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Similar to Topic reciprocal regulation of purine and pyrimidine metabolism
Topic reciprocal regulation of purine and pyrimidine metabolism
- 1. TOPIC:RECIPROCAL REGULATION OFPURINE AND PYRIMIDINE METABOLISMPRESENTER:DR. J. KISHORE PHUKANPGT,BIOCHEMISTRY
- 2. INTRODUCTIONPurine and pyrimidineare nitrogenous bases.Purine base contains adenine, guanine and hypoxanthine.Pyrimidine base contains cytosine, uracil and thymine.Nucleoside consists purine/pyrimidine base and ribose/deoxyribose.Nucleotide consistspurine/ pyrimidine base ribose/deoxyribose and phosphates.
- 3. INTRODUCTIONPurinesand pyrimidinesconstitute aclass of nitrogen containing heterocycles of major biologic importance.The biosynthesis ofpurineand pyrimidine are precisely regulated events coordinated by feedback mechanisms that ensure their production in appropriate quantities and at times appropriate to varying physiologic demand (eg. Cell division).Purine andpyrimidinebiosynthesis are coordinately regulated through PRPP( phosphoribosyl pyrophosphate).
- 4. INTRODUCTIONHuman diseases thatinvolve abnormalities in purinemetabolism include gout, lesch-nyhan syndrome, adenosinedeaminase deficiency and purine nucleoside phoshorylasedeficiency(PNP).Diseases of pyrimidine metabolism are more rare and include oroticacidurias. The products of pyrimidine catabolism are highly soluble (carbon dioxide, βalanin,andβ amino isobutyrates). There are fewer clinically significant disorders of pyrimidine metabolism.
- 5. REGULATION OF PURINEMETABOLISMInosinemonophosphate(IMP) is the parent nucleotide of purine from which both AMP and GMP are formed.Synthesis of IMP from the amphibolic intermediate such as glycine, glutamine,tetrahydrofolatederivatives, aspartate and ATP. The pathway then branches , one path leading from IMP to AMP, the other from IMP to GMP.
- 6. REGULATION OF PURINEMETABOLISMPhosphoribosyl Pyrophosphate (PRPP) pool size regulates purine nucleotide biosynthesis.The major determinant of the overall rate of the de-novo purine nucleotide (AMP and GMP) biosynthesis is the concentration of PRPP.
- 7. REGULATION OF PURINEMETABOLISMConcentration of PRPP reflects the relatives rate of PRPP synthesis , utilization and degradation.The enzyme PRPP synthaseis sensitive both to phosphate concentration and to the purineribonucleotides(AMP and GMP) that act as its allosteric regulators.
- 8. REGULATION OF PURINE METABOLISMATPAMPα-D-ribosePRPP synthase5-phosphatePRPP Mg₂⁺Rate of PRPP synthesis depends on ribose-5-phosphate and on the activity of PRPP synthase.
- 9. REGULATION OF PURINEMETABOLISMAMP and GMP feedback regulate PRPP glutamylamidotransferase glutamine glutamateH₂OPPiPRPP5-phospho β-D PRPP glutamylamidotransferaseribosylamine * The committed step in purine nucleotide biosynthesis is the conversion of PRPP into phosphoribosylamine by PRPPglutamylamidotransferase.
- 10. REGULATION OF PURINEMETABOLISMPRPP glutamylamidotransferaseis feedback inhibited by purine nucleotide particularly AMP and GMP, the final products of the pathway which inhibit competitively with PRPP. InosineMonophosphate(IMP) is the branch point in the synthesis of AMP and GMP.
- 11. REGULATION OF PURINEMETABOLISMAMP and GMP feedback regulate their formation from IMP.AMP inhibits the enzyme adenylosuccinatesynthasewhich involves the conversion of inosinate (IMP) into adenylosuccinate.Adenylosuccinate is a immediate precursor of AMP biosynthesis.
- 12. REGULATION OF PURINEMETABOLISMGMP inhibits the enzyme IMP dehydrogenase which involves in conversion inosinate (IMP) into xanthylate (XMP).Xanthylate( XMP) is a immediate precursor of GMP biosynthesis.
- 13. REGULATION OF PURINEMETABOLISMGTP is a substrate in the synthesis of AMP, whereas ATP is a substrate in the synthesis of GMP.This reciprocal substrate relation tends to balance the synthesis of adenine and guanineribonucleotide.
