生物化学资料：22-nucleotide metabolism-(李)-15年-上

1、Unit IV Nitrogen Metabolism 第四单元 氮代谢 Chapter 22 Nucleotide metabolism 第22章 核苷酸代谢,I. Overview,Functions of nucleotides,1. building blocks for DNA and RNA synthesis: ATP,UTP,CTP,GTP RNA dATP, dTTP, dCTP,dGTP DNA 2. energy currencies: ATP,GTP 3. messengers mediating cell signaling: cAMP, cGMP 4. coenzy

2、mes: FAD, NAD+, NADP+, CoA 5. active intermediates: UDPG,CDP-choline, CDP-DAG, SAM,II. Nucleotide structure,Typical structure,II. Nucleotide structure,A. Purine and pyrimidine structures,Unusual bases are derived from such bases through: Acetylation Reduction Methylation Glycosylation,Unusual bases,

3、B. Nucleosides 核苷,The addition of a pentose sugar to a base,C. Nucleotides 核苷酸,AMP, GMP, CMP, UMP NMP ADP, GDP, CDP, UDP NDP ATP, GTP, CTP, UTP NTP,dAMP, dGMP, dCMP, dTMP dNMP dADP, dGDP, dCDP, dTDP dNDP dATP, dGTP, dCTP, dTTP dNTP,The addition of one or more phosphate groups to a nucleoside,e.g., a

4、denosine monophosphate (AMP) adenosine diphosphate (ADP) adenosine triphosphate (ATP) deoxyadenosine triphosphate (dATP) nucleoside triphosphate (NTP,Cyclic nucleotides 环核苷酸,cAMP,cAMP cGMP,III. Synthesis of purine nucleotide,The pathways of nucleotide synthesis include: 1. de novo pathway (从头合成途径 )

5、2. salvage pathway (补救合成途径,the de novo pathway of nucleotide synthesis a pathway through which nucleotides are synthesized by using simple molecules, such as ribose 5-phosphate, amino acids, one carbon units and CO2,de novo synthesis,Location: liver, small intestine, thymus (note: but not brain and

6、bone marrow,R-5-P,ATP,AMP,PRPP synthetase,PP-1-R-5-P （PRPP,Gln, Gly, one carbon unit, CO2, and Asp are added,IMP,AMP,GMP,H2N-1-R-5-P （PRA,Gln,Glu,Gln:PRPP amidotransferase,Pathway in brief,A. Synthesis of 5-phosphoribosyl-1-pyrophospate (PPRP,PRPP: the activated pentose and donor of ribose 5-phospha

7、te,PRPP synthetase,B. Synthesis of 5-phosphoribosylamine (PRA,C. Synthesis of inosine monophosphate (次黄嘌呤核苷酸，IMP,D. Synthetic inhibitors of purine synthesis,Synthetic inhibitors: PABA analog: Sulfonamides Folic acid analog: Methotrexate,Dihydrofotate reductase as a chemotherapeutic target,Synthetic

8、inhibitors of human purine synthesis are extremely toxic to tissues, esp. bone marrow, skin, gastrointestinal tract, immune system, or hair follicles. As a result, individuals taking such anticancer drugs can experience adverse effects, including anemia, scaly skin, GI tract disturbances, immunodefi

9、ciencies, and baldness,E. Conversion of IMP to AMP and GMP,E. Conversion of IMP to AMP and GMP,霉酚酸,F. Conversion of NMP to NDP and NTP,Regulation of purine de novo synthesis,G. Salvage pathway for purines,the salvage pathway of nucleotide synthesis a pathway through which nucleotides are synthesiaed

10、 by using the existing nitrogenous bases or nucleosides from the normal turnover of cellular nucleic acids, or from the diet,APRT: adenine phosphoribosyltransferase HGPRT: hypoxanthine-guanine phosphoribosyltransferase,1. conversion,2. Lesch-Nyhan syndrome,X-linked recessive disorder,Pathgenesis,2.

11、Lesch-Nyhan syndrome,Clinical manifestation,kidney stones, arthritis motor dysfunction cognitive deficits behavioral disturbances(self-mutilation,H. Interconversion between purine nucleotides,IV. Synthesis of deoxyribonucleotide,reductase,A. Ribonucleotide reductase,B. Regulation of deoxyribonucleot

12、ide synthesis,A. Degradation of dietary uncleic acids,V. Degradation of purine nucleotides,B. Formation of uric acid,Phosphorolysis reaction,C. Diseases associated with purine degradation,1. gout,Gout: a disease with high levels of uric acid in blood (hyperuricemia),causes,Underexcretion of uric aci

13、d: primary or secondary kidney disorders. Overproduction of uric acid: Primary hyperuricemia: mutations in PRPP synthetase activity overproduction of purines Lesch-Nyhan syndrome Secondary hyperuricemia: myeloproliferative disorder patients with chemotherapy excessive consumption of ethanol and diet

14、(seafood, animal viscera, etc.,Deposition of monosodium urate crystals in joints,kidney,etc. Gouty arthritis, kidney stones, tophi, etc,pathogenesis,Definitive diagnosis: Exam the synovial fluid from aspiration by arthrocentesis,Diagnosis,Treatment,1. Low purine diet 2. Treatment of primary diseases

15、 3. Treatment of inflammation 4. Allopurinol administration,allopurinol,2. Adenosine deaminase deficiency,Autosomal recessive disorder,Treatment Bone marrow replacement Enzyme replacement,VI. Pyrimidine synthesis and degradation,de novo synthesis,Sources of the individual atoms in the pyrimidine rin

16、g,A. Synthesis of carbamoyl phosphate,CPS-II,Comparison between CPS-I and CPS-II,B. Synthesis of orotic acid,C. Formation of pyrimidine nucleotide,二氢乳清酸,乳清酸,乳清酸核苷酸 the parent pyrimidine mononucleotide,D. Synthesis of UTP and CTP,E. Synthesis of TMP from dUMP,Structures of pyrimidine antimetabolites,胸腺嘧啶(T,5-氟尿嘧啶(5-FU,5,5,Pyrimidine antimetabolites,5-fluorouracil,Inhibitions,F. Salvage of pyrimidines,Regulations of pyrimidine synthesis,ATP + CO2+ glutamine,carbamoyl pho