Lecture 19 (2009)

Lecture 19 (2009) - Lecture 19 Nucleotide synthesis ROS and...

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Unformatted text preview: Lecture 19 Nucleotide synthesis ROS and carcinogens Detoxification Principles of regulation Nucleotide Biosynthesis RNA Monomers (NTPs) NH2 N HO H O N H N N HO H O H H OH H H OH OH N N N O N NH NH2 O HO O H H H OH H OH H N HO O H H OH O N NH2 HN O Nucleobase H H OH OH Ribose Adenosine Guanosine Cytidine Uridine DNA Monomers (dNTPs) NH2 N N HO H O H H H OH H N N HO H O H H OH H H H OH H N N N O N NH O NH2 HO O H H H H OH H H N HO O H H O N NH2 HN O Nucleobase Deoxy-ribose Deoxyadenosine Deoxyguanosine Deoxcytidine Deoxythymidine p. 105 Activation of Ribose-5-P (from Pentose-P Pathway) R5P + ATP PRPP + AMP 5-Phospho-ribosyl1-pyrophosphate "Salvage" Pathway Recycling of free nucleobases De novo Synthesis Synthesis of nucleobase structure "Salvage" Pathway PRPP + Nucleobase NMP + PPi ( 2Pi) (A, G, C, T, U) De novo Synthesis Purine bases (A, G): assembled on PRPP platform PRPP Gln, Gly, Asp, CO2, N10-formyl-THF Pyrimidine bases (C, T, U): transfer to PRPP platform Carbamoyl-P, Asp Orotate PRPP Purine Nucleotide Biosynthesis Source of purine atoms CO2 Asp Glycine C6 N1 C5 N7 C8 N10-formyl-THF C2 N3 C4 N9 N10-formyl-THF GLN (amide N) p. 106 Purine synthesis Synthesis of nucleobase on ribose O -O P OH O H OH O O O P O OH OH O P OO- Nucleotide Biosynthesis 5-Phosphoribosyl--pyrophosphate "Activated sugar" 11 steps Inosine monophosphate (IMP) Hypoxanthine base AMP GMP p. 107 Purine Nucleotides Fumarate GDP + Pi Aspartate GTP NAD+ +H2O NADH Purines NH2 N N N N H HN H2N N O N N H HN N O N N H O HN O N H N N H Adenine Guanine Hypoxanthine Xanthine Glutamate AMP + PPi Glutamine ATP At the stage of nucleotides Purine synthesis Synthesis of nucleobase on ribose O -O P OH O H OH O O O P O OH OH O P OO- Nucleotide Biosynthesis 5-Phosphoribosyl--pyrophosphate "Activated sugar" 11 steps Inosine monophosphate (IMP) Hypoxanthine base GTP ATP AMP GMP Reciprocal regulation p. 107 Pyrimidine Nucleotide Biosynthesis Source of pyrimidine atoms C4 ASP Carbamoyl-P N3 C5 C2 N1 C6 p. 106 Pyrimidine synthesis Addition of ribose to synthesized nucleobase O -O P OH O H OH O H O OH O P O OO P OO- O HN O N H COOOrotate 5-Phosphoribosyl--pyrophosphate "Activated sugar" Use of same activated sugar PPi OMP UMP UDP UTP CTP p. 107 Pyrimidine Nucleotides Glu + ADP + Pi Gln + ATP Pyrimidines O HN O N H COON H O NH2 N N H O NH O N H O NH O Orotate Cytosine Uracil Thymine CO2 At the stage of nucleotides Conversion of Ribonucleotides to Deoxyribonucleotides AMP GMP NDP NADH ADP GDP dNDP H 2O GTP dNTP Ribonucleotide Reductase p. 107 Methylation of dUMP to dTMP F-dUMP ("suicide" inhibition) dUTP dUMP dTMP Thymidylate Synthase N5, N10 Methylene THF Gly DHF NADPH + H+ THF DHF Reductase NADP+ Ser Methotrexate (analog of DHF) kills rapidly dividing cells (Anticancer drugs, chemotherapy, many side effects) p. 107 Role of Metabolism in Carcinogenesis Neoplasia Cancer DNA Damage (covalent modification) Reactive Oxygen Species (ROS) SOD Catalase ProCarcinogens (Diet) Phase 1 Enzymes Reactive Intermediates (Carcinogens) Phase 2 Enzymes Detoxification Products (Excretion) p. 108 100,000 mutations per cell and day (rats) (healthy cells, more mutations during infection) Neoplasia Cancer DNA Damage (covalent modification) Reactive