Nucleotide Metabolism

I. Overview

• Produce RNA/DNA
• ATP
• Intermediates -- UDP-glucose
• FAD, NAD
• cAMP

II. Structure

• Sugar: Ribose
• Base: Purines/Pyrimidines
• phosphate(s)
• Nucleoside: base + sugar
• Nucleotide: base + sugar + phosphate
• Charge: -2,-3,-4 (Mono,di, tri)
• Have resonance structure: keto vs enol form

III. Synthesis Overview

• Multienzyme complex
• small pools
• cytosolic enzymes
• De novo: liver and placenta, transport via blood to other tissues
• Both use Ribose 5-phosphate from Pentose P pathway

IV. Purine synthesis

• start with PRPP
• build ring on sugar
• 10 step pathway
• IMP branch point (IMP part of tRNA molecule)
• produce AMP and GMP
• GTP and ATP substrates in opp rxn
• 10/1 ratio of ATP/GTP

V. Pyrimidine synthesis

• CPS II in cytosol (same rxn as CPS I in mito)
• make ring first then attach to sugar
• dihydroorotate dehydrogenase on outer side of inner mitochondria
• Orotate added to PRPP
• UTP makes CTP, with ATP and glutamine as NH2 donor

VI. Regulation

• production of NDP and NTP by kinases
• PRPP not regulated step
• 1st step (amidotransferase): allosteric IMP, GMP, AMP and ratio
• GMP and AMP downregulate their own production
• CPS II regulated step
• PRPP and IMP up regulate, UMP down regulate