Nucleotide Metabolism I

• Overview• Structure• Synthesis Overview• Purine synthesis• Pyrimidine synthesis• Regulation

Overview

• Produce RNA/DNA • ATP • Intermediates -- UDP-

glucose • FAD, NAD • cAMP

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

Structures

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

Purine synthesis

• Start with PRPP • Build ring on sugar • 10 step pathway

Pathway

Purine Rings

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

Pyrimidine synthesis

• Make ring first then attach to sugar

Pyrimidine synthesis

• CPS II in cytosol(same rxn as CPS I in mito)

Pathway

• dihydroorotate dehydrogenase on outer side of inner mitochondria

• Orotate added to PRPP

UTP CTP

• UTP makes CTP, with ATP and glutamine as NH2 donor

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