1. Nucleotide metabolism Chapter 10

2. Function of neucleotides  Precursors for RNA and DNA synthesis  Energy substance in body (ATP)  Physiological Mediators (cAMP)  Components of coenzymes (NAD + ) 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. Digestion and absorption of nucleotide Nucleoprotein ProteinNucleic acid Nucleases Nucleotide Nucleotidase PhosphateNucleoside Nucleosidase Base Ribose Absorption Blood

5. Metabolism of Purine nucleotides  Biosynthesis of purine nucleotides de novo synthesis salvage pathway GMPAMP

6. 1.De novo synthesis of purine nucleotides CO 2 Glycine One carbon unit Glutamine Aspartate

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. R-5-P （ 5’-phosphoribose ） ATPAMP PRPPK Gly, one carbon units, Gln, CO 2, Asp involved step by step IMP AMP GMP H 2 N-1-R-5´-P （ 5´-phosphoribosyl-amine ） Gln Glu Glutamine PRPP amidotransferase (GPRT) PP-1-R-5-P （ 5’- phosphoribose 1’- pyrophosphate, PRPP ）

9. R-5-P （ 5’-phosphoribose ） ATPAMP PRPPK Gly, one carbon units, Gln, CO 2, Asp involved step by step IMP AMP GMP H 2 N-1-R-5´-P （ 5´-phosphoribosyl-amine ） Gln Glu Glutamine PRPP amidotransferase (GPRT) PP-1-R-5-P （ 5’- phosphoribose 1’- pyrophosphate, PRPP ）

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

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

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

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

15. IMP Neucleo -tidase Excretion

16. Metabolsm of pyrimidine nucleotides  Biosynthesis of pyrimidine nucleotides de novo synthesis salvage pathway

17. 1.De novo synthesis of pyrimidine nucleotides Aspartate Glutamine CO 2 1 5 4 3 6 2

18.  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.

19. Process of de novo synthesis of UMP  1. formation of Carbamoyl phsphate (CP) CO 2 + glutamine + H 2 O + 2ATP C O H2NH2N O ~ PO 3 2- + 2ADP + Pi carbamoyl phosphate Carbamoyl phosphate synthase Ⅱ (CPS Ⅱ )

20. The diffirents between Carbamoyl phosphate synthase Ⅰ, Ⅱ Location Source of nitrogen Activator Function NH 3 Glutamine NoneN-acetylglutamate Mitochondria of liver cells cytosol of all cells Formation of urea Formation of pyrimidine

21. C O H2NH2N O ~ PO 3 2- carbamoyl phosphate + Aspartate Carbamoyl aspartate PRPP Orotate UMP 2. Formation of UMP

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

23. Regulation of de novo synthesis of pyrimidine nucleotides ATP + CO 2 + glutamine Carbamoyl phosphate UMP Carbamoyl aspartate UTP CTP aspartate ATP + 5-phosphate ribose PRPP Pyrimidine nucleotides - + - - - Purine nucleotides - + 1.Activated by substrates 2.Inhibited by products

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

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

26. Cytosine NH 3 Uracil dihydrouracil H 2 O CO 2 + NH 3 β-alanine Thymine β-ureidoisobutyrate H2OH2O Acetyl CoA TAC liver Urea ++ β-aminoisobutyrare Succinyl CoA TACGlucose Excreted in urine

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

28. Biosynthesis of NDP and NTP AMPADPATP ADPATP Kinase ADPATP Kinase XMP XDP XTP YDPYTP Kinase YDPYTP Kinase

29. Section 10.3 Dysmetabolism of nucleotides and antimetabolites

30. 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

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

32.  Purine ribonucleotide metabolite analogs 6-mercaptopurine(6-MP)  Pyrimidine ribonucleotide metabolite analogs : 5-fluorouracil(5-FU), Hypoxanthine (6-MP) (T)(5-FU)

33.  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)

34. NAD + AMP

35. 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

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

37. 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)

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

39. Nucleotide metabolism  Function of neucleotides  de novo synthesis of purine and pyrimidine nucleotides material, character, main steps,  Salvage pathway of purine and pyrimidine  Degradation of purine and pyrimidine nucleotides products  Deoxyribonucleotide biosynthesis

40. 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?