Metabolism of Nucleotides

Metabolism of Nucleotides

• Pyrimidines and purines are the parent compounds of two types of nitrogen-containing heterocyclic aromatic compounds.
• Important pyrimidines in DNA are cytosine and thymine; cytosine and uracil are pyrimidines in RNA.
• Adenine and guanine are the principal purines in both DNA and RNA.
• Nucleosides are structures formed by combining a nitrogen base and a sugar.

Nucleotides

• Nucleotides are phosphoric acid esters of nucleosides.
• Examples of nucleosides paired with their corresponding nucleotides include:
  • Adenosine → Adenylate (AMP)
  • Guanosine → Guanylate (GMP)
  • Thymidine → Thymidylate (TMP)
  • Cytidine → Cytidylate (CMP)
  • Uridine → Uridylate (UMP)

Degradation of Purine Nucleotides

• AMP is broken down into adenosine, then inosine, then hypoxanthine, and finally xanthine.
• GMP breaks down into guanosine, then guanine, then hypoxanthine, and finally xanthine.
• Xanthine is further broken down to uric acid.

Disorders of Purine Metabolism: Gout

• Gout is a metabolic disorder associated with the overproduction of uric acid.
• In gout, uric acid is found in a more soluble form as sodium urate in the body.
• Normal serum uric acid levels are 3-7 mg/dL.
• High levels of uric acid can deposit as crystals in soft tissues, especially joints (tophi), causing inflammation and gouty arthritis.
• Lesch-Nyhan syndrome is another disorder related to purine metabolism.

Types of Gout

• Primary gout is exclusively in males and a common cause of inflammatory arthritis in men over 40 years old.
• Secondary gout occurs due to renal impairment or drug use.

Primary Metabolic Gout

• This is an inborn error of purine metabolism causing overproduction of uric acid.
• Causes include increased activity of PRPP synthetase, overactivity of PRPP amidotransferase, HGPRT (Hypoxanthine-guanine phosphoribosyltransferase) deficiency, or glucose-6-phosphatase deficiency.

Secondary Metabolic Gout

• Secondary gout occurs due to diseases like leukemia, polycythemia, lymphoma, psoriasis, trauma, or starvation, where increased tissue breakdown leads to higher uric acid levels.

Secondary Renal Gout

• This involves defective glomerular filtration of urate due to generalized renal failure.

Kidney Stones

• High uric acid concentrations can precipitate in the kidneys, forming stones.
• Stones can cause pain, infection, and kidney damage.

Treatment of Gout

• Colchicine is used to remove urates from joints.
• Probenecid, sulfinpyrazole, and salicylates are uricosuric drugs to remove urates from the body.
• Allopurinol inhibits the enzyme xanthine oxidase, reducing uric acid production.

Lesch-Nyhan Syndrome

• X-linked metabolic disorder due to a mutation in the gene for HGPRT.
• Affects males and characterized by excessive uric acid production and neurological abnormalities such as mental retardation, aggressive behavior, and learning disabilities.