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1、Chapter 8Nucleotide MetabolismNucleotides are bilding blocks of nucleic acids.They are non-essential nutrients , because they can besynthesized in the body.Nucleic acids occur in the nucleoprotein.Dietary nucleoprotein is digested in the stomach to yield protein and nucleic acids.Nucleic acids are f
2、urther digested in the small intestine togenerate nucleotides.Nucleotides are absorbed into intestinal mucosa cells , wherethey are degraded to three components : base , pentose andphosphate.Pentose is absorbed but base is degraded and excreted.Fnuctions of Nucleotides1. They serve as building block
3、s of nucleic acids.2. ATP plays an important pole in energy transformation.3. ATP , ADP, and AMP may function as allosteric regula-tors and participate in regulation of many metabolic path-ways. ATP involves in covalent modification of enzymes.4. CAMP and cGMP are second messengers.5. They are compo
4、nents of some coenzymes , such asADP in FAD , ADP in HSCoA etc.6 . They are carriers of active metabolic intermediatessuch as UDPG , SAM , CDP-DG etc.Purine Nucleotide MetabolismAnabolismThere are two pathways of synthesis of purine nucleotides :the de novo synthesis pathway and the salvage pathway.
5、The former is the main synthesis pathway of nucleotides , the latter is important I brain and bone marrow.The de novo synthesis of purine nucleotide means usingphosphoribose , amino acids , one carbon units and CO2as raw materials to synthesize purine nucleotide from thebeginning.fig 8-2The pathway
6、can be divided into two stages.Stage one : formation of inosine monophosphate ( IMP )Stage two : conversion of IMP to either AMP or GMPStage OnePRPP synthetase R5P + ATP-PRPP + AMPamidotransferase PRPP + Gln-PRA + GluOnce PRA is formed , the building of the purine ringstructure begins.In nine succes
7、sive reactions the first purine nucleotideIMP is formed.fig. 8-3Stage TwoThe conversion of IMP either to AMP or GMP requirestwo reactions.GTP,Mg+,adenylosuccinate synthase IMP + Asp-adenylosuccinateadenylosuccinate lyase Adenylosuccinate-AMP + fumarateIMP dehydrogenase IMP + H2O + NAD+-XMP + NADH +
8、H+ATP, Mg+, GMP synthase XMP + Gln-GMP + GluNucleoside triphosphates are the most common nucleotide used in metabolism.ATP is synthesized from ADP and Pi via oxidative phos-phorylation or substrate level phosphorylation.ADP is synthesized from AMP in a reaction catalyzed byadenylate kinase.AMP + ATP
9、- 2ADPOther NTPs are also synthesized in ATP-requiring reactionscatalyzed by corresponding NMP kinases.NMP + ATP-NDP + ADPNDP kinase catalyzes the formation of NTP.NDP + ATP-NTP + ADPRegulation of de novo PathwayPRPP activates amidotransferase.IMP , AMP and GMP inhibit PRPP synthetase.AMP inhibits c
10、onversion of IMP to GMP and GMP inhibitsconversion of IMP to GMP.ATP stimulates conversion of IMP to GMP and GTP stimulatesconversion of IMP to AMP.That ensures a balanced synthesis of both families of purine nuc-leotides.Salvage Pathway of Purine NucleotidesMany cells have mechanisms to retrieve pu
11、rine bases and purine nucleosides. They are used to synthesize purine nu-cleotides.This is the salvage pathway.From Base to NucleotidesAPRT A + PRPP-AMP + ppiHGPRT H + PRPP- IMP + ppiHGPRT G + PRPP-GMP + ppiFrom Nucleoside to NucleotideAR kinase AR + ATP-AMP + ADPIn comparison to de novo pathway, sa
12、lvage pathway is energy-saving. In brain and bone marrow tissues salvage pathway is theonly pathway of nucleotide synthesis.Deficiency of HGPRT causes Lesch Nyhan syndrome.Formation of DeoxynucleotidesDeoxynucleotides are formed by reducing ribonucleotide diphosphates.ribonucleotide reductaseNDP + N
13、ADPH + H+-dNDP + H2O + NADP+In the reaction hydrogen atoms are not directly donated by NADPH.Thioredoxin, a protein with two sulfhydryl groups mediates the trans-fer of hydrogen atoms from NADPH to ribonucleotide reductase.Then the enzyme catalyzes the reduction of NDP, to form dNDP.NDP reductaseNDP
14、 + thioredoxin ( SH )2 -dNDP + thioredoxin (-S-S-)The regeneration of reduced thioredoxin is catalyzed by thioredoxin reductase.thioredoxin (-S-S-) +NADPH +H+ thioredoxin ( SH )2+NADPHNDP reductase is an allosteric enzyme, Its activity is controled by various NTPs and dNTPs.Antimetabolites of Purine
15、 NucleotidesAntimetabolites of purine nucleotides are analogues of purine,amino acids or folic acid.They either act as competitive inhibitors of enzymes in purine nucleotides synthesis or can be incorporated into purine nucleo-tides.Thus they block purine nucleotides synthesis or interfere in nuc-leic acids synthesis.6-MP and 6-MG are purine analogues6-MP can be converted to 6-MP nucleotide in the body.6-
