated uric acid levels

- Lesch-Nyhan Syndrome results in decreased salvage of hypoxanthine and guanine

- Secondary hyperuricaemia can be caused by increased availability of purines (myeloproliferative disorders) or by unrelated metabolic diseases (von Gierke disease)

Types of Hyperuricaemia:

Metabolic (high production of uric acid)

Primary Metabolic Hyperuricaemia:

- Enzyme defect (of amidotransferase)

- High synthesis of purines de novo, but low salvage pathways

Secondary Metabolic Hyperuricaemia:

- High uptake of purines by food

- High degradation of NA (also in destruction of cells, by tumors, or cytostatics) Renal (low excretion of uric acid):

Primary Renal Hyperuricaemia:

- Defect in transport system leads to low secretion by tubules

Secondary Renal

Treatment:

- Acute attacks: treated by anti-inflammatory agents (colchicine, indomethacin)

- Long-term therapeutic strategies:

• Lowering uric acid level beyond the saturation point
• For underexcretion: By uricosuric agents (probenicid or sulfinpyrazone)
• For overproduction: allopurinol (analog of hypoxanthine) converted to oxypurinol, which inhibits XO (febuxostat - non-purine inhibitor of XO)