3nucleotidessynthsis

1、biosynthesis and degradation of nucleotidescontents1.de novo purine nucleotide synthesis2.de novo pyrimidine nucleotide synthesis3.nucleoside monophoshates are converted to nucleoside triphosphates4.ribonucleotides are the precursors of deoxy-ribonucleotides5.degradation of purine and pyrimidine 6.t

2、he salvage pathways for purine and pyrimidine7.many chemotherapeutic agents target enzymes in the nucleotide biosynthetic pathwaystwo types of pathway lead to nucleotidesnde novo synthesis of nucleotides begins with their metabolic precursors: amino acids, ribose 5-phosphate, nh3, and co2. nsalvage

3、pathways recycle the free bases and nucleosides released from nucleic acid breakdown.overviewnthe purine ring is assembled on ribose phosphate to make amp and gmp; the pyrimidine ring is first synthesized as orotate, which is then attached to ribose phosphate before being converted to utp and ctp (d

4、tmp is made from dump).nthe deoxyribonucleotides (dndps) are synthesized by reduction of ribonucleotides (ndps).the free bases are not intermediates during the de novo synthesisthe origin of the atoms in the purine and pyrimidine rings radioisotope tracer experiments revealed the origin of the atoms

5、 in the purine and pyrimidine rings nbuchanan and greenberg did this by feeding a variety of isotopically labeled compounds to pigeons (1940s).nthe atoms of the purine rings were found to be derived from formate, co2, gly, asp, and gln.nthe atoms of the pyrimidine rings were found to be derived from

6、 asp, gln and hco3-.radioisotope tracer experiments revealedthe origins of the ring atoms of purinesgln amidehco3-cthe atoms of the pyrimidine rings are derived from hco3-, gln and asp.1. de novo purine nucleotide synthesis begins with prppprpp is synthesized from ribose 5-p in areaction catalyzed b

7、y prpp synthetase.the bases are not synthesized and then attached to ribosethe purine ring is built up one or a few atoms at a time, attached to ribose throughout the process.the enzymes of imp synthesis appear to be organized as large multienzyme complexes steps 1, 3, and 5; steps 7 and 8 ;steps 10

8、 and 11 are catalyzed by a multifunctional protein respectively in some eukaryotic cells. in bacteria, these activities are found on separate proteins, but a large noncovalent complex may exist in these cells.amidotransferasethe biosynthesis of amp and gmp is regulated by feedback inhibition three m

9、ajor feedback mechanism cooperate n prpp synthetase and glutamine-prpp amidotransferase are both inhibited by the end products imp, amp and gmp (amp and gmp act synergistically).n amp inhibits adenylosuccinate synthetase and gmp inhibits imp dehydrogenase.n amp and gmp synthesis is balanced by the f

10、ollowing mechanism: gtp is needed for amp synthesis and atp for gmp synthesis.the de novo synthesisof amp and gmp is regulated mainly by sequential feedbackinhibition.summary nthe first intermediate to have a complete purine ring is imp (inosinate次黃嘌呤單核苷酸).nimp is converted to amp by accepting an am

11、ino group from asp, and converted to gmp by accepting an amino group from gln (catalyzed by an amidotransferase).nthe production of amp from imp requires gtp, and the production of gmp from imp requires atp.2. de novo pyrimidine nucleotide synthesisnpyrimidine( (嘧啶) ) nucleotides are made from aspar

12、tate, prpp, and carbamoyl phosphatenthe pyrimidine ring is synthesized as orotate, attached to ribose phosphate, and then converted to the common pyrimidine mucleotides used in nucleic acid synthesis (the six-numbered pyrimidine ring is made first and then attached to ribose 5-phosphate).nthe pyrimi

13、dine ring is synthesized as orotate (乳清酸), attached to ribose phosphate, and then converted to the common pyrimidine mucleotides used in nucleic acid synthesis (the six-numbered pyrimidine ring is made first and then attached to ribose 5-phosphate).nctp is derived from utp by accepting an amino grou

14、p from gln or nh4+.nin eukaryotic cells, carbamoyl phosphate synthetase ii, aspartate transcarbamoylase, and dihydroorotase, are part of a trifunctional proteins called cad.synthesis of carbamoyl phosphatenin animals the carbamoyl phosphate synthesis requires different enzymes and takes place in dif

15、ferent cellular compartments in urea synthesis(synthetase i, mitochondra) and in pyrimidine synthesis(synthetase ii, cytosol).nin bacteria, a single enzyme supplies carbomoyl phosphate for the synthesis of arginine and pyrimidinespyrimidine nucleotide biosynthesis is regulated by feedback inhibition

16、naspartate transcarbamoylase (atcase) is inhibited by ctp, the end product of the de novo pyrimidine nucleotide biosynthesis pathway. ctp binds to the regulatory subunits, they undergo a changes in conformation. this change is transmitted to the catalytic subunits. atp is able to prevent the changes

17、 induced by ctp.3. nucleoside monophosphates are converted to nucleoside triphosphaatesnnucleoside monophosphate kinases atp +nmp adp + ndp specific for the base, nonspecific for the sugarnnucleoside dimonophosphate kinases ntpd +ndpa ndpd + ntpa not specific for the base or the sugar ntpd is almost

