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Nucleotide metabolism

Chapter 10. Nucleotide metabolism. Function of neucleotides. Precursors for RNA and DNA synthesis Energy substance in body (ATP) Physiological Mediators (cAMP) Components of coenzymes (NAD + ) Allosteric effectors and donor of phosphate group (phosphorylation)

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Nucleotide metabolism

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  1. Chapter 10 Nucleotide metabolism

  2. Function of neucleotides • Precursors for RNA and DNA synthesis • Energy substance in body (ATP) • Physiological Mediators (cAMP) • Components of coenzymes (NAD+) • Allosteric effectors and donor of phosphate group (phosphorylation) • Formation of activated intermediates UDP-glucose, CDP-choline

  3. Section 10.2 Nucleotide Synthesis and Degradation

  4. Nucleoprotein Protein Nucleic acid Nucleases Nucleotide Nucleotidase Absorption Phosphate Nucleoside Nucleosidase Base Ribose Digestion and absorption of nucleotide Blood

  5. Metabolism of Purine nucleotides • Biosynthesis of purine nucleotides de novo synthesis salvage pathway AMP GMP

  6. CO2 Glycine Aspartate One carbon unit One carbon unit Glutamine 1.De novo synthesis of purine nucleotides

  7. Characteristics of de novo synthesis of purine nucleotides 1. in cytosol 2. form IMP first, then synthesize AMP and GMP from IMP. 3. formation of purines is based on the ribosyl group of 5’-phosphoribose

  8. AMP ATP PRPPK Gln Glutamine PRPP amidotransferase (GPRT) Glu AMP GMP PP-1-R-5-P（ 5’-phosphoribose 1’-pyrophosphate, PRPP） R-5-P （5’-phosphoribose） H2N-1-R-5´-P （5´-phosphoribosyl-amine） Gly, one carbon units, Gln, CO2, Asp involved step by step IMP

  9. AMP ATP PRPPK Gln Glutamine PRPP amidotransferase (GPRT) Glu AMP GMP PP-1-R-5-P（ 5’-phosphoribose 1’-pyrophosphate, PRPP） R-5-P （5’-phosphoribose） H2N-1-R-5´-P （5´-phosphoribosyl-amine） Gly, one carbon units, Gln, CO2, Asp involved step by step IMP

  10. _ _ _ + + R-5-P PRPPK GPAT IMP _ ATP GMP GTP XMP GDP _ Adenyl-succinate ADP ATP AMP _ + + _ Regulation of de novo synthesis of purine nucleotides PRPP PRA Adenyl-succinate GTP ATP AMP ADP IMP XMP GTP GMP GDP ATP

  11. 2. Salvage synthesis of purine nucleotides • Material: PRPP, purine (conjunction) nucleosides (phosphorylation) • Location: brain and bone marrow or

  12. APRT adenine+PRPP AMP + PPi HGPRT hypoxanthine+PRPP IMP + PPi HGPRT guanine+PRPP GMP + PPi Adenylate kinase adenosine AMP ATP ADP APRT: adenine phosphoribosyltransferase HGPRT: inosine-guanine phosphoribosyl transferase

  13. Degradation of purine nucleotides nucleotide nucleosides ribose-1-phosphate purine salvage pathway uric acid Nucleotidase Nucleoside phosphorylase

  14. IMP Neucleo-tidase Excretion

  15. Metabolsm of pyrimidine nucleotides • Biosynthesis of pyrimidine nucleotides de novo synthesis salvage pathway

  16. 1.De novo synthesis of pyrimidine nucleotides 4 Glutamine 3 5 Aspartate CO2 2 6 1

  17. Characteristics of de novo synthesis of pyrimidine nucleotides 1. mostly in cytosol 2. form UMP first, then synthesize other pyrimidine nucleotides from UMP. 3. in the synthesis of UMP, pyrimidine ring is formed first , then combined with PRPP.

