Synthesis of Pyrimidines and Purines.pptx

MBBS, BDS, NURSING STUDENTS

1. Purines and Pyrimidine Metabolism Dr. Apeksha Niraula Assistant Professor Institute of Medicine TUTH Maharajgunj

2. Your Text here Nucleotides: ---- Nitrogenous Base ---- Pentose Monosachharides ---- One/Two or Three Phosphate Groups Nitrogeneous Bases PURINES PYRIMIDINES

3. Purine and Pyrimidine Structure Both DNA and RNA contain the same Purine bases : Adenine (A) and Guanine (G) Both DNA and RNA contain the same Pyrimidine structure cytosine (C), differ in their second Thymidine base : DNA contains Thymine (T) RNA contains Uracil (U) Nucleosides: Addition of Pentose sugar to a base through a Glycosidic bond produces a Nucleoside. E.g : Ribonucleoside,Deoxyribonucleoside .

4. Functions Participate in metabolic functions as diverse as energy metabolism , protein synthesis , regulation of enzyme activity, and signal transduction. Linked to vitamins or vitamin derivatives, nucleotides form a portion of many coenzymes. ATP and ADP are the principal players in the energy transductions that accompany metabolic interconversions and oxidative phosphorylation. Cyclic nucleotides cAMP and cGMP serve as the second messengers in hormonally regulated events. Medical applications : Use of synthetic purine and pyrimidine analogs that contain halogens, thiols , or additional nitrogen atoms in the chemotherapy of cancer and AIDS, and as suppressors of the immune response during organ transplantation.

5. Can Cells Synthesize Purine Nucleotides?? Nearly all organisms synthesize purines and pyrimidines “denovo biosynthesis Pathway“. Many Organisms also “Salvage "purines from diet and degradative pathways

6. Your Text here How do Cells synthesize the Purine Nucleotides??

7. Synthesis of Purine Nucleotides denovo Synthesis Total Ten Steps in synthesis of Purine Nucleotide. Salvage Pathway

8. Synthesis of 5-Phosphoribosyl -1-pyrophosphate

9. Synthesis of 5-Phosphoribosylamine Committed step in Purine Synthesis.

10. C. Synthesis of Inosine Monophosphate, the “PARENT’ Purine Nucleotide Next Nine steps in Purine biosynthesis leads to formation of Inosine Monophosphate(IMP). Four Steps require ATP as an energy source and two steps in the pathway require N 10 -formyltetrahydrofolate as a one carbon donor.

11. Synthesis of Adenosine and Guanosine Monophosphate Two step Energy-requiring pathway. Synthesis of AMP requires GTP and Synthesis of GMP requires ATP Cross Regulation

12. Inosine monophosphate (IMP)

13. If both AMP and GMP are present in adequate amounts, the de-novo pathway of purine synthesis is TURNED OFF at the Amidotransferase step.

14. Synthetic Inhibitors of Purine Synthesis Sulfonamides Methotrexate Designed to inhibit the growth of rapidly dividing microorganisms without interfering with human cell functions.

15. How is Pyrimidine synthesized???? In contrast to Purine ring, Pyrimidine ring is completed before the addition of 5-ribose Phosphate. Carbamoyl Phosphate and Aspartate are the precursors of the Six-membered Pyrimidine Ring.

16. A. Synthesis of Carbomyl Phosphate Glutamine + CO 2 C Carbomyl Phosphate Synthetase II Regulated Step in this pathway. Carbomyl Phosphate

17. Your Text here Lorem ipsumconsectetuer CPS I CPS II Cellular Location Mitochondria Cytosol Pathway Involved Urea Cycle Pyrimidine Synthesis Source of Nitrogen Ammonia Glutamine Regulators Acivator : N-acetyl- Glutamate Activator :PRPP Inhibitor : UTP Comparison between CPS I and CPS II

18. B. Synthesis of Orotic Acid Second Step Formation of CarbomylAspartate .

19. C. Formation of a Pyrimidine Nucleotide Orotidine Monophosphate(OMP) Parent Pyrimidine mononucleotide formed from Completed Pyrimidine ring. OMP Orotidylate Decarboxylase Uridine Monophosphate (UMP) removes carboxylic group. Orotate Phosphoribosyltransferase and Orotidylate Decarboxylase are also catalytic domains of a single Polypeptide chain called UMP Synthase.

