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基因體學研究在藥學上之應用 Nucleic Acid Structure DNA Structure nitrogenous bases – A, T, G, C pentose sugar – deoxyribose usually a double helix, composed of two complementary strands – base pairing rules A with T G with C nucleoside = nitrogenous base + pentose sugar phosphodiester bond two polynucleotide chains are antiparallel RNA Structure nitrogenous bases – A, G, C, U (instead of T) pentose sugar – ribose usually consists of single strand – can coil back on itself forms hair-shaped structures with complementary base pairing and helical organization base pairing rules – A with U – G with C Types of RNA three types – ribosomal RNA (rRNA) – transfer RNA (tRNA) – messenger RNA (mRNA) differ from each other in function, site of synthesis in eucaryotic cells, and structure The Central Dogma Pattern of DNA Synthesis semiconservative – each parental strand is conserved – two parental strands separate and serve as templates for synthesis of new strands transcription recognition site for ribosome synthesis continues until terminator reached E. coli ribosome site where amino acid is attached complementary to codon in mRNA Aminoacyl-tRNA amino acid rest of tRNA initiation codon transpeptidation reaction Pharmacogenomics • prolonged muscle relaxation after Suxamethonium v.s. inherited deficiency of plasma cholinesterase Hemolysis after antimalarial therapy v.s. inherited level of erythrocyte glucose 6phosphate dehydrogenase • peripheral neutropathy of isoniazid v.s. inherited differences in acetylation of isoniazid • Pharmacogenetics define the more narrow spectrum of inherited differences in the drug metabolism and disposition • Genes are considered to be polymorphic when variant alleles exist stably in the population - Gene Polymorphism • Gene locus A specific place on a chromosome where a gene is located • Allele One of the different forms of a gene that can exist at a single locus • Allele frequency The proportion of all alleles of that gene in the population that are of this specific type P AA Gametes aa X a A Zygote Locus Aa ½A ½a ½A ¼ AA ¼ Aa ½a ¼ Aa ¼ aa • Multiple allelle A, B, C, D…. Etc. Genetic variation at the galactosemia locus • gene encodes galactose-1-phosphate uridyltransferase (GALT) • recessive mutation results in inability to metabolize galactose • causes mental retardation and death • some protection afforded by complete removal of milk from the diet • variant alleles exist in addition to several galactosemia (g) alleles • spectrum of enzymatic activities indicates that “normal” individuals do not all have the same enzymatic activity levels Genotype Frequency G/G G/D G/LA G/g D/D D/LA LA/LA D/g LA/g g/g 87.4% 7.5 3.7 0.9 0.16 0.16 0.04 0.04 0.02 0.0025 Enzyme Activity 100 75 120 50 50 95 140 25 70 <5 Phenotype Normal Normal Normal Normal Normal Normal Normal Borderline Normal Galactosemia Relative number of individuals Population distribution of “normal” GALT activities G/G G/g G/LA G/D g/g 0 20 40 60 80 100 120 140 Relative GALT enzyme activity 160 CLASSIFICATION Phase I (Functionalization): Phase II (Conjugation): Oxidation Cytochrome P450(CYP) Alcohol Dehydrogenase(ADH) Monoamine Oxidase Reduction Cytochrome P450 Hydrolysis Esterases Amidases Glucuronosyltransferases(GT) N-Acetyltransferases(NAT) Sulfotransferases (ST) Methyltransferases (MT) Glutathione Transferases(GST) Amino Acid Transferases • Single nucleotide polymorphism - Common variations among DNA of individuals Nature Biotechnology May 2000 Volume 18 Number 5 pp 505 - 508 The use of single-nucleotide Polymorphism maps in pharmacogenomics Jeanette J. McCarthy1 & Rolf Hilfiker2 1. Millennium Predictive Medicine, Inc., Cambridge, MA 02139. 2. Solvias AG, Basel, Switzerland. • Metabolic polymorphism • Polymorphism of target proteins (e.g. receptors) • Transporter polymorphism Genetic Polymorphisms in Drug Metabolism and Disposition • Pharmacogenomics Refer to the entire spectrum of genes that determine the drug behavior and sensitivity