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Nucleotides metabolism

Nucleotides metabolism. 【 目的与要求 】. 记住嘌呤核苷酸有 两条 合成途径。结合嘌呤核苷酸结构与从头合成途径，说出嘌呤核苷酸各元素或组件的 材料来源 。熟记二磷酸核苷还原生成脱氧嘌呤核苷酸。写出与嘌呤核苷酸补救合成有关的酶的名称、功能、酶缺陷相关的疾病 结合嘌呤核苷酸合成途径、调节，熟记嘌 呤核苷酸 抗代 谢药物作用机理 及临床意义 记住嘌呤核苷酸体内分解代谢终产物 - 尿酸 及其与医学的关系 熟记嘧啶核苷酸从头合成的原料及合成调节。说出嘧啶核苷酸补救合成所需的酶及其催化的反应。明白嘧啶核苷酸抗代谢药物作用机理，记住嘧啶核苷酸分解代谢产物名称.

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Nucleotides metabolism

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  1. Nucleotides metabolism

  2. 【目的与要求】 • 记住嘌呤核苷酸有两条合成途径。结合嘌呤核苷酸结构与从头合成途径，说出嘌呤核苷酸各元素或组件的材料来源。熟记二磷酸核苷还原生成脱氧嘌呤核苷酸。写出与嘌呤核苷酸补救合成有关的酶的名称、功能、酶缺陷相关的疾病 • 结合嘌呤核苷酸合成途径、调节，熟记嘌呤核苷酸抗代谢药物作用机理及临床意义 • 记住嘌呤核苷酸体内分解代谢终产物-尿酸及其与医学的关系 • 熟记嘧啶核苷酸从头合成的原料及合成调节。说出嘧啶核苷酸补救合成所需的酶及其催化的反应。明白嘧啶核苷酸抗代谢药物作用机理，记住嘧啶核苷酸分解代谢产物名称

  3. Outline • 8.1 Purine metabolism -8.1.1 The Biosynthesis of Purines -8.1.2 Purine Salvage -8.1.3 De-oxyribonucleotide Synthesis -8.1.4 Purine Degradation • 8.2 Pyrimidine metabolism -8.2.1 Biosynthesis of Pyrimidines -8.2.2 Pyrimidine Degradation

  4. Biological Roles of Nucleotides • Monomeric units of nucleic acids * • “ Energy currency”(ATP) * • Regulation of physiological processes • Adenosine controls coronary(冠脉) blood flow • cAMP and cGMP serve as signaling molecules • Precursor function (GTP to tetrahydrobiopternin) • Coenzyme components ( 5’-AMP in FAD/NAD+) • Activated intermediates: UDP-Glucose • Allosteric effectors- regulate themselves and others

  5. Nuclear acid digestion food (stomach) protein nuclear acid(RNA and DNA) (intestine) RNase (phosphodiesterase) Endonucleases DNase mononucleotide ribonucleotidemmol Deoxyribonucleotideumol (phosphoesterase) Nucleotidase nucleoside Phosphate nucleosidase Uric acid (purines) Ribose or ribose-1-phosphate base β-ureidopropionate ( primidines) (戊糖代谢) excrete

  6. 思 考？ 利用所学知识，试评价“珍奥核酸”的功能

  7. 8.1.1 Nucleotide Biosynthesis • For both purines and pyrimidines there are two means of synthesis - de novo (from bits and parts) - salvage (recycle from pre-existing nucleosides,and bases) • Ribose generates energy, but purine and pyrimidine rings do not • Nucleotide synthesis pathways are good targets for anti-cancer/antibacterial strategies

  8. Bases/Nucleosides/Nucleotides Base + Sugar= Nucleoside Base + Sugar + Phosphate= Nucleotide Base Deoxyadenosine 5’-triphosphate (dATP) Adenine Deoxyadenosine

