20. Purine Metabolism

URINE METABOLISM

• Presented by Ahmad Tarmidi Sailan, Dept. of Clinical Oral Biology, Faculty of Dentistry, UKM.

References

1. Biochemistry: Lippincott’s Illustrated Review, 2nd edition.

2. Marks, D.B., Marks, A.D., and Smith, C.M. (2013). Basic Medical Biochemistry: A Clinical Approach. Williams and Wilkins, Maryland, USA.

3. Murray, R.K., Granner, D.K., Mayes, P.A. and Rodwell, V.W. (1996). Harper’s Biochemistry. 24th Edition, Prentice-Hall International, Inc, USA.

4. Additional references from the Department of Clinical Oral Biology, Faculty of Dentistry, UKM.

Objectives

• List the function of purine and pyrimidine nucleotides.

• Recognize purine and pyrimidine bases and identify their precursors for biosynthesis.

• Differentiate between bases, nucleosides, and nucleotides.

• Describe the de novo and salvage synthesis of purine nucleotides and their regulation.

• Outline purine nucleotide catabolism.

• Explain biochemically associated diseases, e.g., gout.

Purines and Pyrimidines

• Characteristics:

  • Purines and pyrimidines are heterocyclic compounds.

  • They are biologically important nitrogen-containing heterocycles.

  • Principal derivatives include:

    • Nucleosides: purine or pyrimidine + cyclized sugar.

    • Nucleotides: purine or pyrimidine + cyclized sugar + phosphate group.

Structures of Nucleosides and Nucleotides

• Nucleosides:

  • Adenosine

  • Guanosine

  • Cytidine

  • Uridine

• Nucleotides:

  • Adenosine 5'-monophosphate (AMP)

  • Guanosine 5'-monophosphate (GMP)

  • Cytidine 5'-monophosphate (CMP)

  • Uridine 5'-monophosphate (UMP)

Major Biochemical Functions of Purines and Pyrimidines

• Important Roles:

  • Phosphate transfer reactions of ATP.

  • Other NTPs drive endergonic reactions.

  • UDP-glucose and UDP-galactose in carbohydrate synthesis.

  • Coenzymes such as FAD, NAD+, NADP+.

  • cAMP as a secondary messenger.

  • Monomer units in RNA and DNA.

Derivatives of Purines and Pyrimidines in RNA

• Purines: Adenine (A), Guanine (G).

• Pyrimidines: Cytosine (C), Thymine (T - DNA), Uracil (U - RNA).

Hypoxanthine and Xanthine

• Intermediate metabolites in adenine and guanine metabolism.

• Found in cells and derived from dietary sources.

• Methylxanthines are common in various foods.

Pathways of Purine Metabolism

1. De novo pathways: Synthesized using low molecular weight precursors.

2. Salvage pathways: Phosphoribosylation of free purines using PRPP.

3. Regulation: Feedback mechanisms maintain homeostasis between synthesis and degradation.

Purine Synthesis Overview

• Major Sites: Liver is the primary site for purine nucleotide biosynthesis.

• Two main pathways:

  • De novo synthesis from basic elements.

  • Salvaging pre-existing purines.

Conversion of Ribose 5-P to PRPP

• Key Enzymes: PRPP synthase catalyzes the formation.

Enzymatic Reactions Leading to Purine Formation

• The reactions involve multiple enzymatic steps that incorporate various atoms from amino acids and metabolites.

Genetic Disorders Related to Purine Metabolism

• Lesch-Nyhan Syndrome: Caused by HGPRT deficiency; characterized by hyperuricemia and severe gout.

• Gout: Metabolic disorder due to overproduction or under-excretion of uric acid, leading to joint inflammation and pain.

Purine Salvage Pathway Overview

• Requires less energy than de novo synthesis.

• Particularly important in brain cells where de novo synthesis is absent.

• Deficiency of HGPRT leads to gout due to increased PRPP levels.

Summary of Gout and Related Disorders

• Purine metabolism anomalies can lead to various clinical conditions.

• Major implicating factors include dietary influences, metabolic rates, and enzyme deficiencies.

Treatment Approaches for Gout

• Drugs Used: Allopurinol inhibits uric acid formation.

• Dietary Management: Reduced intake of purine-rich foods to manage symptoms.

Conclusion

• Understanding purine and pyrimidine metabolism is crucial for addressing related diseases and developing therapeutic strategies.