Class Note for BIOC 461 at UA
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Date Created: 02/06/15
Page i of 17 Chapter 25 Notes Biochemistm 461 Fall 2008 CHAPTER 25 BIOSYNTHESIS 0F NUCLEOTIDES Learning objectives Know the structures ofthe building blocks ofnucleic acids purine and pyrimidine bases nucleosides nucleotides ribonucleotides and deoxyribonucleotides Know key reactions in biosynthesis ofthe triphosphate forms ofthe four ribonucleotidesfor RNA and the four deoxyribonucleotides for DNA Know how nucleotides can be intercoverted betweem mono di and triphosphate forms Understand the biosynthesis odeMP Know why nucleotide analogs and inhibitors ofthymidylate synthase are used in drug therapy for diseases such as cancer AIDS herpes etc Fig 5 iA nucleic acid DNA RNA is a polymerconsisting of ipentose sugars 5 Carbon 2 phosphate 3 Nitrogenous bases Nrcontaining ring structures Phosphate Phosphate Phosphate Phosphate Phosphate Page 2 of 17 Sugars in Nucelic Acids Fig 52 Ribose RNA Deoxyribose DNA Deoxyribose Purine and P rimidine bases Fig 54 Parent Bases Bases in DNA and RNA PURINES 7 NH O N H N quot WM SW 3 3 A A H N N H N N HzN N quotf H H H Purine Adenine Guanine PYRIMIDINES NH 2 0 O HK 6 0A DANH OXN N N Pyrimidine Cytosine Uracil Thymine Page 3 of 17 Nucleotides Base pentose sugar phosphate Fig 55 A nucleosideadenosine NH2 N BGlycosidic linkage N N C NJ H HO O HO OH A Nucleoside Pentose Sugar Base A Nucleotide Pentose Sugar Base Phosphate 539ATP A ribonucleotide A deogribonucleotide Fig 55 A deoxynueleotide NUCLEOTIDE EXAMPLES Fig 56 Above Left a 539 nucleoside triphosphate Above Right a nucleoside 339 monophosphate Page 4 of 17 NOMENCLATURE Table 251 I TABLE 25 Nomenclature of bases nucleosides and nucleotides RNA Ribonucleotide Base Ribonucleoside E539monnphospltatel Adcnine Al Adenosine Adenylate Ah1P Guanine G Guanosine Guanylate CM Pl Uracil Ll l Uridine Liridylatc UMP Cytosine Cl Cytidine Cytidylate UMP DNA Denxyribt muclentide Base Deoxyrlbonucleuside 5 39 monophosphatel Adenine A ll Dcuxyadcnnsine leoxyaLlenylate d M lquot Guanine G Deoxyguanosine Deoxyguanylate lchMP39J Thymlne T Thymldine Tltymldylale TMP J Iytasine C Deoxycytidine leoxycytidylale dCNl P Svnthesis bv de novo and salvaqe paths are two wavs to make nucleotidesFig251 SALVAGE PATHWAY Activated ribose PRPP base Nutleallde DE NOVO PATHWAY Adivated ribnse PRPP amino acids ATP CD Nucleotide PRPP is a kev compound in both paths as well as in pvrimidine de novo svnthesis De novo pyrimidine nucleotide synthesis Fig252 Bicarbonate NH mi Carbamoyl phosphate Aspartate C K 5134 35 J Cir EC Pyrimidine ring PRPP a ribose phosphate UTP CO CTP i i TMP dCTP Y0 DNA to RNA Page 5 of 17 CTP is made from UTP by NH2 transfer from glutamine CTP is made from UTP Pl i ATP Hie Giutamaxe gt ADPP2H39 NH2 transfer 0 Ribose riphusphate Uridine tri hnsphme Ribose triphosphate Cvtidine tri hospham Stryu m editinn Fig 745 Page 6 of 17 Purine Bios nthesis De novo ath Fig 256 Aspartate C I N UFormyl NlGE tetrahydrofoiate 7 3951 800 t 3 am ne NIOeFormer N k u I tetrahydrofolate ribosep Purine ring structure i IMP I ATP GTP to RNA i i dATP dGTP 10 DNA Clutamine First committed step in purine nulceotide synth 1 requires PRPP Purine Biosynthesis Committed step o CH2 o H H H H O 5Phosphoribosyl OH OH 1 yrophosphatePRPP 2driven by PPi to 2Pi j r quot1 y 3quot 3 NH2 transfer from glutamine gt Glutamate PP 7 2 Pi 5PhosphoZ D ribosylamine Page 7 of 17 Purine Bios nthesis De nova ath 0 AMP and GMP Hg 25 9 no N we u GDP K A Was igt Prams N 3 Adan sumnam Adevwiaxz AMP 4 N m m H m P 2 Hm W N 7 p H mg w Hp NADH H 0 Maxim N M N Xanlhy a e m up Guanv an mm m m Purine Bios nthesisDenovo ath and its re ulationFg 2516 Pyrln drne WW Hismine nucleanes WIMP MW Isumnam Mquot Ribus Phusphmibosw 5phusplvam WPquot quotquot amine quot 39Mquot hvlws jp quotxanthyme 4 amp and 6M1 rnhubned by GMP Page 8 of 17 Nucleotide interconversions To change of phosphates by successive ATPdriven phosphorylations catalyzed by kinase enzymes NMP NDP NTP 39 for RNA dNMP dNDP dNTP for DNA Same require ATP name use ulher nucleulidel ND ur NTPI with high Ellery phnsphnte ATP ADP ATP ADP j j N Purine Salvaqe