Biochemistry: De Novo Purine Synthesis

Overview

• Purines: Key substances in DNA, RNA, ATP, GTP, cyclic cGMP, and co-enzymes.
• Importance: Essential for cellular functions; defects in regulation can lead to cancer, neurological, and immunological diseases.
• Objective: Generate inosine 5'-monophosphate (IMP) which can be converted to AMP or GMP.
• Energy Requirement: Energy-intensive process requiring substrates and co-factors from other biochemical reactions.

Pathway

Starting Point

• Ribose 5-phosphate: Derived from the pentose phosphate pathway.

Key Steps

1. Ribose 5-phosphate to PRPP
   • Enzyme: PRPP synthetase
   • Requires ATP
2. PRPP to 5-phosphoribosylamine (5P)
   • Enzyme: Glutamine phosphoribosyl amidotransferase (GPAT)
   • Rate-limiting step
   • Converts glutamine to glutamate

Subsequent Reactions

• 5P to IMP
  • Series of reactions (enzymes not required to memorize).
  • Required substances: glycine, formal tetrahydrofolate, glutamine, CO2, aspartate.
  • Mnemonic: Go Forward And Go Create An IMP (G - Glycine, F - Formal THF, G - Glutamine, C - CO2, A - Aspartate).

Conversion of IMP

• To AMP or GMP
  • Enzyme for GMP: Inosine monophosphate dehydrogenase
  • IMP as a branch point for selecting nucleotide synthesis.

Feedback Mechanisms

• Product Inhibition
  • GMP and AMP inhibit GPAT (rate-limiting enzyme).
  • GMP or AMP alone: Partially inhibit GPAT.
  • GMP and AMP together: Fully inhibit GPAT.

Medications Affecting the Pathway

General Inhibitors

• Azathioprine and 6-mercaptopurine: Inhibit overall de novo purine synthesis.

Specific Enzyme Inhibitors

• Mycophenolate and Ribavirin: Inhibit inosine monophosphate dehydrogenase.
• Role: Used as immunosuppressive agents.

Future Videos

• Part 2: Pyrimidine Base Production
• Part 3: Purine Salvage Deficiency

Keep an eye out for these upcoming videos!