- 14. REGULATION OF PURINEMETABOLISM
- 15. REGULATION OF PURINEMETABOLISM
- 16. REGULATION OF PYRIMIDINEMETABOLISMBiosynthesis of pyrimidine(UMP and CMP)from the amphibolic intermediate such as PRPP, glutamine, carbon dioxide, aspartate, and for thymine nucleotides, tetrahydropholate derivatives.The activities of the first enzyme i.e, carbamoyl phosphate synthase ii of pyrimidine nucleotide biosynthesis is controlled by allosteric regulation.
- 17. REGULATION OF PYRIMIDINEMETABOLISMCO₂ (—) +carbamoyl phosphate synthase iiglutaminecarbamoylcarbamoyl+(—)ATP (+)PRPP phosphataspartate ATP (—)GTPUMP UDP UTP *carbamoyl phosphate synthase ii is inhibited by UTP and purine nucleotide particularly ATP and GTP. *carbamoyl phosphate synthase ii is activated by PRPP.
- 18. REGULATION OF PYRIMIDINEMETABOLISMThe activity of the second enzyme i.e, Aspartatetranscarbamoylase (ATCase) of pyrimidine nucleotide biosynthesis are controlled by allosteric regulation. (—) AspartateAspartatetranscarbamoylase +carbamoylaspartatecarbamoyl(+)ATP UMP UDP UTP phosphateCTP
- 19. REGULATION OF PYRIMIDINEMETABOLISMAspartatetranscarbamoylaseis inhibited by the CTP, the final product of pyrimidine biosynthesis and stimulated by ATP.The first three enzyme i.e, carbamoyl phosphate synthaseii,aspartatetranscarbamoylaseanddihydro-orotaseand the last two enzymes i.e,OPRTase and OMP decarboxylaseof the pyrimidine biosynthesis pathways are regulated by co-ordinate repression and derepression
- 20. REGULATION OF PYRIMIDINEMETABOLISM
- 21. REGULATION OF DEOXYRIBONUCLEOTIDESMETABOLISMThe synthesis of deoxyribonucleotides is controlled by the regulation of ribonucleotide reductase.The reduction ofribonucleotidesto deoxyribonucleotidesis precisely controlled by allostericinteractions. ADP (—) dADPdATPGDPribonucleotide reductasedGDPdGTPUDPdUDPTTPCDP(+)ATP dCDPdCTP
- 22. REGULATION OF DEOXYRIBONUCLEOTIDETheoverall catalytic activity of ribonucleotide reductase is diminishedby the binding of dATP, which signals an abundance of deoxyribonucleotidesThe overall catalytic activity of ribonucleotide reductase is stimulatedby the binding of ATP for the production of deoxyribonucleotides.
- 23. REGULATION OF DEOXYRIBONUCLEOTIDEThe binding of dATP or ATP to the substrate specificity control site enhances the reduction of UDP and CDP todUDPand dCDPrepectively.ADPdADPdATP (ATP) (+)GDPdGDPdGTP(+)(—)UDPdUDPTTP (+) (—)CDPdCDPdCTP (+)
- 24. REGULATION OF DEOXYRIBONUCLEOTIDEThebinding of thymidinetriphosphate (TTP) promotes the reduction of GDP and inhibits the further reduction of pyrimidineribonucleotides particularly UDP and CDP.The subsequent increase in the level of dGTP stimulates the reduction of ATP to dATP.This complex pattern of regulation supplies the appropriate balance of the four deoxyribonucleotidesneeded for the synthesis of DNA.
- 25. Purine and pyrimidinenucleotide biosynthesis are co-ordinately regulated.Every mole of purine biosynthesis parallels with every mole of pyrimidine nucleotide biosynthesis.PRPP is synthesized by the enzyme PRPP synthase.PRPP forms a precursor essential for both purine and pyrimidine biosynthesis process.
- 26. The synthesis ofPRPP by the enzyme PRPP synthaseis inhibited by feedback mechanism by bothpurine(AMP and GMP) and pyrimidine (UMP and CMP) nucleotides.There is requirement of ATP for CTP formation and there is stimulatory effect of GTP on CTP synthetasefor CTPformation from UTP.By these effects ensure a balanced synthesis ofpurineand pyrimidine.