Purine biosynthesis and catabolism are vital processes in nucleotide metabolism. These pathways ensure cells have the building blocks for DNA and RNA, while also recycling and breaking down excess purines. Understanding these processes is key to grasping how cells maintain their genetic material.

The de novo synthesis pathway builds purines from scratch, while salvage pathways recycle existing bases. Regulation of these processes is crucial to maintain proper nucleotide levels. Catabolism breaks down purines to uric acid, which can cause issues like gout if levels get too high.

Purine biosynthesis, de novo

Pathway Overview and Initial Steps

• De novo purine biosynthesis occurs in the cytosol of cells, resulting in inosine monophosphate (IMP) formation
• Process begins with ribose-5-phosphate conversion to phosphoribosyl pyrophosphate (PRPP) by PRPP synthetase
• PRPP converts to 5-phosphoribosyl-1-amine (PRA) via glutamine phosphoribosyl amidotransferase (GPAT)
  • GPAT catalyzes the first committed step in purine biosynthesis
• Purine ring assembles on the ribose sugar through 10 enzymatic reactions
  • Incorporates atoms from various sources (glutamine, glycine, aspartate, formate, CO2)

Key Intermediates and Energy Requirements

• Important pathway intermediates include:
  • 5-phosphoribosyl-1-amine (PRA)
  • Glycinamide ribonucleotide (GAR)
  • 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)
• Final product, IMP, serves as a branch point for adenine and guanine nucleotide synthesis
• Pathway requires significant energy input
  • Consumes 6 ATP molecules for each IMP molecule produced
• Examples of energy-consuming steps:
  • PRPP formation from ribose-5-phosphate (1 ATP)
  • Conversion of glycinamide ribonucleotide to formylglycinamide ribonucleotide (1 ATP)

Salvage pathways for purines

Key Enzymes and Reactions

• Salvage pathways recycle purine bases and nucleosides, conserving energy and resources
• Two crucial enzymes in purine salvage:
  • Adenine phosphoribosyltransferase (APRT)
  • Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
• APRT catalyzes adenine conversion to AMP using PRPP as a co-substrate
• HGPRT catalyzes two conversions:
  • Hypoxanthine to IMP
  • Guanine to GMP
  • Both reactions use PRPP as a co-substrate
• Nucleoside phosphorylases convert purine nucleosides to their respective bases
  • Purine nucleoside phosphorylase (PNP) catalyzes phosphorolysis of inosine, guanosine, and their deoxy forms
• Adenosine deaminase (ADA) converts adenosine to inosine
  • Inosine can then be acted upon by PNP

Metabolic Disorders and Significance

• Deficiencies in salvage pathway enzymes lead to various metabolic disorders
  • Lesch-Nyhan syndrome results from HGPRT deficiency
    • Characterized by excessive uric acid production, neurological problems, and self-mutilating behavior
  • Severe combined immunodeficiency (SCID) caused by ADA deficiency
    • Results in compromised immune system function and increased susceptibility to infections
• Salvage pathways play a crucial role in maintaining nucleotide pools
  • Particularly important in cells with limited de novo synthesis capacity (erythrocytes)
• Some cancer therapies target salvage pathways to disrupt nucleotide metabolism in rapidly dividing cells

Regulation of purine biosynthesis

Allosteric Regulation

• Purine biosynthesis tightly regulated at multiple levels to maintain appropriate nucleotide pools
• First committed step (GPAT) subject to allosteric feedback inhibition by purine nucleotides
  • Inhibited by AMP, GMP, and IMP
• PRPP synthetase inhibited by ADP and GDP
  • Prevents excessive PRPP production when energy levels are low
• Ribonucleotide reductase allosterically regulated to maintain balanced dNTP pools
  • ATP stimulates reduction of CDP and UDP
  • dATP inhibits reduction of all four NDPs
• IMP branching to AMP or GMP regulated by cellular nucleotide levels
  • Adenylosuccinate synthetase (first step in AMP synthesis from IMP) inhibited by AMP
  • IMP dehydrogenase (first step in GMP synthesis from IMP) inhibited by GMP

Transcriptional and Other Regulatory Mechanisms

• Transcriptional regulation of purine biosynthetic enzymes occurs in response to cellular purine levels and growth signals
  • Purine-rich diet can lead to decreased expression of biosynthetic enzymes
  • Growth factors can stimulate increased expression to support cell proliferation
• Post-translational modifications also play a role in regulating enzyme activity
  • Phosphorylation of PRPP synthetase can modulate its activity
• Compartmentalization of enzymes can influence pathway efficiency
  • Some enzymes form multi-enzyme complexes (purinosomes) to enhance substrate channeling

Purine catabolism and uric acid formation

Catabolic Pathway and Enzymes

• Purine catabolism breaks down nucleotides, nucleosides, and bases to form uric acid in humans and primates
• Process begins with nucleotide dephosphorylation to nucleosides by 5'-nucleotidases
• Nucleosides converted to respective bases:
  • Purine nucleoside phosphorylase acts on guanosine and inosine
  • Adenosine deaminase converts adenosine to inosine
• Base conversions:
  • Adenine deaminase converts adenine to hypoxanthine
  • Guanine deaminase converts guanine to xanthine
• Xanthine oxidase catalyzes two oxidation steps:
  • Hypoxanthine to xanthine
  • Xanthine to uric acid
  • Produces hydrogen peroxide as a byproduct

Uric Acid and Evolutionary Aspects

• Uric acid serves as the final product of purine catabolism in humans
  • Result of evolutionary loss of uricase enzyme
• Uricase converts uric acid to more soluble allantoin in most other mammals
• Elevated uric acid levels (hyperuricemia) can lead to gout
  • Painful inflammatory condition caused by uric acid crystal deposition in joints and tissues
• Further metabolism of uric acid varies among organisms:
  • Most mammals convert uric acid to allantoin
  • Bony fish metabolize it to allantoic acid
  • Marine invertebrates break it down to urea and glyoxylate
• Evolutionary loss of uricase in humans may have provided advantages:
  • Uric acid acts as an antioxidant
  • May have played a role in maintaining blood pressure in early hominids