第08章核苷酸改

,*,第 八 章,核 苷 酸 代 谢,Metabolism of Nucleotides,Digestion&Absorption of Nucleic Acids,Introduction,Dietary nucleoproteins,Nuclease in,Proteins,RNA,and,DNA,）,stomach acid,Polynucleotides,Pancreatic,Nuclease,Nucleosides,Phosphates,Phosphodiesterases,nucleotidases,Bases,Pentose,phosphorylases,核苷酸的生物功用,作为核酸合成的原料,To provide materials for DNA,RNA synthesis,体内能量的利用形式,To provide energy that drive most of our biochemical reactions,参与代谢和生理调节,Metabolic regulation,组成辅酶,To constitute coenzymes,活化中间代谢物,Active metabolic intermediates,尼克酰胺腺嘌呤二核苷酸,(NAD,+,),AMP,第一节 嘌呤核苷酸的代谢,Metabolism of Purine Nucleotides,GMP,AMP,The structure of purine,一、嘌呤核苷酸的合成代谢,从头合成途径,(,de novo synthesis pathway,),补救合成途径,(,salvage synthesis pathway,),嘌呤核苷酸的从头合成途径是指利用磷酸核糖、氨基酸、一碳单位及二氧化碳等简单物质为原料，经过一系列酶促反应，合成嘌呤核苷酸的途径。,肝,是体内,从头合成嘌呤,核苷酸的主要器官，其次是,小肠,和,胸腺,，而,脑、骨髓,则无法进行此合成途径。,（一）嘌呤核苷酸的从头合成,定义：,合成部位,：,Element source of Purine biosynthesis,CO,2,Aspartate,Glysine,Formyl group.,（,one carbon unit）,Two moles of glutamine,（,amide group）,Formyl group,（,one carbon unit）,Processes;,1.The synthesis of IMP,2.Production of AMP and GMP,R-5-P,（5-,磷酸核糖）,ATP,AMP,PRPP,合成酶,PP-1-R-5-P,（,磷酸核糖焦磷酸）,在谷氨酰胺、甘氨酸、一碳单位、二氧化碳及天冬氨酸的逐步参与下,IMP,AMP,GMP,H,2,N-1-R-5,-P,（5,-,磷酸核糖胺）,谷氨酰胺,谷氨酸,酰胺转移酶,ribose-5-phosphate,PRPP,synthetase,amidotransferase,1.The synthesis of IMP,腺苷酸代琥珀酸合成酶,IMP,脱氢酶,腺苷酸代琥珀酸裂解酶,GMP,合成酶,2.Production of AMP and GMP,AMP,ADP,ATP,ADP,ATP,Kinase,ADP,ATP,Kinase,GMP,GDP,GTP,ADP,ATP,Kinase,ADP,ATP,Kinase,嘌呤核苷酸是在磷酸核糖分子上逐步合成的。,IMP,的合成需5个,ATP，6,个高能磷酸键。,AMP,或,GMP,的合成又需1个,ATP。,嘌呤核苷酸从头合成,特点：,从头合成的调节,R-5-P,ATP,PRPP,合成酶,PRPP,酰胺转移酶,PRA,IMP,腺苷酸代,琥珀酸,AMP,ADP,ATP,XMP,GMP,GDP,GTP,+,+,_,_,_,_,_,IMP,腺苷酸代,琥珀酸,XMP,AMP,ADP,ATP,GMP,GDP,GTP,ATP,GTP,_,_,+,+,调节方式：,反馈调节,和,交叉调节,Feed-back and cross regulation,利用体内游离的嘌呤或嘌呤核苷，经过简单的反应，合成嘌呤核苷酸的过程，称为补救合成（或重新利用）途径。,（二）嘌呤核苷酸的补救合成途径,定义：,腺嘌呤磷酸核糖转移酶,(,adenine phosphoribosyl transferase,APRT,),次黄嘌呤-鸟嘌呤磷酸核糖转移酶,(,hypoxanthine-guanine phosphoribosyl transferase,HGPRT,),腺苷激酶,(,adenosine kinase),参与补救合成的酶：,adenine,+,PRPP,AMP,+,PPi,APRT,hypoxanthine,+P,RPP,IMP,+,PPi,HGPRT,Guanine,+,PRPP,HGPRT,GMP,+,PPi,The process of nucleotide,adenine,nucleoside,AK,ATP,ADP,AMP,补救合成的生理意义,补救合成节省从头合成时的能量和一些氨基酸的消耗。,体内某些组织器官，如脑、骨髓等只能进行补救合成。,Save energy and amino acids,The salvage pathway is the only purine synthetic pathway which can be use in brain and bone marrow.,（三）嘌呤核苷酸的相互转变,IMP,AMP,腺苷酸代,琥珀酸,XMP,GMP,NH,3,腺苷酸脱氨酶,鸟苷酸还原酶,NADPH+H,+,NADP,+,NH,3,adenylosuccinate,（四）脱氧核糖核苷酸的生成,在核苷二磷酸水平上进行,（,N,代表,A、G、U、C,等碱基）,Ribonuclotide reductase,dNDP,+,ATP,激酶,dNTP,+,ADP,二磷酸脱氧核苷,NDP,dNDP,二磷酸核糖核苷,NADP,+,NADPH+H,+,核糖核苷酸还原酶，,Mg,2+,还原型硫氧化还原蛋白,-(SH),2,氧化型硫氧化还原蛋白,S,S,硫氧化还原蛋白还原酶,（,FAD,）,脱氧核苷酸的生成,（五）嘌呤核苷酸的抗代谢物,嘌呤核苷酸的抗代谢物是一些嘌呤、氨基酸或叶酸等的类似物。