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Synthesis of Pyrimidine Nucleotides

Synthesis of Pyrimidine Nucleotides. Dr. Shumaila Asim Lecture # 5. De-novo synthesis of Pyrimidines ( Uracil , Thymine & Cytosine). Biosynthesis of pyrimidines is simple than that of purines.

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Synthesis of Pyrimidine Nucleotides

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  1. Synthesis of Pyrimidine Nucleotides Dr. Shumaila Asim Lecture # 5

  2. De-novo synthesis of Pyrimidines (Uracil, Thymine & Cytosine) • Biosynthesis of pyrimidines is simple than that of purines. • Unlike purine synthesis, pyrimidines are synthesized as bases and latter it is added to ribose sugar, i.e., the ring is completed before being it is linked to ribose-5-phosphate.

  3. Synthesis of Pyrimidine Nucleotides • Precursors • Amino acids (Aspartate, Glutamine) • CO2 (from HCO3-) • Ribose-5-phosphate (HMP shunt & nucleosides) • Enzymes • Coenzymes and Cofactors • NAD+, NADPH, Mg++ • ATPs • Energy • PRPP formation

  4. Sources of Atoms of Pyrimidine Nucleus • N1, C6, C5 and C4 are derived from aspartate • N3 is derived from glutamine • C2 is derived from HCO3- (bicarbonate)

  5. Step-1:Synthesis of carbamoyl phosphate: With the hydrolysis of two ATP molecules, bicarbonate and amide nitrogen of glutamine combine to form carbamoyl phosphate in the presence of enzyme carbamoylphosphatesynthetase II. • Step-2: Synthesis of carbamoylaspartate: Carbamoyl phosphate reacts with aspartate to yield carbamoylaspartate catalyzed by the enzyme aspartatetranscarbamoylase (ATCase). • Step-3:Ring closure & dihydroorotate formation: By the elimination (condensation reaction) of one molecule of water, the carbamoylaspartate is converted to a ring compound – dihydroorotate catalyzed by dihydroorotase enzyme.

  6. Step-4: Oxidation of dihydroorotate: Dihydroorotate is dehydrogenated to form orotate with the enzyme dihydroorotatedehydrogenase. • Step-5: Acquisition of the ribose phosphate moiety: Orotate reacts with PRPP to produce orotidine-5′-monophosphate (OMP) with the enzyme orotatephosphoribosyl transferase. The anomeric form of pyrimidine nucleotides is fixed in in the β-configuration. • Step-6: Decarboxylation to form UMP:OMP undergoes decarboxylation with assistance of enzyme OMP decarboxylase (ODCase) to form uridinemonophosphate (UMP).

  7. Synthesis of CTP • CTP is synthesized by the amination of UTP by the enzyme CTP synthase. • In animals amino group is donated by glutamine whereas in bacteria, the amino group is donated directly by ammonia

  8. Synthesis of Thymine (5-methyluracil) as deoxyTTP: • Thymine, which is present in DNA and not in RNA, is a methylateduracil residue. • Thymine in the cell is synthesized as dTTP from dUMP by methylation in four steps. • Step-1: dUTP is hydrolyzed to dUMP and PPi by the enzyme dUTPdiphosphohydrolase (dUTPase) • Step-2: dUMP is then methylated to form dTMP • Step-3 & 4: dTMP is then phosphorylated with ATP in two rounds to form dTTP

  9. Regulatory Control of Pyrimidine Synthesis • Regulation at carbamoyl phosphate synthetase II • UDP and UTP inhibit enzyme; ATP and PRPP activate it • UMP and CMP competitively inhibit OMP Decarboxylase *Purine synthesis inhibited by ADP and GDP at ribose phosphate pyrophosphokinase step, controlling level of PRPP  also regulates pyrimidines

  10. Synthesis Of Pyrimidine Nucleotides By Salvage Pathway

  11. salvage of Uracil • The salvage of pyrimidine bases has less clinical significance than that of the purines, owing to the solubility of the by-products of pyrimidine catabolism. • Uracil can be salvaged to form UMP through the action of uridinephosphorylase and uridinekinase, as indicated: uracil + ribose-1-phosphate <——> uridine + Pi uridine + ATP ——> UMP + ADP

  12. salvage of Deoxyuridine • Deoxyuridine is also a substrate for uridinephosphorylase. • Formation of dTMP, by salvage of dTMP requires thymine phosphorylase and the previously encountered thymidinekinase: thymine + deoxyribose-1-phosphate <——> thymidine + Pi thymidine + ATP ——> dTMP + ADP

  13. salvage of deoxycytidine • The salvage of deoxycytidine is catalyzed by deoxycytidinekinase: deoxycytidine + ATP <——> dCMP + ADP • Deoxyadenosine and deoxyguanosine are also substrates for deoxycytidinekinase, although the Km for these substrates is much higher than for deoxycytidine.

  14. salvage of thymidine • The salvage pathway to dTTP synthesis involves the enzyme thymidinekinase which can use either thymidine or deoxyuridine as substrate: thymidine + ATP <——> TMP + ADP deoxyuridine + ATP <——> dUMP + ADP • The activity of thymidinekinase (one of the various deoxyribonucleotide kinases) is unique in that it fluctuates with the cell cycle, rising to peak activity during the phase of DNA synthesis; it is inhibited by dTTP.

  15. Synthesis of deoxyribonucleotides

  16. Summary of pyrimidine biosynthesis UMP

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