Synthesis of Nucleotides: Purine and Pyrimidine Synthesis

Key Components of Nucleotides

1. Nitrogenous Base
2. Pentose Sugar
   • Deoxyribose (in DNA) or Ribose (in RNA)
3. Phosphate Groups

Nitrogenous Bases

• Purines: Adenine (A) and Guanine (G)
• Pyrimidines: Cytosine (C), Uracil (U), and Thymine (T)

Purines

1. Adenine (A) → Adenosine Monophosphate (AMP)
   • Adenine + Ribose + Phosphate = AMP
   • Adenine + Deoxyribose + Phosphate = dAMP
2. Guanine (G) → Guanosine Monophosphate (GMP)
   • Guanine + Ribose + Phosphate = GMP
   • Guanine + Deoxyribose + Phosphate = dGMP

Pyrimidines

1. Cytosine (C) → Cytidine Monophosphate (CMP)
   • Cytosine + Ribose + Phosphate = CMP
   • Cytosine + Deoxyribose + Phosphate = dCMP
2. Uracil (U) → Uridine Monophosphate (UMP)
   • Uracil + Ribose + Phosphate = UMP
   • Uracil + Deoxyribose + Phosphate = dUMP
3. Thymine (T) → Thymidine Monophosphate (TMP)
   • Thymine + Ribose + Phosphate = TMP
   • Thymine + Deoxyribose + Phosphate = dTMP

Synthesis Pathways

Pentose Phosphate Pathway

1. Glucose to PRPP
   • Glucose phosphorylated by hexokinase/glucokinase ➔ Glucose-6-phosphate
   • Glucose-6-phosphate dehydrogenase converts it to 6-phosphoglucono-δ-lactone
   • Lactamase converts it to 6-phosphogluconate
   • 6-phosphogluconate dehydrogenase converts it to Ribulose-5-phosphate
   • Isomerase converts it to Ribose-5-phosphate
   • Ribose phosphate pyrophosphokinase forms PRPP

Pyrimidine Synthesis

1. Formation of Carbamoyl Phosphate
   • Glutamine + Bicarbonate + ATP ➔ Carbamoyl Phosphate (via Carbamoyl Phosphate Synthetase II)
2. Formation of Orotate
   • Carbamoyl Phosphate + Aspartate ➔ Carbamoyl Aspartate (via Aspartate Transcarbamoylase)
   • Carbamoyl Aspartate ➔ Orotate (via Dihydroorotase)
3. Formation of OMP and UMP
   • Orotate + PRPP ➔ Orotidine Monophosphate (OMP) (via Orotate Phosphoribosyltransferase)
   • OMP ➔ Uridine Monophosphate (UMP) (via UMP Synthase)
4. Conversions
   • UMP ➔ UDP ➔ UTP
   • UTP ➔ CTP (by adding amino group from Glutamine)
   • CTP ➔ CMP
   • CMP ➔ dCMP (via Ribonucleotide Reductase)
   • dCMP can be used for DNA synthesis

Thymidine Synthesis

1. Formation from dUMP
   • dUMP ➔ dTMP (via Thymidylate Synthase using Tetrahydrofolate)

Purine Synthesis

1. Starting with PRPP
   • PRPP + Glutamine + Bicarbonate + Formate + Glycine + Aspartate ➔ Inosine Monophosphate (IMP)
2. IMP to AMP and GMP
   • IMP ➔ Adenylosuccinate (via Adenylosuccinate Synthase with Aspartate)
   • Adenylosuccinate ➔ AMP (by releasing Fumarate via Adenylosuccinate Lyase)
   • AMP ➔ ADP ➔ ATP for RNA
   • AMP ➔ dADP ➔ dAMP for DNA (via Ribonucleotide Reductase)
3. Synthesis of GMP
   • IMP ➔ XMP ➔ GMP
   • GMP ➔ GDP ➔ GTP for RNA
   • GMP ➔ dGDP ➔ dGMP for DNA (via Ribonucleotide Reductase)

Summary

• Nucleotides have three components: nitrogenous base, pentose sugar, and phosphate group
• Purines have double ring structures; Pyrimidines have single ring structures.
• PRPP is a key intermediate for both purine and pyrimidine synthesis.
• Enzymes like ribonucleotide reductase play a crucial role in converting ribonucleotides to deoxyribonucleotides.
• Purines synthesized in 10 steps involving substrates like glutamine, glycine, and aspartate.
• Pyrimidines synthesized starting from glutamine, bicarbonate, and aspartate. The key intermediates include carbamoyl phosphate and orotate.