,嘌呤类似物,氨基酸类似物,叶酸类似物,6-巯基嘌呤,6-巯基鸟嘌呤,8-氮杂鸟嘌呤等,氮杂丝氨酸,等,氨蝶呤,氨甲蝶呤,（,MTX,）,等,次黄嘌呤,(IMP),6-巯基嘌呤,(6,-MP),6-巯基嘌呤,的结构,甲酰甘氨酰,胺核苷酸,（,FGAR）,PRPP,谷氨酰胺,（,Gln）,=,PRA,甘氨酰胺,核苷酸,（,GAR）,=,=,甲酰甘氨,脒核苷酸,（,FGAM）,5-氨基异咪唑-,4-甲酰胺核苷酸,（,AICAR）,=,5-甲酰胺基咪唑-,4-甲酰胺核苷酸,（,FAICAR）,IMP,次黄嘌呤,（,H）,PRPP,PPi,=,AMP,=,PRPP,PPi,=,腺嘌呤（,A）,GMP,=,=,PRPP,PPi,鸟嘌呤(,G),6-,MP,6-,MP,6-,MP,6-,MP,6-,MP,6-,MP,氮杂丝氨酸,氮杂丝氨酸,氮杂丝氨酸,MTX,MTX,二、嘌呤核苷酸的分解代谢,Nucleotides,Nucleosides,Nuclease,Pi,Nucleoside phosphorylase,Bases,Ribose-1-phosphates,嘌呤碱的最终,代谢产物,AMP,GMP,IMP,（次黄嘌呤）,鸟,嘌呤,XMP,（黄嘌呤）,黄嘌呤氧化酶,黄嘌呤氧化酶,正常人血浆中尿酸含量约为,0.12,0.36mmol,L(2-6mg,),超过,8mg,时，尿酸盐晶体即可沉积,。,鸟嘌呤,酶,Xanthine oxydase,Uric acid,痛风症的治疗机制,鸟嘌呤,次黄嘌呤,黄嘌呤,尿酸,黄嘌呤氧化酶,黄嘌呤氧化酶,别嘌呤醇,第二节,嘧啶核苷酸的代谢,Metabolism of Pyrimidine Nucleotides,The structure of pyrimidines,De novo synthesis pathway,Salvage synthesis pathway,一、,Pyrimidine Nucleotide Biosynthesis,（一）嘧啶核苷酸的从头合成,主要是肝细胞胞液,嘧啶核苷酸的从头合成是指利用磷酸核糖、氨基酸、一碳单位及二氧化碳等简单物质为原料，经过一系列酶促反应，合成嘧啶核苷酸的途径。,定义：,合成部位：,Element origin:,aspartate,Carbamoyl phosphate,氨基甲酰磷酸,Synthetic process:,1.The synthesis of UMP,Gln+,HCO,3,-,Carbamoyl phosphate,II,2,ATP,2,ADP+Pi,Glu+,Carbamoyl phosphate,谷氨酰胺,氨基甲酰磷酸合成酶,II,谷氨酸+,氨基甲酰磷酸,2.,胞嘧啶核苷酸的合成,ATP,ADP,尿苷酸激酶,UDP,二磷酸核苷激酶,ATP,ADP,UTP,CTP,合成酶,谷氨酰胺,ATP,谷氨酸,ADP+Pi,UMP kinase,UDP kinase,CTP,synthase,3.dTMP,或,TMP,的生成,TMP,合酶,N,5,N,10,-,甲烯,FH,4,FH,2,FH,2,还原酶,FH,4,NADP,+,NADPH+H,+,dUMP,脱氧胸苷一磷酸,dTMP,UDP,脱氧核苷酸还原酶,dUDP,CTP,CDP,dCDP,dCMP,Deoxyribonucleotide reductase,TMP,synthase,FH2,reductse,从头合成的调节,-,-,-,ATP+CO,2,+,谷氨酰胺,氨基甲酰磷酸,UMP,氨基甲酸天冬氨酸,UTP,CTP,天冬氨酸,嘌呤核苷酸,ATP+5-,磷酸核糖,嘧啶核苷酸,PRPP,-,（二）,Salvage synthetic pathway,Pyrimidine,+,PRPP,Pyrimidine nucleotide+,PPi,PPRT,Uridine,+,ATP,Uridine kinase,UMP,+,ADP,Thymidine,+,ATP,TK,TMP,+,ADP,（三）嘧啶核苷酸的抗代谢物,嘧啶类似物,Pyromidine analogs,胸腺嘧啶,(T),5-氟尿嘧啶(5-,FU),Thymine,5-,fluorodeoxyuridine monophosphate,某些改变了核糖结构的核苷类似物,UMP,UTP,CTP,CDP,dCDP,UDP,dUDP,dUMP,dTMP,氮杂丝氨酸,阿糖胞苷,氨甲碟呤,氮杂丝氨酸,二、,Catabolism of pyrimidine nucleotides,Pyrimidine base,1-,ribose phosphate,Nucleotides,Ribonucleotidase,PPi,Nucleoside phosphor,Pyrimidine nucleotide,核苷磷酸化酶,核苷酸酶,二、嘧啶核苷酸的分解代谢,嘧啶碱,1-磷酸核糖,嘧啶核苷酸,核苷,核苷酸酶,PPi,核苷磷酸化酶,胞嘧啶,NH,3,尿嘧啶,二氢尿嘧啶,H,2,O,CO,2,+NH,3,-丙氨酸,胸腺嘧啶,-脲基异丁酸,-氨基异丁酸,H,2,O,丙二酸单酰,CoA,乙酰,CoA,TAC,肝,尿素,甲基丙二酸单酰,CoA,琥珀酰,CoA,TAC,糖异生,cytosine,thymine,uricil,Dihydrouracil,-,ureidoisobutyric acid,glyconeogenesis,Actyl CoA,urea,