--- module: 090-03 language: en chapter: 90 title: "Amino-Acid, Nitrogen, Haem, and Nucleotide Metabolism" module_title: "Purine and pyrimidine synthesis, salvage, degradation, and inborn errors" source_sha256: 0694dc90df0ccef97f481656b1de8e0cd5702df8e85ec52e98ba00ec91b97b40 --- # Purine and pyrimidine metabolism ## Nucleotide basics and PRPP ### Nucleic acids, energy, coenzymes, signalling ### De novo synthesis or salvage ### Imbalance increases mutation ### Nucleoside lacks phosphate ### Purines two rings, pyrimidines one ### Kinases interconvert mono-, di-, triphosphates ### PRPP from ribose 5-phosphate and ATP #### Central ribose donor, including salvage #### Excess drives purine and uric-acid production ## De novo purine synthesis ### Ring built on PRPP ribose ### Atoms from glutamine, glycine, aspartate, folate ### Amidophosphoribosyltransferase step #### Activated by PRPP #### Inhibited by purine nucleotides ### Inosine monophosphate is first product #### AMP branch uses aspartate and GTP #### GMP branch uses glutamine and ATP #### Cross-use of energy balances pools ## Salvage and Lesch-Nyhan syndrome ### HGPRT salvages hypoxanthine and guanine ### Adenine phosphoribosyltransferase salvages adenine ### Saves energy, restrains de novo synthesis ### Brain depends heavily on salvage ### Severe HGPRT loss: Lesch-Nyhan syndrome #### Hyperuricaemia, dystonia, self-injury #### Neurology persists despite urate lowering ### Partial deficiency: gout or stones ## Degradation, urate, and gout ### Converges on hypoxanthine or xanthine ### Xanthine oxidoreductase forms uric acid #### Oxidase form generates reactive oxygen ### Humans lack uricase ### Hyperuricaemia mostly from reduced renal excretion #### Turnover, tumour lysis, diet raise production #### Necessary but not sufficient for gout ### Crystals need supersaturation, pH, time #### Innate inflammation, tophi, stones ### Allopurinol, febuxostat block oxidoreductase ### Rapid urate change can trigger flares ## Immune-deficiency enzyme defects ### Adenosine deaminase deficiency #### Deoxyadenosine nucleotides accumulate #### Ribonucleotide reductase inhibited #### Lymphocyte injury: severe combined immunodeficiency ### Purine-nucleoside-phosphorylase deficiency #### T cells preferentially impaired ## De novo pyrimidine synthesis ### Ring built first, then attached to PRPP ### Cytosolic carbamoyl-phosphate synthetase two #### Uses glutamine, bicarbonate, ATP #### Multifunctional complex #### Differs from urea-cycle synthetase one ### Dihydroorotate dehydrogenase on inner membrane #### Links pyrimidine synthesis to respiratory chain ### UMP synthase forms uridine monophosphate ### UTP gains glutamine amino group to form CTP ### Uridine sugars for glycogen, glycosylation ### Hereditary orotic aciduria #### Megaloblastic anaemia, no hyperammonaemia #### Uridine bypasses the block #### Contrast: ornithine-transcarbamylase deficiency ## Deoxynucleotides and folate ### Ribonucleotide reductase makes deoxy forms #### Activity and specificity sites balance pools #### High dATP inhibits overall activity #### Hydroxyurea inhibits it ### Thymidylate synthase methylates dUMP #### Methylene tetrahydrofolate becomes dihydrofolate #### Dihydrofolate reductase regenerates it ### Folate lack: uracil misincorporation, DNA breaks ## Antimetabolites and analogues ### Methotrexate inhibits dihydrofolate reductase #### Folinic acid bypasses reduction ### Trimethoprim, pyrimethamine favour microbial enzymes ### Fluorouracil metabolite inhibits thymidylate synthase ### Mercaptopurine and thioguanine need activation #### Xanthine-oxidase inhibition: adjust the dose ### Mycophenolate inhibits IMP dehydrogenase #### Lymphocytes rely on de novo pathway ### Nucleoside analogues terminate DNA chains #### Selectivity: uptake, kinases, affinity, removal #### Mitochondrial or marrow toxicity ### Kinases activate, phosphatases oppose #### Tissue enzyme differences alter exposure ## Pyrimidine breakdown, pools, tumour lysis ### Ring opens to soluble products ### Dihydropyrimidine dehydrogenase starts breakdown #### Deficiency: fluoropyrimidine toxicity ### Mitochondrial DNA needs balanced deoxynucleotides ### Plasma levels do not show intracellular pools ### Tumour lysis releases potassium, phosphate, nucleic acids #### Purines become urate, injuring kidney #### Uricase for rapid urate removal