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  <head>
    <title>090-03 Purine and pyrimidine synthesis, salvage, degradation, and inborn errors</title>
    <ownerName>Integrated Medical Foundations</ownerName>
  </head>
  <body>
    <outline text="Purine and pyrimidine metabolism">
      <outline text="Nucleotide basics and PRPP">
        <outline text="Nucleic acids, energy, coenzymes, signalling"/>
        <outline text="De novo synthesis or salvage"/>
        <outline text="Imbalance increases mutation"/>
        <outline text="Nucleoside lacks phosphate"/>
        <outline text="Purines two rings, pyrimidines one"/>
        <outline text="Kinases interconvert mono-, di-, triphosphates"/>
        <outline text="PRPP from ribose 5-phosphate and ATP">
          <outline text="Central ribose donor, including salvage"/>
          <outline text="Excess drives purine and uric-acid production"/>
        </outline>
      </outline>
      <outline text="De novo purine synthesis">
        <outline text="Ring built on PRPP ribose"/>
        <outline text="Atoms from glutamine, glycine, aspartate, folate"/>
        <outline text="Amidophosphoribosyltransferase step">
          <outline text="Activated by PRPP"/>
          <outline text="Inhibited by purine nucleotides"/>
        </outline>
        <outline text="Inosine monophosphate is first product">
          <outline text="AMP branch uses aspartate and GTP"/>
          <outline text="GMP branch uses glutamine and ATP"/>
          <outline text="Cross-use of energy balances pools"/>
        </outline>
      </outline>
      <outline text="Salvage and Lesch-Nyhan syndrome">
        <outline text="HGPRT salvages hypoxanthine and guanine"/>
        <outline text="Adenine phosphoribosyltransferase salvages adenine"/>
        <outline text="Saves energy, restrains de novo synthesis"/>
        <outline text="Brain depends heavily on salvage"/>
        <outline text="Severe HGPRT loss: Lesch-Nyhan syndrome">
          <outline text="Hyperuricaemia, dystonia, self-injury"/>
          <outline text="Neurology persists despite urate lowering"/>
        </outline>
        <outline text="Partial deficiency: gout or stones"/>
      </outline>
      <outline text="Degradation, urate, and gout">
        <outline text="Converges on hypoxanthine or xanthine"/>
        <outline text="Xanthine oxidoreductase forms uric acid">
          <outline text="Oxidase form generates reactive oxygen"/>
        </outline>
        <outline text="Humans lack uricase"/>
        <outline text="Hyperuricaemia mostly from reduced renal excretion">
          <outline text="Turnover, tumour lysis, diet raise production"/>
          <outline text="Necessary but not sufficient for gout"/>
        </outline>
        <outline text="Crystals need supersaturation, pH, time">
          <outline text="Innate inflammation, tophi, stones"/>
        </outline>
        <outline text="Allopurinol, febuxostat block oxidoreductase"/>
        <outline text="Rapid urate change can trigger flares"/>
      </outline>
      <outline text="Immune-deficiency enzyme defects">
        <outline text="Adenosine deaminase deficiency">
          <outline text="Deoxyadenosine nucleotides accumulate"/>
          <outline text="Ribonucleotide reductase inhibited"/>
          <outline text="Lymphocyte injury: severe combined immunodeficiency"/>
        </outline>
        <outline text="Purine-nucleoside-phosphorylase deficiency">
          <outline text="T cells preferentially impaired"/>
        </outline>
      </outline>
      <outline text="De novo pyrimidine synthesis">
        <outline text="Ring built first, then attached to PRPP"/>
        <outline text="Cytosolic carbamoyl-phosphate synthetase two">
          <outline text="Uses glutamine, bicarbonate, ATP"/>
          <outline text="Multifunctional complex"/>
          <outline text="Differs from urea-cycle synthetase one"/>
        </outline>
        <outline text="Dihydroorotate dehydrogenase on inner membrane">
          <outline text="Links pyrimidine synthesis to respiratory chain"/>
        </outline>
        <outline text="UMP synthase forms uridine monophosphate"/>
        <outline text="UTP gains glutamine amino group to form CTP"/>
        <outline text="Uridine sugars for glycogen, glycosylation"/>
        <outline text="Hereditary orotic aciduria">
          <outline text="Megaloblastic anaemia, no hyperammonaemia"/>
          <outline text="Uridine bypasses the block"/>
          <outline text="Contrast: ornithine-transcarbamylase deficiency"/>
        </outline>
      </outline>
      <outline text="Deoxynucleotides and folate">
        <outline text="Ribonucleotide reductase makes deoxy forms">
          <outline text="Activity and specificity sites balance pools"/>
          <outline text="High dATP inhibits overall activity"/>
          <outline text="Hydroxyurea inhibits it"/>
        </outline>
        <outline text="Thymidylate synthase methylates dUMP">
          <outline text="Methylene tetrahydrofolate becomes dihydrofolate"/>
          <outline text="Dihydrofolate reductase regenerates it"/>
        </outline>
        <outline text="Folate lack: uracil misincorporation, DNA breaks"/>
      </outline>
      <outline text="Antimetabolites and analogues">
        <outline text="Methotrexate inhibits dihydrofolate reductase">
          <outline text="Folinic acid bypasses reduction"/>
        </outline>
        <outline text="Trimethoprim, pyrimethamine favour microbial enzymes"/>
        <outline text="Fluorouracil metabolite inhibits thymidylate synthase"/>
        <outline text="Mercaptopurine and thioguanine need activation">
          <outline text="Xanthine-oxidase inhibition: adjust the dose"/>
        </outline>
        <outline text="Mycophenolate inhibits IMP dehydrogenase">
          <outline text="Lymphocytes rely on de novo pathway"/>
        </outline>
        <outline text="Nucleoside analogues terminate DNA chains">
          <outline text="Selectivity: uptake, kinases, affinity, removal"/>
          <outline text="Mitochondrial or marrow toxicity"/>
        </outline>
        <outline text="Kinases activate, phosphatases oppose">
          <outline text="Tissue enzyme differences alter exposure"/>
        </outline>
      </outline>
      <outline text="Pyrimidine breakdown, pools, tumour lysis">
        <outline text="Ring opens to soluble products"/>
        <outline text="Dihydropyrimidine dehydrogenase starts breakdown">
          <outline text="Deficiency: fluoropyrimidine toxicity"/>
        </outline>
        <outline text="Mitochondrial DNA needs balanced deoxynucleotides"/>
        <outline text="Plasma levels do not show intracellular pools"/>
        <outline text="Tumour lysis releases potassium, phosphate, nucleic acids">
          <outline text="Purines become urate, injuring kidney"/>
          <outline text="Uricase for rapid urate removal"/>
        </outline>
      </outline>
    </outline>
  </body>
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