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The nomenclature of pyrimidine depends on their linkage to a pentose Nucleotidase Phosphorylase Cytosine Base Cytidine Nucleoside* Base Cytidine Monophosphate Nucleotide Base (P04 ester) shorter pathway than for purines base is made first, then attached to ribose-P (unlike purine biosynthesis) only 2 precursors (aspartate and glutamine, plus HCO3-) contribute to the 6-membered ring requires 6 steps (instead of 11 for purine) the product is UMP (uridine monophosphate) Condensation of glutamine, bicarbonate in the presence of ATP Carbamoyl phosphate synthetase exists in 2 types: CPS-I which is a mitochondrial enzyme and is dedicated to the urea cycle and arginine biosynthesis) CPS-II, a cytosolic enzyme used here CPS-II is the major site of regulation in animals: UDP and UTP inhibit the enzyme and ATP and PRPP activate it It is the committed step in animals •enzyme (ATCase) is aspartate transcarbamoylase •catalyzes the condensation of carbamoyl phosphate with aspartate with the release of Pi •ATCase is the major site of regulation in bacteria; it is activated by ATP and inhibited by CTP •carbamoyl phosphate is an “activated” compound, so no energy input is needed at this step enzyme: dihydroorotase forms a pyrimidine from carbamoyl aspartate water is released in this process In E. coli, the first 3 enzymatic reactions are catalyzed by 3 separate proteins/enzymes In animals, all 3 steps are found in a multifunctional enzyme (210 kD). The acronym CAD is used as a name for the multienzyme: carbamoyl phosphate synthetase, aspartate transcarbamoylase and dihydroorotase An irreversible reaction Enzyme: dihydroorotate dehydrogenase Oxidizing power is derived from quinones (thru coenzyme Q) Enzyme: orotate phosphoribosyl transferase Ribose phosphate originates from PRPP product (OMP) orotate phosphoribosyl transferase is also used in salvage of uracil and cytosine to their corresponding nucleotide is orotidine-5’-monophosphate enzyme: OMP decarboxylase product: uridine monophosphate (UMP) In animals, steps 5 and 6 are catalyzed by a single polypeptide with 2 active sites PRPP O HO P O H CH2 O OH H O O O H O H P O P O- HN OH O N O- O- OH COOPPi orotate phosphoribosyl transferase H O O HN HN O HO P O O O CH2 N COOHO O OH H CO2 P OH orotidine monophosphate (OMP) N O H H H O CH2 OH H OH O OMP decarboxylase (uses no cofactors) H H H OH OH An inherited human disease caused by a deficiency in the multifunctional enzyme that catalyzes the last 2 steps in the pyrimidine synthesis large amounts of orotic acid in urine retarded growth and severe anemia treat by administration (injection) of uridine and/or cytidine UMP + ATP UDP + ADP nucleoside diphosphate kinase UTP + ADP UDP + ATP CTP synthase (cytidylate synthetase) O H glutamine + ATP Glutamate + ADP +Pi NH2 N O N N Ribose 3 phosphate UTP (in bacteria, ammonia donates the amino group) O N Ribose 3 phosphate CTP Glutamine + HCO 3- + ATP carbamoyl phosph. synthetase Carbamoyl phosphate Orotate orotate phosphoribosyl transferase UTP + CTP UMP UTP and CTP are feeback inhibitors of CPS II OMP All pathways shown previously led to synthesis of ribonucleotides ribonucleotide reductase OH OH P Base O CH2 O OH O H H H OH P Base O CH2 O H OH OH O H H H H OH H dADP, dGDP, dUDP and dCDP are all synthesized by the same enzyme Synthesized from nucleoside diphosphate (not mono or triphosphate) by ribonucleotide reductase Methylation of d-UMP via N5,N10methylene THF Reaction inhibited fluorouracil (Efudex) by 5- O H H HN N H2N N H H O O-O P O N HN H N O CH2 O O N H H H R H H H OH H d-UMP O CH3 H HN N H2N O O-O P O N H H N O H H H OH H HN CH2 O O N H H N R Catabolism of a pyrimidine