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Nucleotide Metabolism I
• Overview• Structure• Synthesis Overview• Purine synthesis• Pyrimidine synthesis• Regulation
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Overview
• Produce RNA/DNA • ATP • Intermediates -- UDP-
glucose • FAD, NAD • cAMP
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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 enolform
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Structures
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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
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Purine synthesis
• Start with PRPP • Build ring on sugar • 10 step pathway
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Pathway
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Purine Rings
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AMP and GMP
• IMP branch point (IMP part of tRNAmolecule)
• Produce AMP and GMP
• GTP and ATP substrates in opp rxn
• 10/1 ratio of ATP/GTP
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Pyrimidine synthesis
• Make ring first then attach to sugar
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Pyrimidine synthesis
• CPS II in cytosol(same rxn as CPS I in mito)
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Pathway
• dihydroorotate dehydrogenase on outer side of inner mitochondria
• Orotate added to PRPP
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UTP CTP
• UTP makes CTP, with ATP and glutamine as NH2 donor
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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