20 - REVIEW of PROBLEM SET Pyrimidine synthesis and...

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REVIEW of PROBLEM SET
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Pyrimidine synthesis and chemotherapeutics that target nucleotide synthesis Amanda MacFarlane, PhD Health Canada
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Pyrimidine synthesis Less complicated than purine synthesis One less ring to synthesize Assembled as the free base whereas purines were made using ribotide intermediates No branch point, just interconversion of UMP to CTP and TTP UMP derived from: Glutamine (N3) Aspartate (N1, C4, C5, C6) Bicarbonate ion (C2) PRPP
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Uridine monophosphate synthesis 1 2 3 4 5 6 1. Carbamoyl phosphate synthetase II, CPSII 2. aspartate transcarbamoylase, ATCase 3. carbamoyl aspartate dehydratase 4. dihydroorotate dehydrogenase 5. orotate phosphoribosyltransferase 6. orotidine-5'-phosphate carboxylase quinone Reduced quinone
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1. Synthesis of carbamoyl phosphate Carbamoyl phosphate synthetase II (CPSII) Don’t confuse with CPSI from the urea cycle Phosphate from ATP and amide from Glutamine transferred to bicarbonate ion
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2. Synthesis of carbamoyl aspartate Aspartate transcarbamoylase (ATCase) Condensation of aspartate with carbamoyl phosphate *flux generating/rate- limiting step*
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3. Ring closure to form dihydroorotate dihydroorotase Intramolecular condensation Releases water
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4. Oxidation of dihydroorotate Dihydroorotate dehydrogenase (DHODH) DHODH on outer membrane of mitochondria in close proximity of ubiquinone in eukaryotes Two REDOX steps
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Eukaryotic DHODH does not use NAD+ or NADP+ as electron acceptors Prosthetic flavin and ubiquinone are proximal, and cytochrome C and molecular oxygen are final electron acceptors *pyrimidine de novo synthesis is directly connected with the mitochondrial electron transport chain and energy regeneration dysfunctional electron transport chain can impair UTP, TTP, and CTP synthesis => RNA/DNA synthesis • lack of oxygen • inherited or acquired deficiencies of enzymes within the electron transport chain • inhibitors of electron transport chain
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5. Acquisition of ribose phosphate moiety
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20 - REVIEW of PROBLEM SET Pyrimidine synthesis and...

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