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Metabolism of nucleotides
This document summarizes metabolism of nucleotides. It discusses that nucleotides containing purine and pyrimidine bases are essential for life as they are required for DNA and RNA synthesis. Nucleotides can be taken in through diet or synthesized endogenously in the body. The document describes the pathways for de novo synthesis and salvage pathways for purine and pyrimidine nucleotides. It also discusses the regulation and catabolism of purine and pyrimidine nucleotides.
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Metabolism of nucleotides
- 1. Metabolism of Nucleotides R.C. Gupta Department of Biochemistry National Institute of Medical Sciences Jaipur, India
- 2. Nucleotides containing purineand pyrimidine bases are essential for life They are required for the synthesis of DNA and RNA Many nucleotides, e.g. ATP, cAMP, cGMP etc, perform other important functions
- 3. Nucleotides are bothtaken in diet and are synthesized in the body Dietary nucleotides cannot be used in our body We are dependent exclusively on endogenously synthesized nucleotides
- 4. In food, nucleotidesare present mainly in the form of nucleoproteins The protein part is degraded by proteolytic enzymes in the GIT The nucleic acids are hydrolysed by nucleases Digestion
- 5. DNA is hydrolysedby deoxyribonuclease and RNA by ribonuclease Polynucleotidases hydrolyse small poly- nucleotides into mononucleotides Nucleotidases hydrolyse nucleotides into nucleosides and phosphate
- 6. Nucleosides are absorbedby mucosal cells of intestine They are broken down to their final end products in intestinal mucosal cells The end products are released into circulation, and are excreted in urine
- 7. Synthesis of nucleotides Onlyendogenously synthesized purine and pyrimidine nucleotides are used for various purposes in our body There are two pathways for the synthesis of nucleotides: • De novo synthesis • Salvage pathway
- 8. De novo synthesis Nucleotides aresynthesized afresh from amphibolic inter- mediates Bases or nucleosides released from catabolism of pre-existing nucleic acids and nucleotides are reutilized Salvage pathway
- 9. The salvage pathwayis energy-efficient It prevents wastage of raw materials
- 10. Liver is themajor site for de novo synthesis of purine nucleotides Synthesis can occur in several other tissues The synthesis occurs in the cytosol De novo synthesis of purine nucleotides
- 11. Different carbon andnitrogen atoms are provided by: Glycine Glutamine Aspartate Carbon dioxide Single-carbon moiety carried by tetrahydrofolate
- 12. The nitrogen atposition 1 is provided by aspartate Carbon 2 comes from N10-formyltetra- hydrofolate Nitrogen 3 and nitrogen 9 come from the amide group of glutamine
- 13. Carbon atoms 4and 5, and the nitrogen atom at position 7 are provided by glycine Carbon 6 comes from carbon dioxide Carbon 8 is provided by N5,N10-methenyl tetrahydrofolate
- 15. The first reactionis formation of 5- phosphoribosyl-1-pyrophosphate (PRPP) PRPP is required for the synthesis of pyrimidine nucleotides also By a series of reactions, PRPP is converted into inosine monophosphate
- 22. AMP and GMPare converted into ADP and GDP respectively by nucleoside monophosphate kinase ADP and GDP are converted into ATP and GTP respectively by nucleoside diphosphate kinase Formation of ATP and GTP
- 24. PRPP synthetase catalysesthe first reaction of de novo synthesis It is an allosteric enzyme It is inhibited by AMP, ADP, GMP and GDP Regulation of de novo synthesis
- 25. PRPP synthetase isnot unique to purine nucleotide synthesis PRPP is required for the synthesis of pyrimidine nucleotides as well Therefore, PRPP synthetase is not the main regulatory enzyme
- 26. PRPP glutamyl amidotransferase catalysesthe first reaction unique to purine nucleotide synthesis This is the main regulatory enzyme It is allosterically inhibited by GMP
- 27. Synthesis of adenineand guanine nucleo- tides is cross-regulated Conversion of IMP into AMP requires GTP; conversion of IMP into GMP requires ATP This ensures a balanced production of AMP and GMP
- 28. Conversion of IMPinto AMP and GMP is also regulated by allosteric mechanism AMP is an allosteric inhibitor of adenylo- succinate synthetase Similarly, GMP is an allosteric inhibitor of IMP dehydrogenase
- 29. Pre-existing purine basesand nucleosides may be salvaged to form new nucleotides Conversion of purine bases into nucleotides is catalysed by two enzymes: Synthesis of purine nucleotides by salvage pathway Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) Adenine phosphoribosyl transferase (APRT)
- 30. APRT acts onadenine HGPRT acts on hypoxanthine and guanine These enzymes transfer a phosphoribosyl group to their substrates PRPP provides the phosphoribosyl group
- 32. Purine nucleosides maybe salvaged by adenosine kinase and deoxycytidine kinase Adenosine kinase acts on adenosine and deoxyadenosine Deoxycytidine kinase acts on deoxyadeno- sine, deoxyguanosine and deoxycytidine
- 34. The salvage pathwayis regulated mainly by the availability of PRPP The available PRPP is used primarily for salvage reactions, and secondarily for de novo synthesis Regulation of salvage pathway
