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1、核苷酸代谢核苷酸代谢Nucleotide metabolism1 1核苷酸的生物功能l l核酸合成的原料synthesis materials for nucleic acidl l能量Nucleotides Carry Chemical Energy in Cells l l代谢生理调节Some Nucleotides Are Intermediates in Cellular Communication l l组成辅酶Nucleotides Are Components of Many Enzyme Cofactors l l活化中间代谢物 UDPG2 2Energy in Nucleot
2、ides3 3l lThe phosphate ester and phosphoric acid anhydride bonds The phosphate ester and phosphoric acid anhydride bonds of ATP. of ATP. Hydrolysis of an anhydride bond yields more energy Hydrolysis of an anhydride bond yields more energy than hydrolysis of the esterthan hydrolysis of the ester. A
3、carbon anhydride and ester . A carbon anhydride and ester are shown for comparison are shown for comparison 磷酸酐4 4环化核苷酸环化核苷酸l lcAMPcAMPl lcGMPcGMP5 5Intermediates in Cellular Communicationl l细胞内第二信使细胞内第二信使 l lppGppppGpp 是细菌内在氨基酸缺乏时抑制是细菌内在氨基酸缺乏时抑制rRNArRNA和和tRNAtRNA合成的信使。合成的信使。6 6For protein modificat
4、ionl l单聚单聚ADP-ADP-核糖或多聚核糖或多聚ADP-ADP-核糖对蛋白质的核糖对蛋白质的修饰，修饰， l l如白喉毒素常常催化受体蛋白质加上单个如白喉毒素常常催化受体蛋白质加上单个ADP-ADP-核糖，核糖，l l白喉毒素活化的受体使白喉毒素活化的受体使NADNAD上的腺苷二磷酸上的腺苷二磷酸集团转移到集团转移到eEF-2eEF-2上，失活。上，失活。7 7 Nuclear protein digestion l l peptic acidpeptic acid proteinsproteinsl lnuclear proteinnuclear proteinl lfrom foo
5、d nucleic acidsfrom food nucleic acidsl l pancreas nucleasepancreas nuclease nucleotidesnucleotides pancreas,bowel pancreas,bowel nucleotasenucleotase base base phosphate nucleoside phosphate nucleoside nucleosidasenucleosidase pentose pentose8 8单核苷酸l l嘌呤核苷酸嘌呤核苷酸 嘧啶核苷酸嘧啶核苷酸碱基9 9核苷酸合成代谢1010Metabolism
6、 of purine nucleotidesl l l l De novo synthesis l l liverl lAnabolisml l Salvage pathwayl l brain,bone marrow 1111l l先合成次黄嘌呤核苷酸先合成次黄嘌呤核苷酸( (IMP)IMP)；l lIMPIMP再转化变成腺嘌呤核苷酸再转化变成腺嘌呤核苷酸( (AMP)AMP)与与鸟嘌呤核苷酸鸟嘌呤核苷酸( (GMP)GMP)；l lATP,GTPATP,GTP的合成。的合成。De novo synthesis1212嘌呤的元素来源天冬氨酸谷氨酰胺甲酰基甲酰基1313IMP的合成 1PRPP
7、合成酶磷酸核糖焦磷酸1414IMP的合成 21-氨基-5-磷酸核苷酰胺转移酶1515IMP的合成 2-5甘氨酸甲炔FH4谷氨酰胺GAR合成酶转甲酰基酶转酰胺酶转酰胺酶AIR合成酶Stage 1Formation of 5-aminoimidazole ribonucleotide from PRPP2. Addition of glycine3. Formylation 4. Adding of amino group from Gln.5. Imidazole ring closure. 1616IMP的合成 6-10环水解酶Second stage of purine biosynthes
8、is:Formation of inosinate from 5-aminoimidazole ribonucleotide6. Carboxylation7.Addition of aspartate8.Eliminaton fumarate(leaving the amino group)9.Formylation by N10-formylterahydrofolate10.Dehydration and ring closure17171818嘌呤核苷酸从头合成特点l l是在磷酸核糖分子上逐步合成嘌呤核苷酸，而不是首先单独合成嘌呤碱后再与磷酸核糖结合的。l l即一开始就沿着合成核苷酸的