  9. The Pyrimidine Ring The Purine Ring

  10. NH2 C C N N N C N C CH CH HC C C C N H N H N N Purine 腺嘌呤A O 6 2 H2N 鸟嘌呤G

  11. C HN CH O C CH N CH3 H O NH2 C HN C C CH O N H Pyrimidine Thymine Cytosine

  12. De novopurine biosynthesis • John Buchanan (1948) "traced" the sources of all nine atoms of purine ring 1. In de novo synthesis, Inosine-5'-P(Inosine Monophosphate, IMP) is the first nucleotide formed 2. It is ,then, converted to either AMP or GMP Location: liver cellularCytoplasm De novo purinenucleotide synthesis proceeds by the synthesis of the purine base upon the ribose sugar moiety

  13. N-1:aspartic acid • C-2:THF - one carbon units • N-3: glutamine • C-4, C-5, N-7: glycine • C-6: CO2 • C-8: THF - one carbon units • N-9: glutamine 甘氨当中站, 谷氮坐两边, 左上天冬氨, 头顶CO2 二八俩一碳 N-7 C-5 C-4 N-9 H C-6 N-1 C-8 C-2 N-3 The metabolic origin of the nine atoms in the purine ring system

  14. 1. First,synthesis Inosine-5'-P(Inosine Monophosphate, IMP)

  15. ATP P_ P R-5'-P PRPP synthetase PP-1'-R-5'-P(PRPP)

  16. 5-磷酸核糖胺,PRA T1/2 30s

  17. 甘氨酰胺核苷酸(GAR)

  18. 甲酰甘氨酰胺核苷酸 (FGAR)

  19. 甲酰甘氨咪核苷酸(FGAM)

  20. 5-氨基咪唑核苷酸 (AIR)

  21. 5-氨基咪唑-4-羧酸核苷酸

  22. 5-氨基咪唑-4-(N-琥珀酸) -甲酰胺核苷酸(SAICAR)

  23. 5-氨基咪唑-4-(N-琥珀酸) -甲酰胺核苷酸(SAICAR)

  24. 5-氨基咪唑-4-甲酰胺 核苷酸(AICAR)

  25. 5-甲酰胺基咪唑- 4-甲酰胺核苷酸(FAICAR)

  26. (2) ATP dependent step NH3 via glutamine ATP dependent step 1 carbon via folate 1 carbon via folate ATP dependent step NH3 via glutamine ATP dependent step ATP dependent step PRPP Inosine monophosphate NH3 via aspartyl- succinate

  27. 2.Second, Making AMP and GMP

  28. kinase kinase kinase kinase ATP AMP ADP ADP ATP ADP ATP GTP GDP GMP ADP ATP ADP ATP

  29. Purines are synthesized on the Ribose ring • Committed Steps • (at the first two steps ): PRPP , PRA (A bunch of steps you don’t need to know) 2.End product inhibition and “feed forward” regulation Regulation of De Novo Synthesis 3. “cross regulation” occurs from IMP to AMP and GMP ATP provides the energy for GMP synthesis GTP provides the energy for AMP synthesis Feedback Inhibition

  30. Committed Step

  31. Hypoxanthine or Guanine + PRPP = IMP or GMP + PPi Hypoxanthineguanosylphosphoribosyl transferase (HGPRTase) Adenine + PRPP = AMP + PPi Adeninephosphoribosyltransferase (APRTase) 8.1.2 Salvage Pathway for Purines Salvage pathways are particularly important in brain/marrow that lack de novo purine synthesis

  32. Lesch-Nyhan Syndrome(莱-尼综合症) • Absence of HGPRTase • X-linked (Gene on X) • Occurs primarily in males • Characterized by: • purine synthesis is increased 200-fold • Increased uric acid • Spasticity(痉挛) • Neurological defects • Aggressive behavior • Self-mutilation(自残)

  33. NADPH NH3 NH3 Adenine Deaminase Guanine Reductase NADP+ Inter-conversion of Purine nucleotides GMP AMP AMPS （腺苷酸代琥珀酸） XMP IMP