- 35. The sites ofcatabolism are intestinal mucosa, liver and kidneys The dietary purines are catabolized in intestinal mucosa Purines synthesized endogenously are catabolized in liver and kidneys Catabolism of purines
- 36. The pathway ofpurine catabolism is similar in all the tissues Adenosine and guanosine are the substrates for the catabolic enzymes The end product of purine catabolism is uric acid
- 37. N N N | Ribose N Adenosine deaminase H2O NH3 NH2 Adenosine 6PiRibose-1-P Inosine Purine nucleoside phosphorylase Hypoxanthine O2 + H2O Xanthine oxidase XanthineUric acid H2O2 N HN N H N O III Ribose N HN N N O II O O N H HN N H H N O II O N H HN N H N O II 6 6 O2 + H2O Xanthine oxidase H2O2 6 6
- 38. Guanosine Guanase Guanine O2 + H2O Xanthine oxidase XanthineUric acid H2O2 Pi Ribose-1-P Purinenucleoside phosphorylase O O N H HN N H H N O II O N H HN N H N O II 6 6 H2N I Ribose N HN N N O II H2N N HN N H N O II H2O NH3
- 39. Uric acid isreleased from tissues into circulation Circulating uric acid is excreted in urine
- 40. In some species,uric acid is the end product of protein catabolism as well These species include amphibians, birds and reptiles Uric acid is the main vehicle for excretion of nitrogenous waste in these organisms Such organisms are said to be uricotelic
- 41. In many organisms,including man, urea is the major form of nitrogenous waste Such organisms are said to be ureotelic
- 42. De novo synthesisof pyrimidines occurs in several tissues The pathway is located in cytosol with the exception of one reaction The exception is synthesis of orotate, which occurs in mitochondria De novo synthesis of pyrimidine nucleotides
- 43. The first reactionin de novo synthesis is formation of carbamoyl phosphate It is formed from glutamine, CO2 and ATP
- 44. Formation of carbamoylphosphate is also the first reaction in synthesis of urea But this reaction occurs in mitochondria in urea cycle The amino group comes from ammonia instead of glutamine
- 46. Carbamoyl aspartate H2N O || HO−C CH2 CHC O COOHN H Carbamoyl phosphate Carbamoyl grouptransferred to aspartate Second reaction Aspartate transcarbamoylase PiO~ NH2 I C O COOH CH2 CH−NH2 COOH Aspartate
- 48. Dihydro-orotate Orotate N H HN O || C CH CC O HN O || C CH2 CHC O COOHN H COOH Dihydro-orotate dehydrogenase NADH+H+NAD+ Dihydro-orotateoxidized to orotate Fourth reaction
- 51. UMP is thefirst pyrimidine nucleotide to be formed Cytidine and thymidine nucleotides are formed from UMP For the formation of cytidine nucleotides, the amino group is provided by glutamine
- 52. First, UMP isconverted into UDP, and UDP into UTP The 4-oxy group is replaced by amino group to form CTP
- 54. Thymidine nucleotides occuronly in DNA The sugar in thymidine nucleotides is deoxyribose The synthesis occurs from UDP Thymidylate
- 55. The ribose residueof UDP is reduced to deoxyribose by ribonucleotide reductase Deoxyuridine diphosphate (dUDP) is dephosphorylated to dUMP dUMP is methylated to form dTMP (also termed TMP) by thymidylate synthetase
- 56. The methyl groupis provided by N5, N10- methylene-H4-folate During this reaction: Methylene group is reduced to methyl group Tetrahydrofolate is oxidised to dihydrofolate
- 58. For continued synthesisof TMP, dihydro- folate has to be reduced to tetrahydrofolate This reaction is catalysed by dihydrofolate reductase Amethopterin and aminopterin are competitive inhibitors of this enzyme They inhibit TMP synthesis and decrease cell division
- 59. Regulation occurs byallosteric mechanism The regulatory enzymes are: Carbamoyl phosphate synthetase Aspartate transcarbamoylase Regulation of de novo synthesis
- 60. Carbamoyl phosphate synthetaseis activated by PRPP, and inhibited by UTP Aspartate transcarbamoylase is inhibited by CTP
- 61. Human beings lackenzymes that can salvage free pyrimidine bases However, pyrimidine nucleosides can be salvaged and used for nucleotide synthesis Synthesis of pyrimidine nucleotides by salvage pathway
- 62. Uridine and cytidineare phosphorylated by a common enzyme, uridine-cytidine kinase Thymidine (deoxythymidine) is phospho- rylated by thymidine kinase Deoxycytidine is phosphorylated by deoxy- cytidine kinase
- 65. Deoxyribonucleotides are requiredfor DNA synthesis They are synthesized from ribonucleotides Formation of deoxyribonucleotides
- 66. Formation of deoxyribo- nucleotidesrequires: Ribonucleotide reductase Thioredoxin (a protein having two sulphydryl groups) Thioredoxin reductase (a flavoprotein)
- 67. Ribose residue reactswith the sulphydryl groups of thioredoxin Ribonucleotide reductase removes an oxygen atom from ribose and two hydrogen atoms from thioredoxin as water Thioredoxin is oxidized in this reaction
- 68. Oxidised thioredoxin isreduced by thioredoxin reductase The hydrogens atom are provided by NADPH
- 70. This enzyme systemcan act on ADP, GDP, CDP and UDP The products are dADP, dGDP, dCDP and dUDP dADP is the inhibitor of this reaction while ATP is its activator
- 71. Catabolism of pyrimidines Cytosineand uracil are catabolised to b- alanine, carbon dioxide and ammonia b-Alanine may be utilized in the body or is excreted in urine
- 73. Thymine is catabolisedto b-aminoiso- butyrate, carbon dioxide and ammonia b-Aminoisobutyrate is excreted in urine Ammonia released from pyrimidines and purines is disposed off as urea