Synthesis of Nucleotides

Jun 24, 2024

Synthesis of Nucleotides: Purine and Pyrimidine Synthesis

Overview of Nucleotide Components

  • Three main components of nucleotides:
    1. Nitrogenous Bases
      • Purines: Adenine, Guanine
      • Pyrimidines: Cytosine, Uracil (RNA), Thymine (DNA)
    2. Pentose Sugars
      • Ribose sugar (RNA)
      • Deoxyribose sugar (DNA)
    3. Phosphate Groups

Nitrogenous Bases and Their Nucleotides

  • Adenine (A)
    • Adenosine Monophosphate (AMP) or Deoxyadenosine Monophosphate (dAMP)
  • Guanine (G)
    • Guanosine Monophosphate (GMP) or Deoxyguanosine Monophosphate (dGMP)
  • Cytosine (C)
    • Cytidine Monophosphate (CMP) or Deoxycytidine Monophosphate (dCMP)
  • Uracil (U) - RNA only
    • Uridine Monophosphate (UMP)
  • Thymine (T) - DNA only
    • Thymidine Monophosphate (TMP) or Deoxythymidine Monophosphate (dTMP)

Synthesis Pathways

Pentose Phosphate Pathway

  • Glucose → Glucose-6-Phosphate
    • Enzyme: Hexokinase/Glucokinase
  • Glucose-6-Phosphate → 6-Phosphoglucono-δ-lactone
    • Enzyme: Glucose-6-Phosphate Dehydrogenase (utilizes NADP+ → NADPH)
  • 6-Phosphoglucono-δ-lactone → 6-Phosphogluconate
    • Enzyme: Lactonase (adds water)
  • 6-Phosphogluconate → Ribulose-5-Phosphate
    • Enzyme: 6-Phosphogluconate Dehydrogenase (utilizes NADP+ → NADPH)
  • Ribulose-5-Phosphate → Ribose-5-Phosphate
    • Enzyme: Isomerase
  • Ribose-5-Phosphate → Phosphoribosyl Pyrophosphate (PRPP)
    • Enzyme: Ribose Phosphate Pyrophosphokinase (utilizes ATP)

Pyrimidine Synthesis

  • Starting molecules: Glutamine, Bicarbonate, ATP
    • Enzyme: Carbamoyl Phosphate Synthetase II (produces Carbamoyl Phosphate)
  • Carbamoyl Phosphate + Aspartate → Carbamoyl Aspartate
    • Enzyme: Aspartate Transcarbamoylase
  • Carbamoyl Aspartate → Dihydroorotate
    • Enzyme: Dihydroorotase (dehydration reaction)
  • Dihydroorotate → Orotate
    • Enzyme: Dihydroorotate Dehydrogenase
  • Orotate + PRPP → Orotidine Monophosphate (OMP)
    • Enzyme: Orotate Phosphoribosyltransferase
  • OMP → Uridine Monophosphate (UMP)
    • Enzyme: OMP Decarboxylase
  • UMP → UTP (adds two phosphates)
    • Enzyme: Nucleoside Diphosphate Kinase
  • UTP → CTP (amine added from glutamine)
    • Enzyme: CTP Synthetase
  • Converting to deoxyribonucleotides:
    • Enzyme: Ribonucleotide Reductase
    • UDP → dUDP
    • dUDP → dUMP
    • dUMP + Tetrahydrofolate (adds methyl group) → dTMP
      • Enzyme: Thymidylate Synthase

Purine Synthesis

  • Precursors: PRPP, Glutamine, Bicarbonate, Formate, Glycine, Aspartate
  • PRPP + Glutamine → Inosine Monophosphate (IMP) through a series of reactions
    • IMP → AMP
      • Enzyme: Adenylosuccinate Synthetase (adds Aspartate)
      • Enzyme: Adenylosuccinate Lyase (removes Fumarate)
    • IMP → GMP
      • Enzyme: IMP Dehydrogenase (adds NAD+ → NADH + H+)
      • Enzyme: GMP Synthase (adds Glutamine, releases Glutamate)
  • Converting to deoxyribonucleotides:
    • AMP → ADP → dADP → dAMP (Ribonucleotide Reductase)
    • GMP → GDP → dGDP → dGMP (Ribonucleotide Reductase)

Conclusion

  • Importance of understanding the synthesis pathways of nucleotides for RNA and DNA.
  • Reminder: Nucleotides are essential for genetic material and cellular functions.