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Transcript
Nucleotides Nucleotide Synthesis purine Main functions: a. to form components of nucleic acids, DNA and RNA b. to form components of essential cofactors (ATP, NAD, FAD, CoA) base CO2 O O O-P-O-CH O O || C methyl THFA CH HN carbamyl P N H N O Purine ring amide of gln N ORIGIN of ATOMS N C methyl THFA O glycine C O P HO O O-P-O-CH O ORIGIN of ATOMS O || C asp HN N N | N N HN sugar Location in cell: in cytoplasm of most cells pyrimidine OH OH aspartate CH C pyrimidine ring N uracil hypoxanthine Origin of Atoms - all atoms in the pentose sugar and phosphates of nucleotides originate from PRPP O O=P-O CH O H ribose-5-P O O O O-P-O ~ P = O O O from ATP Nucleotide Metabolism Endproducts: purine path - AMP, GMP pyrimidine path -UMP Pyrimidine de novo path Pyrimidine de novo path COO HC-NH3 NH2 -C-O-P-O CH2 O C=O asp carbamyl P ATCase O O NH2 O O= C O-C=O CH2 CH NH COO C=O CH2 HN NH2 O-C=O CH2 CH NH COO O= C O= C N H O Me-THFA C DHFA || HN CH HN OC CH C O C thymine C-CH3 uracil O N P CH N P • thymine nucleotides are found in DNA • uracil nucleotides are found in RNA • rapidly dividing cells must replicate DNA rapidly and require rapid production of thymine nucleotides • by preventing formation of thymine nucleotides, rapidly dividing cells are killed Water-soluble vitamins and their cofactors - many vitamins are converted to adenine nucleotides cofactors inside cells - specific kinase enzymes condense vitamin with ATP to produce the active form of the cofactor orotic acid Thymine vs. Uracil nucleotides Thymine nucleotides • thymine containing nucleotides are formed from uracil nucleotides CH COO Thiamin / TPP thiamin + ATP A-r N N N N S thiamin-PP + AMP A-r-P P~P~P TPP is the cofactor in oxidative decarboxylations (CO2 is removed in a redox reaction) e.g. pyr acetyl CoA Riboflavin / FMN riboflavin + ATP N N N FMN + Pi N A-r-P~P~P N FMN / FAD N FMN + ATP N N N N N N FMN is a cofactor in oxidation/reduction reactions. e.g. in the ETS system N N C-NH2 O P FAD is a cofactor in oxidation/reduction reactions, accepting H atoms. e.g. succinate fumarate NMN + P~P N C-NH2 O NAD + + P~P A-r -P~P~P C-NH2 O N N N P~P~ P N N N r P r NMN is the precursor for NAD NAD+ is cofactor in redox reactions r isocitrate + KG + NAD:H + H+ NAD+ participates in oxidations where a hydride ion (H:) and proton are removed from the substrate. C-NH2 O N P~P N N N r pyridoxal/pyridoxal P (PLP) H O C NAD+ N NMN / NAD+ NMN + P~P P N A-r-P~P Niacin / NMN niacotinamide + Pr-PP N A-r-P~P~P P P FAD + P~P H C-OH H + ATP N pyridoxal + A-r-P~P~P H O C H O C-O-P-O H O + N PLP + A-r-P~P PLP is required in all transamination reactions. Biotin / N-carboxybiotin biotin + HCO3 + ATP HN HO-C=O O- NH S N-carboxybiotin + ADP + P O- S DHfolate THfolate serine glycine methyl-THFA methyl-THfolate adds methyl group in many cellular reactions Methotrexate inhibits THFA formation X DHFA THFA ser THFA R THFA and methyl transfer reactions • FA DHfolate thymine-dr-P uracil-dr-P N-carboxybiotin is used in carboxylations. • folate • folate N -C=O N CH-CH-CH-CH-COO Folic acid / THFA X gly methyl-THFA THFA is required for many methyl transfer reactions in pathways Chemotherapy • methotrexate is a structural anolog of folate and prevents conversion of folate to THFA in cells • only THFA can receive methyl group from serine • in presence of methotrexate THFA is not formed; no T nucleotides are formed and DNA synthesis stops Chemotherapy THFA ser thymine-r-P uracil-r-P gly methyl-THFA THFA Thymine nucleotides are not made and DNA synthesis is stopped. • rapidly dividing cells die when DNA is not replicated; slowly dividing cells usually survive • methotrexate kills cancer cells but must be followed immediately by Leucovorin, methyl THFA , to rescue the normal (non-cancer) cells Synthesis of Nucleotides and vitamin cofactors Tracing pathways - most human cells make nucleotides by condensing nucleosides with ATP Using C14 - labelled alanine , show a plausible route (metabolic pathways) by which each of the following compounds may become labelled with C14. - all the water-soluble vitamins must be activated, often by condensing the vitamin with ATP to form a nucleotide cofactor glycogen glu glu c. acetylCoA g-6-P r-5-P a. glucose b. tripalmitate glu citrate f-6-P glu g-6-P f-6-P gly.P f-1,6-diP 3-PG OAA pyr PEP malate malate DHAP pyr OAA f-1,6-diP gly.P pyr malate DHAP 3-PG acetyl Co A citrate OAA isocitrate succinate succ.CoA G OAA pyr OAA m malate pyr PEP malate pyr ala pyr malate OAA b. ala to tripalmitate a. ala to glucose ala DHAP c malate OAA ala pyr acetyl CoA tripalmitate citrate palmitate citrate c. ace. CoA glucose ala pyr tripalmitate OAA malate malate OAA glycerolP DHAP PEP Tracing pathways a. OAA to pfk Using C14 - labelled OAA , show a plausible route (the metabolic pathways) by which each of the following compounds may become labelled. a. phosphofructokinase b. palmitate b. OAA to palmitate OAA PEP pyr c.acetyl CoA palmitate pyr c. citrate acetyl CoA citrate OAA asp asp-tRNA protein - pfk