Purine/Pyrimidine Synthesis

Nucleotides
1. 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
  1. Not from diet, exogenous nucleotide broken down
    1. Made De novo or Savage pathway, scrap together pieces
2. Structure
  1. Nitrogenous base, pentose sugar, and phosphate groups
    1. Mostley made in lover some in brain, then transfer though blood
      1. Lots goes into making a purine ring, see below
Purine synthesis
1. starts with Ribose-5 P, from pentose phosphate pathway
  1. Add ATP to make PRPP
    1. Then add a bunch of Carbons and Nitrogens
      1. 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
        Annotations:
        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
Pyrimidine Synthesis
1. First thing is to make the ring
  1. Glutamine + CO2 + ATP
    1. Add aspartate, close the ring
      1. 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
      2. CPS-II, aspartate transcarbamoylase and dihydroorotase all on one, produces orotate
      3. Aspartate is the majority of the ring, 4/6 C's, the rest is from carbamoyl phosphate, N from glutamine, C from CO2
2. Salvage
  1. 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
Common Pathway
1. NDP-> dNDP
  1. Ribonucleotide reductase + thioredoxin
    1. Allosteric Regulation
      1. One site regulates its activity
        One regulates its specificity
Purine Degradation
1. Nucleotide -> nucleoside
  1. loss of amino group from adenosine
    1. Loss of sugar to free guanine or hypoxanthine Guanine loses amino,
      1. Xanthine oxidase converts hypoxanthine and xanthine to urate
        Excreted in urine, not very soluble Excess amounts can precipitate
Pyrimidine Degradation
1. Piece of Cake
  1. All products are water soluble
    1. B-alanine
    2. B-aminoisobutyrate
    3. ammonia, water and carbon dioxide

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Purine/Pyrimidine Synthesis

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	Created by Nader I about 9 years ago