Purine/Pyrimidine Synthesis

Purine/Pyrimidine Synthesis

1. Nucleotides

   • Functions :Production of DNA and RNA Energy storage and transfer – ATP, GTP Coenzymes – NAD, FAD, Coenzyme A Activated compounds for synthesis – UDP sugars, CDP in phospholipid synthesis Methyl transfers – SAM Second messengers – cAMP, cGMP Enzyme regulation at allosteric sites
     • Not from diet, exogenous nucleotide broken down
       • Made De novo or Savage pathway, scrap together pieces
   • Structure
     • Nitrogenous base, pentose sugar, and phosphate groups
       • Mostley made in lover some in brain, then transfer though blood
         • Lots goes into making a purine ring, see below

2. Purine synthesis

   • starts with Ribose-5 P, from pentose phosphate pathway
     • Add ATP to make PRPP
       • Then add a bunch of Carbons and Nitrogens
         • IN DETAIL
           • 1.) Ribose 5P
             • ATP + PRPP synthetase
               • 2.) PRPP
                 • glutamine phosphoribosyl amidotransferase
                   • 3.) 5-phosphoribosyl 1 amine
                     • Then add a Glycine molecule to it
                       • + ATP
                       • 4.) Glycinamide Ribosyl 5- Phosphate
                         • ADD a Formyl carbon, a glutamine nitrogen, 2 ATP's
                           • 5.) This closes the linear structure into a ring
                             • Then you donate a carbon from CO2, a nitrogen from aspartate using ATP, then a formyl carbon
                               • 1st purine made IMP
                                 • Inosine Monophosphate
                                 • Base is Hypoxanthine
                                 • Requires 6 ATP's per purine
                                 • Can be made into AMP and GMP
                                   • AMP Production
                                     • aspartate + GTP + adenylosuccinate synthetase
                                       • Adenylosuccinate
                                         • Remove a Fumarate
                                           • AMP
                                             • (-)
                                       • Symmetry
                                   • GMP production
                                     • IMP Dehydrogenase + NADH
                                       • XMP
                                         • ATP + Glutamine + GMP synthetase
                                           • GMP
                                             • (-)
                                 • Not in DNA, but is in tRNA
                                   • Causes wobble effect
                   • Committed Step to becoming a purine
                   • Glutamine give's Nitrogen
               • Activated by P-, GDP & ADP inhibit

3. Pyrimidine Synthesis

   • First thing is to make the ring
     • Glutamine + CO2 + ATP
       • Add aspartate, close the ring
         • Add side chains
           • Make Orotic Acid
             • ADD PRPP
             • UMP
               • CTP
                 • dUMP
                   • dTMP
             • Orotate phosphoribosyl transferase and orotidylic acid decarboxylase on the other, get to UMP
         • CPS-II, aspartate transcarbamoylase and dihydroorotase all on one, produces orotate
         • Aspartate is the majority of the ring, 4/6 C's, the rest is from carbamoyl phosphate, N from glutamine, C from CO2
   • Salvage
     • Free bases converted to nucleosides Pyrimidine nucleoside phosphorylase uses ribose-1-phosphate Preferred reaction is synthesis, not degradation Kinases are more specific, get more specific as more phosphates are added

4. Common Pathway

   • NDP-> dNDP
     • Ribonucleotide reductase + thioredoxin
       • Allosteric Regulation
         • One site regulates its activity
           • One regulates its specificity

5. Purine Degradation

   • Nucleotide -> nucleoside
     • loss of amino group from adenosine
       • Loss of sugar to free guanine or hypoxanthine Guanine loses amino,
         • Xanthine oxidase converts hypoxanthine and xanthine to urate
           • Excreted in urine, not very soluble Excess amounts can precipitate

6. Pyrimidine Degradation

   • Piece of Cake
     • All products are water soluble
       • B-alanine
       • B-aminoisobutyrate
       • ammonia, water and carbon dioxide

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