20. Orotic Aciduria Deficiency of one or both activities of the Bifunctional Enzyme Orotic Acid in Urine. UMP thus formed is converted to UDP and UTP.

21. Synthesis of Cytidine Triphosphate UTP Amination Cytidine Triphosphate (CTP)

22. Your Text here Lorem ipsumconsectetuer E. Synthesis of Deoxythymidine Monophosphate dUMP Thymidylate synthase dTMP

23. Salvage Pathways for Pyrimidine and Purine Bases Denovo Synthesis of Nucleotides is Expensive in terms of the use of high-energy phosphate bonds esp. for Purine biosynthesis. All tissues are not capable of denovo synthesis of Purine nucleotides such as Erythrocytes, Neutrophils, Brain cells They lack PRPP Amido transferase

24. Purine Salvage Pathway Two Pathways available. One step Synthesis Formation of GMP and IMP Hypoxanthine Guanine Phosphoribosyltransferase (HGPRT) catalyzes the One step nucleotide formation from either Guanine or Hypoxanthine using PRPP as the donor of ribosyl moiety. Guanine Similarly, Hypoxanthine PRPP HGPRT HGPRT GMP + PPi Inosine + PPi

25. II. Two Step Synthesis Nucleoside Phosphorylase- Nucleoside kinase pathway. Adenine + Ribose-1-P Nucleoside Phosphorylase Adenosine + Pi ATP Adenosine Kinase AMP + ADP Neither Guanosine nor Inosine Kinase has been detected in mammalian cells.

26. In addition to the above cycle, there is another salvage cycle for purines GMP, IMP as well as their deoxyribonucleotides which is converted to their respective nucleosides by a PURINE-NUCLEOTIDASE Enzyme

27. Lesch-Nyhan syndrome: Rare, X-linked, recessive disorder. Virtually complete deficiency of HGPRT. Results in an inability to salvage hypo -xanthine or guanine, from which excessive amounts of uric acid is produced. Lack of the salvage pathway causes increased PRPP levels and decreased IMP and GMP levels. Denovopurine synthesis is increased.

28. A combination of decreased purine reutilization and increased purine synthesis results in increased degradation of purines and the production of large amounts of uric acid, making Lesch-Nyhan a heritable cause of hyperuricemia Hyperuricemia frequently results in the formation of uric acid stones in the kidneys (urolithiasis) and the deposition of urate crystals in the joints (gouty arthritis) and soft tissues Syndrome is also characterized by motor dysfunction, cognitive deficits, and behavioral disturbances that include self-mutilation (biting of lips and fingers)

29. Pyrimidine Base Salvage Pyrimidine Phosphoribosyl Transferase catalyses the formation of Pyrimidine Nucleotide using PRPP. Pyrimidine Base PRPP Pyrimidine Phosphoribosyl Transferase Pyrimidine Nucleotide + PPi

30. Your Text here Lorem ipsumconsectetuer Q. The rate of DNA synthesis in a culture of cells could be most accurately determined by measuring the incorporation of which of the following radiolabeled compounds? A. Adenine. B. Guanine. C. Phosphate. D. Thymidine.

31. Your Text here Lorem ipsumconsectetuer Q. A 1-year-old female patient is lethargic, weak, and anemic. Her height and weight are both low for her age. Her urine contains an elevated level of orotic acid. The administration of which of the following compounds is most likely to relieve her symptoms? A. Adenine. B. Guanine. C. Hypoxanthine. D. Thymidine. E. Uridine .

32. Your Text here Lorem ipsumconsectetuer