Wk 13&14 Lecture 3: Nucleotide metabolism

Overview of Nucleotide Metabolism

  • Focus on how amino acids contribute to the synthesis of nucleotides, key components of RNA and DNA.

  • Introduction to the structure of nucleotides:

    • Consist of a nitrogenous base, a sugar (ribose for RNA and deoxyribose for DNA), and one to three phosphate groups.

    • Examples: Adenine, Uracil, Cytosine (RNA); Thymine, Guanine (DNA).

Pathways of Nucleotide Biosynthesis

  • Nucleotide biosynthesis pathways:

    • Salvage pathways: Recycle used bases.

    • De novo pathways: Synthesize new nucleotides from scratch using amino acids, ATP, and CO2.

Amino Acids as Precursors

  • Important amino acids involved in nucleotide synthesis:

    • Serine: Precursor for sphingolipid synthesis.

    • Histidine: Converts to histamine, a vasodilator.

    • Tyrosine: Precursor to hormones like thyroxine and neurotransmitters like serotonin.

    • Tryptophan: Precursor of serotonin and melanin derivatives.

Nomenclature of Nucleotides

  • Nucleotides are classified based on their composition:

    • Bases: Purines (Adenine, Guanine), Pyrimidines (Cytosine, Uracil, Thymine).

    • Nucleosides: Bases attached to sugars (e.g., Adenosine, Uridine).

    • Nucleotides: Nucleosides linked to phosphate groups (e.g., AMP, UMP, ATP).

Biosynthesis of Pyrimidines

  • Pyrimidine nucleotides contain uracil and cytosine in RNA, thymine, and cytosine in DNA.

  • Synthesis Steps:

    1. Formation of carbamoyl phosphate from bicarbonate and ammonia (from glutamine).

    2. Combines with aspartate to form carbamoyl aspartate, a precursor to the pyrimidine ring.

    3. Enzyme ATCase catalyzes the committed step in pyrimidine synthesis.

    4. Cyclization to form orotate, which is connected to PRPP to produce UMP and subsequent nucleotides.

Synthesis of Purines

  • Contains adenine and guanine.

  • Synthesis Steps:

    • Initiated by the conversion of PRPP to 5-phosphoribosylamine via glutamine.

    • Requires multiple ATP hydrolysis and various amino acids (e.g. glycine, aspartate) for ring formation.

    • Ten reactions lead to the production of inosinate (IMP), the precursor for AMP and GMP.

Reduction to Deoxyribonucleotides

  • Process involving ribonucleotide reductase to convert ribonucleotides to deoxyribonucleotides:

    • Substrates: ADP, GDP, CDP, UDP.

    • The reaction requires NADPH for reducing power.

    • Tetrahydrofolate plays a critical role in nucleotide modification.

Methylation and Thymidylate Synthesis

  • Thymidylate synthase catalyzes the conversion of dUMP to dTMP, using N5, N10-methylene tetrahydrofolate.

  • Important for DNA synthesis, especially in rapidly dividing cells (e.g., cancer).

  • Chemotherapeutic agents often target thymidylate synthase to inhibit cancer growth.

Regulation of Nucleotide Biosynthesis

  • Feedback mechanisms to maintain balance between nucleotide levels:

    • Pyrimidine pathway regulated by CTP (inhibitor) and ATP (activator).

    • Purine biosynthesis regulated at multiple steps:

      • PRPP amination feedback inhibition by end products (AMP, GMP).

      • Reciprocal regulation between AMP and GMP synthesis (utilizing GTP and ATP, respectively).

    • Ribonucleotide reductase regulated by levels of dATP and ATP to balance deoxyribonucleotide output.

Conclusion

  • Overviewed the biosynthesis processes of nucleotides and the roles of amino acids.

  • Discussed the importance of regulation mechanisms to maintain cellular nucleotide balance.

  • Anticipated next lecture's focus on amino acid degradation and the urea cycle.