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1、核苷酸代谢,1, 背景知识 2，核苷酸的合成 3，核苷酸合成异常与疾病 4，核苷酸合成代谢的调节 5，核苷酸的降解 6，核苷酸代谢和化疗 7，核苷酸类似物与遗传标记,The most common nucleotides found in cells,碱基,核苷酸,核苷,Yet there was one other person whose truly essential contribution to this discovery could not be recognized by the Nobel Committee in 1962. That person was Rosalind
2、 Franklin. After Randall presented Franklins data and unpublished conclusions at a routine seminar, aspects of her results were informally communicated to Watson and Crick by Maurice Wilkins and Max Perutz, without her or John Randalls knowledge. It was Watson and Crick who put all the pieces of the
3、 puzzle together from a variety of sources including Franklins results, to build their ultimately correct and complete description of DNAs structure. Their model for the structure of DNA appeared in the journal Nature in April, 1953, alongside Franklins own report.,Watson, J.D. and F.H. Crick. 1953.
4、 A structure for deoxyribose nucleic acids. Nature 171:737-738. Wilkins, M.H.F., Stokes A.R. and H.R. Wilson. Molecular Structure of Deoxypentose Nucleic Acids. Nature 171:738-740 Franklin R. and R.G. Gosling. 1953. Molecular Configuration in Sodium Thymonucleate. Nature 171:740-741,B-DNA,Z-DNA,1, 背
5、景知识 2，核苷酸的合成 3，核苷酸合成异常与疾病 4，核苷酸合成代谢的调节 5，核苷酸的降解 6，核苷酸代谢和化疗 7，核苷酸类似物与遗传标记,De novo synthesis of nucleotides begins with their metabolic precursors: amino acids, ribose 5-phosphate, CO2, and NH3.,Reference pathway,磷酸核糖焦磷酸,The biosynthetic origins of purine ring atoms,Synthesis of Inosine monophosphsate
6、 (IMP, 肌苷酸/次黄苷酸),Synthesis of GMP and AMP,腺苷琥珀酸 延胡索酸,黄苷酸,肌苷酸/次黄苷酸,Regulatory network of the purine pathway,Synthesis of UMP,Synthesis of CTP,Synthetic pathways to thymine nucleotides,Regulatory network of pyrimidine synthesis,Overview of dNTP biosynthesis,Reutilization of purine and pyrimidine bases
7、,1, 背景知识 2，核苷酸的合成 3，核苷酸合成异常与疾病 4，核苷酸合成代谢的调节 5，核苷酸的降解 6，核苷酸代谢和化疗 7，核苷酸类似物与遗传标记,Immunodeficiency and Defective Purine Catabolism Persons with severe combined immune deficiency (SCID) are totally unable to mount an immune response to antigens. Both the B and T lymphocytes are affected. The disease aris
8、es from an inherited lack of a degradative enzyme, adenosine deaminase (ADA). The reaction shown below illustrates the pathways affected. Lack of ADA allows deoxyadenosine triphophosphate (dATP) to accumulate from the degradation of DNA. High dATP levels inhibit production of the other dNTPs needed
9、for DNA replication because of their allosteric effects on the enzyme ribonucleotide reductase. White blood cells are the most affected by lack of ADA. White blood cells must proliferate for an immune response to occur, and proliferations requires ample synthesis of DNA and its precursors. Thus, DNA
10、 replication is inhibited and white blood cells are unable to proliferate, a necessary step for antibody production.,脱氧肌苷,Hypoxanthine (次黄嘌呤)-guanine phosphoribosyltransferase (HGPRT) is a salvage pathway enzyme for purine metabolism (another is specific for adenine). When a defect in HGPRT reduces
11、its activity to a low level, gout (痛风) is the result. When the defect leads to the complete absence of activity of HGPRT, Lesch-Nyhan syndrome is the result. The gene for HGPRT is found on the X chromosome, so the disease is sex-linked. Patients have severe “gouty” arthritis (关节炎) and a dramatic mal
12、function of the nervous system, manifested as behavioral disorders, learning disabilities, and hostile or aggressive behavior, often self-directed. Individuals with Lesch-Nyhan syndrome rarely live beyond 20 years.,Gout and Lesch-Nyhan syndrome（雷-纳氏综合症）,EC 2.4.2.8: IMP + diphosphate = hypoxanthine +
13、 5-phospho-D-ribose 1-diphosphate Guanine and 6-mercaptopurine can replace hypoxanthine.,Impaired excretion or overproduction of uric acid Uric acid crystals precipitate into joints (Gouty Arthritis), kidneys, ureters (输尿管) (stones) Xanthine (黄嘌呤) oxidase inhibitors inhibit production of uric acid,
14、and treat gout Allopurinol (别嘌呤醇) treatment hypoxanthine (次黄嘌呤) analog that binds to xanthine oxidase to decrease uric acid production,Enzymatic abnormalities in three types of gout,1, 背景知识 2，核苷酸的合成 3，核苷酸合成异常与疾病 4，核苷酸合成代谢的调节 5，核苷酸的降解 6，核苷酸代谢和化疗 7，核苷酸类似物与遗传标记,Ribonucleotide reductase, the enzyme cata
15、lyzing the synthesis of dNDPs from rNDPs, reduces the hydroxyl at carbon 2 to a hydrogen via a free radical mechanism. The following three classes of ribonucleotide reductases are known: Class I ribonucleotide reductases - The most widely distributed form of ribonucleotide reductase. Class I enzyme
16、acts upon ribonucleoside diphosphates (rNDP). The enzyme generates a free radical on a tyrosine residue with the aid of a diferric oxygen bridge. Class II ribonucleotide reductases - Found in cyanobacteria (蓝细菌), some bacteria, and Euglena (眼虫属), the Class II enzyme acts on ribonucleoside triphosphate (rNTP) substrates. It uses adenosylcobalamin, a B12 coenzyme to generate a free radical. Class III ribonucleotide reductases - Found only in facultative or obligate anaerobes (厌氧生