Reactions andrelated diseases BASE NUCLEOTIDE PURINE SALVAGE Phosphoribosyl transferase enzymes A G Base PRPP AGMP PPi gt 2 Pi 1 Adenine PRPP transfernle 2 Hunxnnuiine guanine The hue in m i HGPRT i Salwge nnenen GnugLelcheNyhn 1 PRPP 1 Purine Syntheli 1 Uri neiii Page 9 of 17 Deoxvribonucleotide Biosvnthesis 1 r u a Ribonucleotide Reductase Reaction NDP39s gt dNDP s NADPH NAB 0 foi iocm 0 Base H HI o t Lo ITOCH 0 O H H O 0 H H HO Ribonucleoside Deoxyribonucleoside diphosphate diphosphate All 4 dNDP s AGU0 AMP 6MP UMP I OTP ADP GDP CDP UDP Products of Ribonucleotidereductase ribonudeotide reductase dADP dGDP dCDP dUDP Add P from ATP To get dNTPS For DNA synthesis dATP dGTP dCTP TTP mampg an m 4 MN m m Page 10 of 17 Ribonucleotide Reductase subunits and active site R1 dimer R2 dimer Active site Tyrosine free radical generates X free radical at active site rigquotuse liurnwinry sum 5mm 02W7WHFreeman imampuny Tyrosylradical site Regulation of ribonucleotide reductase reaction Ribonucleotide Reductase Two kinds of reguamry sites I v Allosteric site Active site 39 activity 3 dinerent nucleotide binding sites per R1 subunit Allosteric site specificity Page 11 of 17 Ribonucleotide Reductase Regulation of overall activity ADP GI dADP EATE GDP Ribonucleotide reductase dGDP 539 4 UDP dU DP TTP CDP ATP dCDP dCTP Regulation of substrate specificity ADP e 1gt IADP gtdATPATP dGDP quotgt dGTP GDP UDP CTP Figure 254 Eh Page 12 of 17 S nthesis of dTMP from dUMP to make the first th minecontainin nucleotide Fig 2513 H N N T AWLquot quot Dihydvofolate v n39 0 mt 4k R IiNNVn HJNVNx N5 NiDMglhyleneletrallydrotolale HM K N714 my ANA M P 00 i J C 0 CH1 HN CH HN R 0 HM H H 39 i A g H Enzyme is r H w 7 0 T 7 entymu Hsiemyme o NH decxyribuseP deoxyribcseP i 1hymidylale deaxynbasep TM Deaxyuridine momphosphate dUMP BUT Where does dUMP come from For DNA Thymidylate synthase First Thyminecontaining Nucleotide is dTMP CTP CDP dCDP 5 dCTP nucic hie rllmmicleoudv phosphate dommmg red uciase ki xm e UDP gt dUDP gt dUTP I LIU39I39I use UMP Ppi dUMP 2pi thymidylutv syntlmse 2 more high energi I for dTMP to dTTP dTMP Page uf 17 Hg 25 M 19 JUMP awn Thymldylme Usymhase N5 N OMelhylene Dihydrufolale tetrahydrololate Glycine NADrH H39 unymmmam mdu asc 9 Senne NADP Tehahydrofolate Page 14 of 17 N Enzyme SH HN k 2x I A l 1 c H v 39 s 0 N r 0 N3939 H D HV C S enzyme ideoxyrlboseP deaxyrlboseP Fluoradeoxyuridylate N5N Methylene Stable adduct tetrahydrofulate Coupdi ve In i tm qf Reduth a t crapmtic gents Drug Indications Trimetho prim Antibacterial Antifungal Pyrimethamine Antiprotozoal Antinenplastic Antipsoriatic Anti in ammatory Immunosuppressive Sensitivity of cancers to methotrexate Sensitive Moderately sensitive Not sensitive Acute lylnpllncylic Head and neck cancer Acute myelncylic leukemia leukemia Enrkitts lympluuna Breast cancer Cnlnn cancer Cllnrincarcinnlna Bladder cancer Renal cell cancer Diffuse lymplunna Page150f17 SUMNIARY Main themes of nucleotide biosynthesis gt RNA nucleotides NTPs gt DNA nucleotides dNTPs gt Interconversions ofnucleotides gt Targets of drug chemotherapy Page 16 of 17 SUMMARY S nthesis of RNA nucleotides TPs A G AMP GMP made dc now as purine nucleotides then phosphorylated to ATP and GTP U C UMP to UTP by phosphorylation then add amino group to get CTP SUMMARY Synthesis of DNA nucleotides deTPs dA dG dC le Made from NDPs ADP GDP CDP UDP by ribonucleotide reductase a 14 dNTPs 117111 from dUMP by thymidylate synthase 11 rst dUDP to dUTP to get dUMP dTTP 1 7 SUMMARY INTERCONVERSIONS 0F NUCLEOTIDES High energy Phosphate exchanges PURINE SALVAGE AND DISEASES Gout Lesch Nyhan CHEMOTHERAPY Inhibit speci c enzymes ofnucleotide metabolism Ultimately prevent cell or 57w rzgmm m virus proliferation by inhibiting RNA other nucleutide aiming or DNA synthesis Summam Drugs that affect nucleotide biosynthesis Drugs Anticancer Effects on DNA synthesis Antiviral 1 Thymidylate synthase is target Suicide inhibition reducmse is target Competitive inhibition 3 Nucleotide analogs AZT AIDS Antibrealt cancer ddC Antiviral Stop DNA or RNA synthesis directly polymerase can t use these 2 Dihydrofolate
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