  34. BASE BASE 5´ 1´ 4´ 5´ 1´ 3´ 2´ 4´ 3´ 2´ 8.1.3 Deoxyribonucleotide Biosynthesis Ribonucleotide Reductase Deoxyribonucleoside Ribonucleoside

  35. ribonucleotide reductase ribonucleotide reductase ribonucleotide reductase ribonucleotide reductase ADP dADP GDP dGDP UDP dUDP CDP dCDP TDP dTDP

  36. Deoxyribonucleotide Biosynthesis ? 硫氧还蛋白 Mg2+ Ribonucleotides can be converted to deoxyribonucleotidesby Ribonucleotide Reductaseat the diphosphate level

  37. E. coli Ribonucleotide Reductase Regulates the level of cellular dNTPs The ribonucleotide reductase, An (R1)2(R2)2- type enzyme , has R1 (86 kD) and R2 (43.5 kD) two subunits

  38. phosphorylase kinase kinase kinase kinase dADP+ATP dATP +ADP dGDP+ATP dGTP+ADP dUDP+ATP dUTP+ADP dCTP+ADP dCDP+ATP dNDP dNMP+Pi ? dTTP

  39. Regulation of dNTP Synthesis • The overall activity of ribonucleotide reductase must be regulated • Balance of the four deoxynucleotides must be controlled • ATP activates, dATP inhibits at the overall activity site • ATP, dATP, dTTP and dGTP bind at the specificity site to regulate the selection of substrates and the products made

  40. Regulation of dNTP Synthesis

  41. Tumor over-growth + Heterogeneity ( nucleotides + protein ) How to inhibit the biosynthesis of the tumor cells? for anti-cancer strategies(antibacterial)

  42. 6-巯基嘌呤 （6-mercaptopurine, 6-MP） OH SH SH N N N N N N OH N N N N N N N H H H N N N N H2N H Chemotherapeutic Agents 1. Analogs of purine: inosine 8-氮杂鸟嘌呤 (8-azoguanine) 6-巯基鸟嘌呤 (6-mercaptoguanine)

  43. O NH2 H2N—C—CH2—CH2—CH—COOH O NH2 N+ —N—CH2—C—O—CH2—CH—COOH O NH2 N+ —N—CH2—C—CH2—CH2—CH—COOH 2. Analogs of amino acids: Gln Inhibit the reactions of the Gln 氮杂丝氨酸（azaserine） 6-重氮-5-氧正亮氨酸(diazonnorleucine)

  44. NH2 R H O COOH O COOH H H H N N N H2N —CH2—N— —CH2—N— —C—N—CH —C—N—CH N N CH2 CH2 H2N N C N N CH2 CH2 H H OH COOH COOH 3. Analogs of Folic acid R=H，aminopterin,氨喋呤 R=CH3，methotrexate, 氨甲喋呤,MTX 四氢叶酸,FH4

  45. 6MP MTX PRPP PRA GAR FGAR Gln azaserine 氮杂丝氨酸(azaserine) FGAM PPi PRPP 6MP A AMP MTX PPi PRPP FAICAR IMP AICAR I GMP G 6MP azaserine PPi PRPP The mechanism of the Chemotherapeutic Agents 6MP

  46. 8.1.4 Purine catabolism AMP I XO XO Uric Acid X GMP G Sequential removal of bits and pieces End product is uric acid XO: Xanthine Oxidase Excreted in Urine

  47. Xanthine Oxidase and Gout ＞0.48mmol/L(8mg%), The scale of uric acid (normal value) : 0.12～0.36mmol/L; male, 0.27mmol/L; formale, 0.21mmol/L

  48. Allopurinol, which inhibits XO, is a treatment of gout 别嘌呤醇 次黄嘌呤 I

  49. OH OH H N C N N CH N N N N N H H The mechanism of allopurinol as a treatment of gout allopurinol PRPP ↓ I XO Allopurinol nucleotide X Purine nucleotides Uric acids

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