Purine and Pyrimidine Metabolism

Purine and Pyrimidine Metabolism Overview

  • Forms of Purines and Pyrimidines in the Cell
    • Base itself
    • Base + carbohydrate = nucleoside
    • Ribose found in RNA; Deoxyribose in DNA
    • Nucleoside + phosphates = nucleotide
    • Nucleotide naming as phosphate derivatives of nucleosides

Classification of Bases

  • Purines:
    • Two major forms: Guanine and Adenine
  • Pyrimidines:
    • Three major forms
    • Minor forms are usually modifications of five major forms

Synthesis of Purines

  • Purine Synthesis Pathway:
    • Begins with ribose-5-phosphate
    • Building of purine ring from various compounds
    • First purine (Inosine 5’ phosphate, IMP) appears near end of pathway
    • Pathway branches into AMP and GMP
    • Very energy intensive and actively regulated
    • Cells salvage existing purines

Key Components in Purine Synthesis

  • Activated Ribose (PRPP):

    • Formed from ribose-5-phosphate
    • Involved in purine and pyrimidine nucleotide synthesis
    • Catalyzed by PRPP synthetase (regulated by multiple biomolecules)

  • Energy Requirements:

    • ATP or GTP required at multiple steps
    • De novo AMP formation needs 5 ATP + 1 GTP (6 ATP equivalents)
    • De novo GMP formation requires 7 ATP equivalents
    • Total for 1 ATP synthesis = 10 ATP equivalents; 1 GTP = 11 ATP equivalents

De Novo Purine Biosynthesis

Pathway Overview
  • Involves several steps with intermediates
  • Key Steps include:
    • Amidotransferase and Synthetase reactions
    • Carbon transfer reactions using Tetrahydrofolate (FH4)
    • Final synthesis of Inosinate (IMP)

Regulation of Purine Synthesis

  • Feedback inhibition and regulation at various steps:
    • Ribose 5-phosphate, ADP, AMP, GMP levels impact enzyme activities

Pyrimidine Synthesis: De Novo Pathway

  • Pyrimidine ring synthesized early; base formed first before being linked with PRPP
  • Energy-intensive (less than purine synthesis) and actively regulated
  • Key Enzymes:
    • Carbamoylphosphate synthetase II (CPS II) as key regulatory enzyme

Energy Costs of Pyrimidine Synthesis

  • Involves PRPP formation requiring equivalent of 2 ATPs
  • Synthesis of UTP from UMP takes 2 ATP, and CTP from UTP requires 1 additional ATP
    • Total for 1 UTP = 6 ATP; for 1 CTP = 7 ATP

Formation of Deoxyribonucleotides

  • Catalyzed by ribonucleotide reductase (RR)
  • Enzyme type: α2β2 tetramer
    • α subunit has regulatory sites impacting nucleotide pool levels

Regulation of dNTP Biosynthesis

  • RR is regulated by both ribo- and deoxyribonucleotides
  • Substrate specificity and overall activity influenced by ATP, dATP, dCTP, and other nucleotide levels

Degradation of Purines

  • End product varies by organism:
    • Uric acid in primates, allantoin in other mammals, ammonia in aquatic invertebrates
    • Excess uric acid can cause gout due to sparingly soluble nature

Degradation of Pyrimidines

  • Pathways lead to malonyl-CoA or succinyl-CoA derivatives for further metabolic processing

Salvage Pathways

  • Free nucleotide bases can be salvaged back into nucleotides:
    • Purines:
    • Adenine via adenine phosphoribosyltransferase (APRT)
    • Guanine and hypoxanthine via hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
    • Pyrimidines:
    • Uracil formed into UMP through uridine phosphorylase and kinase actions
    • Deoxycytidine salvaged into dCMP via deoxycytidine kinase