Pyrimidine pdf
- 1. METABOLISM OF PYRIMIDINE NUCLEOTIDES DR BAKHTAWAR FAROOQ MPHILL BIOCHEMISTRY NISHTER MEDICAL UNIVERSITY
- 4. Pyrimidine is a heterocyclic ring. Pyrimidine is first synthesized . Later, it is attached to ribose -5 phosphate
- 7. BIOSYNTHESIS OF PYRIMIDINE RIBONUCLEOTIDES The synthesis of pyrimidines is a much simpler process compared to that of purines. aspartate, gutamine and CO2 contribute to atoms in the formation of pyrimidine ring. Pyrimidine ring is first synthesized and then attached to ribose 5-phosphate. this is in contrast to purine nucleotide synthesis where in purine ring is built upon a pre-existing ribose5-phosphate.
- 9. 1.Formation of carbomyl phosphate: Carbomyl phosphate is formed from ATP, GLUTAMINE and CO2. The reaction is catalysed by CPS –II.
- 10. Differences between CPSI and CPSII : CPS I CPS II •SITE Mitochondria Cytoplasm •Pathway of Urea Pyrimidine •Positive Effector NAG ------ •Source for N Ammonia Glutamine •Inhibitor -------- CTP
- 11. 2. Condensation : Carbomyl phosphate condenses with aspartate to from carbomylaspartate, cataylsed by aspartate- transcarbomylase. Carbomyl phosphate +
- 12. 3. Ring closure: This occurs via loss of water. This reaction is catalysed by dihydroorotase, forming dihydroorotic acid.
- 13. 4. Dehydrogenation : Removal of hydrogen atoms from C5 and C6 , by dihydroorotate dehydrogenase.(mitochondrial).
- 14. 5.Transfer of ribose phosphate : This is transferred from PRPP, forming OMP(orotidylate), catalysed by orotate – phosphoribosyl transferase. PRPP PPI
- 15. 6.Decarboxylation: OMP is decarboxylated forming UMP. UMP is the first true pyrimidine ribonucleotide. co2
- 16. 7. Phosphorylation of UMP forms UDP and UTP , with help of ATP.
- 17. 8.Formation of CTP : UTP is aminated by glutamine and ATP, catalysed by CTP synthase.
- 18. 9.Reduction of ribonucleoside diphosphates to their corresponding dNDP’s .
- 19. 10.Formation of TMP from UDP: dUMP is substrate for TMP synthesis. dUDP is dephosphorylated to d UMP.
- 20. 11. Methylation of dUMP: This occurs at C5 by N5,N10methyleneTHF, forming TMP. This reaction is catalysed by Thymidylate synthase.
- 23. Salvage pathway The pyrimidines (like purines) can also serve as precursors in the salvage pathway to be converted to the respective nucleotides. This reaction is catalysed by pyrimidine phospshoribosyl transferase which utilizes PRPP as the source of ribose 5- phosphate.
- 24. SALVAGE PATHWAY OF PYRIMIDINE SYNTHESIS Pyrimidine base + PRPP pyrimidine phosphoribosyl transferase Pyrimdine nucleotide + PPi
- 25. Regulation of pyrimidine synthesis: •CPSII,aspartate transcarbomylase and dihydrooratase are present as multienzymecomplex. •Orotate phosphoribosyl transferase and OMP – decarboxylase are present as single functional enzyme. Due to clustering of these enzymes , the synthesis is well coordinated. •Dihydroorotate dehydrogenase is mitochondrial enzyme.
- 26. •(CPSII and aspartate transcarbomylase) And (OPRTransferase and OMP-decarboxylase) are sensitive to allosteric regulation. •CPSII is main regulatory enzyme in mammalian cells. •CPS II - inhibited by UTP . - activated by PRPP •Aspartate transcarbomylase : main regulatory enzyme in prokaryotes. - inhibited by CTP ;activated by ATP
- 27. • Requirement of ATP for CTP synthesis and stimulatory effect of GTP on CTP synthase ensures a balanced synthesis of purines and pyrimidines.
- 28. Degradation of pyrimidine nucleotides The pyrimidine nucleotides undergo similar reactions (dephosphorylation, deamination and cleavage of glycosidic bond) like that of purine nucleotides to liberate the nitrogenous bases cytosine, uracil and thymine. The bases are then degraded to highlyl soluble products β-alanine and β-aminoisobutyrate. These are the amino acid which undergo transamination and other reactions to finally produce acetyl CoA and succinyl CoA
- 31. Disorders of pyrimidine metabolism: 1.OROTIC ACIDURIA: Orotic aciduria type I – deficiency of Orotatephosphoribosyl transferase and OMP – decarboxylase. Orotic aciduria type II : Rare, deficeincy of ONLY OMP decarboxylase. Both types are inherited as autosomal recessive disorders.
- 32. Features : •Due to lack of feedback inhibition orotic acid production is excessive.(UMP inhibits OMP decarboxylase) •Rapidly growing cells are affected – anemia •Retarded growth •Crystals excreted in urine causing urinary obstruction. •Both types respond to uridine , as it is converted to UTP . This acts as feed back inhibitor.
- 34. Other causes of orotic aciduria: 1. Deficeincy of liver mitochondrial ornthine – trancarbomylase (X-linked). under utilised substrate carbomyl phosphate enters cytosol Stimulates pyrimidine nucleotide biosynthesis Leading to orotic aciduria
- 35. 2. Drugs may precipitate orotic aciduria: a)ALLOPURINOL , a purine analog is a substrate for Orotate phosphoribosyl transferase. It competes for phosphoribosylation with natural substrate, orotic aicd. The resulting nucleotide product inhibits OMP DECARBOXYLASE leading to Orotic aciduria and orotiduniria
- 36. Reye’s syndrome: This is considered as a secondary orotic aciduria. It is believed that a defect in ornithine trascarbamoylase (or urea cycle ) causes the accumulation of carbamoyl phosphate. This is then diverted for the increased synthesis and excretion of orotic acid.
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