18、 invariably atp4. deoxyribonucleotides are derived from ribonucleotides at the ndp levelnthis occurs by direct reduction at the 2-carbon.nribonucleotide reductase catalyzes all such conversions.nthe electrons are provided by nadph and transmitted to the ribonucleotide reductase through thioredoxin(硫

19、氧還蛋白)or glutaredoxin (谷氧還蛋白).dtmp is derived from dcdp and dumpdtmp is derived from dump via a methylation reaction using n5, n10-methylene h4 folate asdonors of both one-carbon unit and electrons.ndump is formed from dutp in a reaction catalyzed by dutpase (keeping dutp at a low level to prevent it

20、s incorporation into dna).ndump is then converted to dtmp by the catalysis of thymidylate synthase(合酶）, with a methylene group transferred from and reduced by n5, n10-methylene h4 folate (being donors of both one-carbon unit and electrons).nthe reactions catalyzed by ribonucleotide reductase and thy

21、midylate synthase are probably key for the transition from an rna world to one in which dna stores genetic information.5. degradation of purine and pyrimidinenuric acid is the excreted end product of purine catabolism in humans and many other animals.nthe pathways for degradation of pyrimidine gener

22、ally lead to nh4+ production and thus to urea synthesis.(尿囊素）(尿囊酸)(黃嘌呤)次黃嘌呤，6-羥基嘌呤 nuric acid can be further converted to allantoin, allantoate, urea or nh4+ in various animals.nthe deficiency of adenosine deaminase causes the severe immunodeficiency disease in humans (accumulated adenosine is conve

23、rted to datp, which inhibits the formation of other dndps by ribonucleotide reductase).noverproduction of uric acid causes gout (痛風(fēng)).nallopurinol, an inhibitor of xanthine oxidase, is used to treat gout.allopurinol was designed to be a competitive inhibitor ofxanthine oxidase to treat gout by elion

24、and hitchings, who shared the nobel prize in 1988 for their discoveries of important principles for drug treatmentdegradation of pyrimidine produces ureanthe degradation of thymine can produce succinyl-coa.nthe degradation of uracil and cytidine produces malonyl-coa, which is one precursor for fatty

25、 acid biosynthesis.nto a limited extent, catabolism of pyrimidine nucleotides contributes to the energy metabolism of the cell.degradation products ofpyrimdines can enter thecitric acid cyclesuccinyl-coafourth lectureradioisotope tracer experiments revealedthe origins of the ring atoms of purinesgln

26、 amidehco3-cthe atoms of the pyrimidine rings are derived from hco3-, gln and asp.6. purine and pyrimidine bases are recycled by salvage pathwaynadenine phosphoribosyltransferase catalyzes the synthesis of amp from adenine and prpp.nhypoxanthine-guanine phosphoribosyltransferase (hgprt) catalyzes th

27、e synthesis of gmp and imp.nthe lack of hgprt will cause lesch-nyhan syndrome(自毀容貌綜合癥).n pyrimidine bases are recycled in a similar way in microorganisms, but pyrimidine bases does not seem to be salvaged in significant amounts in mammals.the purine bases can be converted to purine nucleotides throu

28、gh the salvage pathways7.many chemotherapeutic agents target enzymes in the nucleotide biosynthetic pathwaysnanalogs of gln, like azaserine (重氮絲氨酸) and acivicin (阿西維辛) , inhibits many amidotransferases used in nucleotide (and amino acid) biosynthesis.nfluorouracil, after being converted to fdump by

29、the salvage pathway, can inhibit the thymidylate synthase, thus inhibit the dtmp synthesis.nmethotrexate(氨甲碟呤）, a folate analog, inhibits the dihydrofolate reductase, thus the dtmp synthesis.azaserine(重氮絲氨酸) and acivicin (阿西維辛), inhibitors of amidotransferases.these analogs of glutamine interfere in

30、 a number of amino acid and nucleotides biosynthetic pathwaysnpurine nucleotides are synthesized from prpp, gln, gly, n10-formyl h4 folate, gln, hco3-, asp through the de novo pathway.npyrimidine nucleotides are synthesized using hco3-, gln, asp, and prpp.nde novo synthesis of nucleotides are regula

31、ted via feedback inhibition.ndeoxyribonucleotides are derived from ribonucleotides at the ndp level.summarynthe dtmp molecule is derived from dump by thymidylate synthase, an enzyme using n5, n10-methylene-tetrahydrofolate as the donor of both one-carbon unit and electrons.ndegradation of purines an

32、d pyrimidines produces uric acid and citric acid cycle intermediate/fatty acid synthesis precursor, respectively.npurine and pyrimidine bases can be reused via the salvage pathway.nmany cancer chemotherapeutic drugs (e.g., azaserine, acivicin, fluorouracil, and methotrexate) inhibits enzymes in the nucleotide biosynthetic pathways.復(fù)習(xí)題名詞解釋：名詞解釋： 1、核苷酸的從頭合成途徑、核苷酸的從頭合成途徑 2、核苷酸的補(bǔ)救合成途徑、核苷酸的補(bǔ)救合成途徑