9、途径进行 。l l肝脏是体内从头合成嘌呤核苷酸的主要器官，其次是小肠粘膜和胸腺。l l先合成IMP,再合成AMP,GMP。1919二、AMP和GMP的合成Aspartate腺苷酸代琥珀腺苷酸代琥珀酸合成酶酸合成酶 GTP脱氢酶IMP脱氢酶脱氢酶NADIMP脱氢酶腺苷酸代琥腺苷酸代琥珀酸裂解酶珀酸裂解酶GMP合成酶合成酶ATP20202121三、ATP和GTP的合成l l在激酶的作用下，以ATP为磷酸供体l lAMP ADP ATPl lGMP GDP GTP2222Regulation of purine biosynthesis2323Regulation of purine biosynt
10、hesis2424嘌呤核苷酸的补救合成腺嘌呤磷酸核糖转移酶腺嘌呤磷酸核糖转移酶次黄嘌呤鸟嘌呤次黄嘌呤鸟嘌呤磷酸核糖转移酶磷酸核糖转移酶2525Salvage pathway of purinel lAdenine + PRPP APRT AMP + PPil lHypoxanthine + PRPP HGPRT IMP + PPil lGuanine + PRPP HGPRT GMP + PPil lAdenonine adenosine adenosine kinasekinase AMPl l ATP ADP2626补救合成生理意义：l lConserve energy可以节省从头合成时能
11、量，保存能量；l lDecrease consumption of amino acid 减少氨基酸的消耗；l l 2727补救合成生理意义l lThere is no de novo synthesis in some organs such as brain and bone marrow.l体内某些组织器官，不能从头合成嘌呤核苷酸，对这些组织器官来说，补救合成途径具有更重要的意义。2828嘌呤核苷酸的相互转变2929Production of deoxynucleotides2位羟基3030Purine analogsl l6-6-巯基嘌呤巯基嘌呤(6(6MP)MP)、l l 6-6-巯
12、基鸟嘌呤。巯基鸟嘌呤。l l竞争性抑制：竞争性抑制：l次黄嘌呤鸟嘌呤磷次黄嘌呤鸟嘌呤磷酸核糖转移酶酸核糖转移酶l l反馈抑制：反馈抑制：lPRPP酰胺转移酶酰胺转移酶-SH取代3131嘌呤的类似物Purine analogsl l8-8-氮杂鸟嘌呤氮杂鸟嘌呤3232四氢叶酸的结构l l四氢叶酸的结构CNHN5NHHHHCH2HN10OCN -L-GluHHN OH2N3333氨喋啉的结构 CN5NCH2HN10OCN -L-GluH N NH2 CH2N氨甲喋氨甲喋啉的结啉的结构为构为CH3CH3N3434Aminioterin and Methotrexate3535二氢叶酸还原酶3636A
13、mino acid analogs l l氮杂丝氨酸氮杂丝氨酸azaserineazaserine 及及6-6-重氮重氮-5-5-氧正亮氨酸，氧正亮氨酸，l l结构与谷氨酰胺类似。结构与谷氨酰胺类似。l l干扰谷氨酰胺参与合成嘌呤的作用干扰谷氨酰胺参与合成嘌呤的作用3737二、嘌呤核苷酸的分解代谢3838Degradation of purine别嘌呤醇3939Pyridine de novo synthesis谷氨酰胺HCO3-氨基甲酰磷酸合成酶II2ATP2ADPPi氨基甲酰磷酸天冬氨酸氨基甲酰基转移酶氨甲酰天冬氨酸40404141UMP的合成乳清酸乳清酸核苷酸尿嘧啶核苷酸脱羧酶磷酸核糖转
14、移酶4242UMP生成UTP4343CTP的合成CTP合成酶UDPdUDPdUMPTMPTMP合成酶dCMP脱氨基44444545Production of dTMP4646Regulation of pyrimidine Synthesisl l ATP + CO2 + aspartic acidATP + CO2 + aspartic acidl l aminoformylphosphateaminoformylphosphatel l CarbamoylCarbamoyl aspartateaspartate purinepurine nucleosides nucleosides l
15、l PRPP PRPP ATP+5-phosphoriboseATP+5-phosphoribosel l UMP UMPl l pyrimidinepyrimidine nucleotide nucleotidel l UTP CTP UTP CTP4747嘌呤和嘧啶核苷酸合成的比较4848Salvage pathway of pyrimidinel l pyrimidinepyrimidine PRPP PRPP phosphoribosylphosphoribosyl transferasetransferasel lPyrimidine+PRPP PMP +PPil lUridine+ATP uridine kinase UMP+ADPl lThymidine +ATP thymidime kinase TMP+ADP4949嘧啶核苷酸的抗代谢物l l嘧啶类似物Pyrimidine analogs: l l 5-氟尿嘧啶5-FU;l l氨基酸类似物Amino acid analogs : azaserine ;l l叶酸类似物l lPyrimidine nucleoside analogs: l lAC-1075, cyclo-c, Ara-C5050Some analogsOH在环的上方Ara-C改变改变515152525353
