Biosynthesis of Purine Nucleotide

  • Biosynthesis of Purine Nucleotide refers to the cellular process by which purine nucleotides primarily adenosine monophosphate (AMP) and guanosine monophosphate (GMP) are synthesized from small molecular precursors.
  • Biosynthesis of Purine Nucleotide pathway involves the stepwise construction of the purine ring directly onto a ribose sugar molecule (from PRPP: 5-phosphoribosyl-1-pyrophosphate), utilizing amino acids (like glycine, glutamine, and aspartate), formyl groups (from N¹⁰-formyl-THF), and carbon dioxide.
Structure of purine Biosynthesis of Purine Nucleotide
Structure of purine

De Novo Purine Synthesis Pathway

  • The de novo synthesis of purines starts with simple molecules like amino acids, carbon dioxide, and tetrahydrofolate.
  • The pathway is a stepwise construction of the purine ring attached to ribose-5-phosphate.
  • Here’s an outline of the main steps:
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  1. Formation of PRPP:

    • Ribose-5-phosphate is converted to 5-phosphoribosyl-1-pyrophosphate (PRPP) by the enzyme PRPP synthetase.
    • Reaction: Ribose-5-phosphate + ATP → PRPP + AMP
  2. Commitment Step of Biosynthesis:

    • PRPP reacts with glutamine to form 5-phosphoribosylamine. This is catalyzed by amidophosphoribosyltransferase.
    • Reaction: PRPP + Glutamine → 5-Phosphoribosylamine + Glutamate + PPi
  3. Formation of Inosine Monophosphate (IMP):

    • Through a series of steps involving the incorporation of atoms from glycine, formate (from N10-formyl-tetrahydrofolate), glutamine, aspartate, and CO₂, the molecule is converted into IMP.
    • Notable intermediates: Glycinamide ribonucleotide (GAR), Formylglycinamide ribonucleotide (FGAR), and 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR).
  4. Conversion of IMP to AMP and GMP:

    • AMP Pathway: IMP is converted to adenylosuccinate-by-adenylosuccinate synthetase, which then gets converted to AMP by adenylosuccinate lyase.
    • GMP Pathway: IMP is oxidized to xanthosine monophosphate (XMP) by IMP dehydrogenase and then converted to GMP-by-GMP synthetase.

Salvage Pathway of Biosynthesis

  • The salvage pathway recycles free purine bases and nucleosides derived from the turnover of nucleic acids. Key enzymes involved include:
    1. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT):

      • Converts hypoxanthine to IMP and guanine to GMP using PRPP.
      • Reactions:
      • Hypoxanthine + PRPP → IMP + PPi
      • Guanine + PRPP → GMP + PPi
    2. Adenine phosphoribosyltransferase (APRT):

      • Converts adenine to AMP.
      • Reaction: Adenine + PRPP → AMP + PPi
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Regulation of Biosynthesis

  • The biosynthesis of nucleotides is tightly regulated through feedback inhibition to ensure balance and meet cellular demands:
    • Purine Synthesis of Biosynthesis:

      • Key regulatory points include inhibition of PRPP synthetase and amidophosphoribosyltransferase by end products (AMP, GMP).

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