Oxygen Species (ROS) Natural Antioxidants (scavengers of free radicals and electrons) Vitamin C (ascorbic acid) Vitamin E (tocopherol, very similar to CoQ) Carotenoids (e.g., lycopene in tomato) Flavanoids (plant-derived products, such as red wine, dark chocolate, dark beer, smoked meat) Superoxide Dismutase Glutathione Peroxidase Catalase Detoxification (ROS H2O, O2) Reactive Oxygen `Species' (ROS) or Intermediates (ROI) Superoxide radical Hydrogen peroxide e2H + Hydroxyl radical eH + O=O e- .O=O- H-O-O-H H2O + .OH eH + 2H2O H+ . O-O-H (2x) H 2 O2 + O2 Catalase H2O + 1.5O2 Superoxide dismutase (SOD) Detoxification p. 108 Glycerol-3-P Shuttle Outer Mitochondrial Membrane G3P DHAP 4H+ + + + + + + + Intermembrane space 4H+ 2H+ + + + + + + + + + + + + + + Cyt c I II - - - - - Q III IV - - - - F0 - - - - O2 NADH + H+ NAD+ O2 O2 + 2H+ H2O ADP + Pi F1 H+ ATP O2 O2 Matrix Biochemistry of Glutathione H3N CH COO CH2 CH2 C O H N CH CH2 SH C O H N CH2COO Glutathione -glutamycysteinylglycine (GSH) p. 109 Antioxidant (scavenger of reactive oxygen species) G3P DHAP 4H+ + + + + + + + Transhydrogenase 4H+ 2H+ + + + + Cyt c I II - - - - - Q III IV NAD+ NADH NADH + H+ NAD+ O2 O2 O2 O2 + 2H+ H2O O2 NADPH NADP+ Superoxide Dismutase 2 G-SH G-S-S-G H2O2 + O2 Glutathione Peroxidase 2 H2 O Role of Metabolism in Carcinogenesis Neoplasia Cancer DNA Damage (covalent modification) Reactive Oxygen Species (ROS) Carcinogens (Diet) Phase 1 Enzymes Reactive Intermediates Phase 2 Enzymes Detoxification Products One-third of cancers are diet-related One-third caused by smoking One-third contributed to chronic infections p. 108 Major Classes of Carcinogens Polycyclic Aromatic Hydrocarbons Aromatic Amines Heterocyclic Aromatic Amines N-Nitroso Compounds Aflatoxins Low MW Unsaturated Compounds ROS/Lipid Peroxidation Products Estrogens Diet, Tobacco, Air Diet, Tobacco Diet, Tobacco Diet, Tobacco Diet Tobacco, Occupation Infection Reproduction Role of Metabolism in Carcinogenesis Phase 1 Enzymes: Monooxygenases (many cytochrome P450s) "Functionalization" (e.g., hydroxylation) Phase 2 Enzymes: Glutathione S-transferases UDP-glucuronosyltransferases Sulfotransferases Quinone oxidoreductases Epoxide hydrolase SOD, Catalase -Glutamylcysteine synthase "Conjugation" followed by excretion p. 108 Biochemistry of Glutathione 4H+ HbFe2+O2 GSSG NADPH + H+ Pentose-P Pathway 2H2O HbFe3+ 2GSH GSH reductase NADP+ G6P 0.5 O2 Prot SH SH GSSG NADPH +H+ Pentose-P Pathway H2 O Prot S 2GSH S GSH reductase NADP+ G6P H2 O Drugs O2 GSSG NADPH + H+ Pentose-P Pathway Drugsox H2O2 2GSH GSH NADP GSH peroxidase reductase + G6P p. 109 Biochemistry of Glutathione NO2 Cl GSH S-transferase S glutathione NO2 + Cl GSH Cl + HCl p. 109 Role of Metabolism in Carcinogenesis Neoplasia Cancer DNA Damage (covalent modification) Reactive Oxygen Species (ROS) Carcinogens (Diet) Phase 1 Enzymes Reactive Intermediates Phase 2 Enzymes Detoxification Products Plant Products p. 108 Broccoli sprouts: An exceptionally rich source of inducers of enzymes that protect against chemical carcinogenesis Proc. Natl. Acad. Sci. USA 94:10367-10372 (1997) Paul Talalay, Johns Hopkins University ...
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This note was uploaded on 09/06/2009 for the course BIS 103 taught by Professor Abel during the Spring '08 term at UC Davis.

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