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Pyrimidine Synthesis and Degradation
This document summarizes the de novo synthesis of pyrimidine nucleotides. It describes the precursors and reactions involved in synthesizing the pyrimidine ring and then attaching it to ribose phosphate to form the pyrimidine nucleotides CMP, UMP and TMP. It also discusses the conversion of UDP to CTP and dTMP, the regulation of pyrimidine synthesis, salvage pathways, catabolism of pyrimidines, and the genetic disorder orotic aciduria caused by a defect in the enzyme UMP synthase.
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Pyrimidine Synthesis and Degradation
- 2. De Novo Synthesisof Pyrimidine Synthesis The pyrimidine nucleotides are…. Cytidine monophosphate (CMP) Uridine monophosphate (UMP) and Thymidine monophosphate (TMP). Unlike the synthesis of purine nucleotide, pyrimidine ring is made first and then attached to ribose phosphate, which is donated by PRPP.
- 3. Precursors for denovo synthesis of pyrimidine C2 C4 N3 N 1 C5 C6 Glutamate CO2 Aspartic acid
- 4. Reactions of De NovoSynthesis of Pyrimidine nucleotide CO2 + Carbamoyl phosphate Synthase II Carbamoyl phosphate (CP) Aspartate transcarbomoylase Aspartic acid Pi Carbamoyl aspatate (CA) Dihydroorotase NAD+ NADH+H+ Orotate Orotate phosphoribosyl transferase PRPP PPi Orotidine monophosphate (OMP) Orotidylate decarboxylaseCO2 Uridine monophosphate (UMP) Kinase ATP Glutamine + ATP ADP UDP
- 5. Conversion of UDPto CTP and dTMP Uridine diphosphate (UDP) Kinase ATP ADP Uridine Triphosphate (UTP) Cytidine triphosphate (CTP) Glutamine ATP CTP Synthase Ribonucleotide reductase NADPH+H+ NADP+ H2O Deoxyuridine diphosphate (dUDP) H2O Pi Deoxyuridine monophosphate (dUMP) N5, N10- methylene THF THF Thymidylate synthase Deoxythymidine monophosphate (dTMP) Anticancer drugs blocks synthesis of dTMP ➢Thymidylate synthase &DHF reductase are the target enzyme in cancer chemotherapy ➢Flurodeoxy-uridylate inhibits TS ➢Aminopterine & methotrexate inhibits THF
- 6. Characteristics CPS-I CPS-II •Cellular location • Pathway involved • Source of Nitrogen • Allostric activator • Mitochondria • Urea Cycle • Ammonia • N-acetylglutamate (NAG) • Cytosol • Pyrimidine Synthesis • Glutamine • NAG does not activate
- 7. Regulation of denovo synthesis of Pyrimidine nucleotide CO2 + CPS- II Carbamoyl phosphate (CP) A. T Carbamoyl aspatate (CA) Glutamine + ATP UMP UTP CTP - - + + PRPP ATP
- 8. Salvage Pathway forPyrimidines Uridine cytidine kinase ATP ADP Uridine UMP ATP ADP Cytidine CMP Thymidine kinase ATP ADP Deoxythymidine TMP Deoxycytidine kinase ATP ADP Deoxycytidine dCMP
- 9. Unlike purines whichare catabolised to sparingly soluble product, uric acid. Pyrimidine are catabolism to highly water soluble compounds. These are… CO2 NH3 β-alanine and β-aminoisobutrate The reactions are as follows…… Degradation of Pyrimidine Nucleotides
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- 11. Since the endproduct of pyrimidine catabolism are highly water soluble, overproduction of pyrimidine catabolites is rarely associated with clinically significant abnormalities. Disorder Associated with Pyrimidine Metabolism
- 12. Orotic aciduria It isa hereditary disorder. It is results from defective in the multifunctional enzyme UMP synthase that converts orotic acid to UMP (in pyrimidine synthesis). Results in the excretion of orotic acid in the urine. UMP synthase is multifunctional enzyme containing both orotate PRTase & orotidylate decarboxylase activity. These are of two types…. Type I:- in this both enzymes are deficient. Type II:- in this only orotidylate carboxylase is deficient. The deficiency in UMP & other pyrimidine nucleotides results in inhibition of DNA & RNA synthesis. This causes megaloblastic anaemia & growth retardation. This can be treated by feeding cytidine and uridine.
- 13. Case study A 50year old female patient complains of pain and swelling in the joints and shows hyperuricemia. Name the probable disease. Name the enzyme defect. What is normal value of serum uric acid? Suggest nutritional therapy.
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