  18. Process of de novo synthesis of UMP • 1. formation of Carbamoyl phsphate (CP) CO2 + glutamine + H2O + 2ATP Carbamoyl phosphate synthaseⅡ (CPSⅡ) O O~PO32- + 2ADP + Pi H2N C carbamoyl phosphate

  19. The diffirents between Carbamoyl phosphate synthaseⅠ,Ⅱ Mitochondria of liver cells cytosol of all cells Location Source of nitrogen NH3 Glutamine N-acetylglutamate None Activator Formation of pyrimidine Function Formation of urea

  20. O O~PO32- H2N C carbamoyl phosphate 2. Formation of UMP + Aspartate Carbamoyl aspartate Orotate PRPP UMP

  21. CTP synthase UMPK NDK ATP ADP Gln ATP ATP ADP Glu ADP dUDP dCMP dTMP dUMP TMP synthase 3. Synthesis of CTP, dTMP or TMP UDP UTP

  22. + - - Purine nucleotides + - Pyrimidine nucleotides Regulation of de novo synthesis of pyrimidine nucleotides ATP + CO2+ glutamine • Activated by substrates • Inhibited by products Carbamoyl phosphate - aspartate Carbamoyl aspartate ATP + 5-phosphate ribose PRPP UMP UTP CTP -

  23. Uracil phosphate ribosyltransferase Uracil +PRPP UMP+ PPi Uridine kinase Uracil ribonucleoside + ATP UMP +ADP Uridine phosphorylase Uracil+ 1-phosphoribose UMP +ADP Salvage pathway of pyrimidine nucleotides

  24. Degradation of pyrimidine nucleotides nucleotide nucleosides phosphoribose pyrimidine Nucleotidase Nucleoside phosphorylase

  25. Thymine β-ureidoisobutyrate H2O β-aminoisobutyrare Excreted in urine Succinyl CoA TAC Glucose Cytosine NH3 Uracil dihydrouracil H2O + + CO2 + NH3 β-alanine liver Acetyl CoA Urea TAC

  26. dNDP NDP Deoxyribonucleotide biosynthesis Ribonucleotide reductase kinase dNDP+ATP dNTP + ADP

  27. Kinase Kinase ATP ADP ATP ADP Kinase Kinase XMP XDP XTP YTP YDP YTP YDP Biosynthesis of NDP and NTP AMP ADP ATP

  28. Section 10.3 Dysmetabolism of nucleotides and antimetabolites

  29. Dysmetabolism of nucleotides • Caused by the genetic defect or regulatory abnormality of some enzymes participating nucleotide metabolism. Gout：pain and tenderness, redness, warmth, and swelling in some joints Causes：too much uric acid forms crystals in joints and cause inflammation

  30. Antimetabolites • The analogs of ribonucleotide metabolite intermediates synthesized artificially. • Can interfere, inhibit and block the ribonucleotide metabolism. • Used as drugs.

  31. Hypoxanthine • Purine ribonucleotide metabolite analogs 6-mercaptopurine(6-MP) • Pyrimidine ribonucleotide metaboliteanalogs : 5-fluorouracil(5-FU), (6-MP) (T) (5-FU)

  32. Amino acid analogs azaserine(AS) • Folic acid analogs methotrexate(MTX) • Nucleoside analogs: arabinosyl cytosine(ara-c), cyclo-cytidine(cyclo-c) • Metabolite analogs applied to ribonucleotide reductase hydroxyurea(HU)

  33. NAD+ AMP

  34. Lipid metabolism • Lipolysis, β-Oxidation (Ketone Bodies), degradation of glycerophospholipids, cholesterol key enzymes, main steps, products • synthesis of palmitic acid, triacylglycerols, glycerolphospholipids, cholesterol key enzymes, main steps, material

  35. Essential Fatty Acids, lipoproteins (classification, function) , HSL • Hyperlipoproteinemia, hypercholesterolemia, • ketonemia, ketonuria, ketoacidosis • reason or mechanism.

  36. Protein catabolism • Nitrogen Balance, Essential Amino Acids , Complementary effect, Putrefaction, Amino acid metabolic pool, Ketogenic amino acids, Ketogenic and glucogenic amino acids. • Digestion of dietary proteins, degradation of protein, deamination, decarboxylation key enzymes, main pathway, main products • ALT, AST(function)

  37. SAM, PAPS, GSH, Dopamine , creatine phosphate (function, formation) • Ammonia, One Carbon Units • carrier, source, utilization • Hyperammonemia, PUK, Albinism • damage, mechanism

  38. Nucleotide metabolism • Function of neucleotides • de novo synthesis of purine and pyrimidine nucleotides material, character, main steps, • Salvage pathwayof purine and pyrimidine • Degradationof purine and pyrimidine nucleotides products • Deoxyribonucleotide biosynthesis

  39. Homework • Explain the following concepts: Essential Amino Acids, Lipolysis Amino acid metabolic pool lipoproteins • Simple questions: 1. describe the source, transport and metabolic pathway of ammonia. 2. what do you know about ketoacidosis?

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