Model Organisms in Drug Discovery

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SACCHAROMYCES CEREVISIAE AND ITS GENOME: A BRIEF PRIMER 11 freezer or even on a desiccated piece of agar in a forgotten petri dish. (Almost every yeast biologist has had the need to test this last assertion.) It is cheap to feed, non-pathogenic and divides every 2 h. It can grow either aerobically or anaerobically, depending on the nutrients provided, and in solid or liquid media. It can exist stably as a haploid or a diploid, and haploids can be mated and put through meiosis to recover haploid progeny in a matter of days. Although a unicellular organism, it can on occasion display such group characteristics as pseudohyphal growth, intercellular signaling and programmed cell death. Finally, a highly versatile transformation (transfection) system has been available for several decades. You can choose a vector that is linear, circular or integrating, high or low copy number, with a positive or negative selection system, and you can express your favorite gene from several types of regulated promoters. In addition, homologous recombination occurs with high efficiency, allowing the integration of transformed DNA into chromosomes at precise locations, replacing and deleting host DNA as desired. The S. cerevisiae genome sequence was completed and almost entirely annotated for genes in 1996 (Goffeau et al., 1996) but it has not remained static (Kumar et al., 2002c). By comparison to most eukaryotes, coding regions are enviably simple to identify in yeast: about 70% of the genome encodes protein, and only about 4% of yeast genes contain introns, usually as a small insertion very near the 5’ end of the coding region. For expedience, the primary annotaters of the genome set the ability to encode a 100-amino-acid protein as the cutoff for a gene (unless other evidence existed). Each resulting open reading frame (ORF) was given a unique and informative sevencharacter identifier, e.g. YOR107w. This name immediately tells a yeast biologist that the gene lies on the Watson strand of the right arm of chromosome XV, 107 genes distal from the centromere. Unlike the Dewey decimal system, this left no room for additions; fortunately there have been relatively few subsequent modifications of genes because these have had to be dealt with by inelegant suffixes (A, -B, etc.; inconsistencies in their syntax are a common source of error in data handling). This systematic name complements and conforms to the yeast genetic nomenclature adopted by consensus in the 1960s, in which the upper case notation informs us that a wild-type gene is being discussed, a lower case notation would indicate a mutant and Yor107w is the name of the encoded protein. All yeast genes thus have a systematic ORF name; about half of them also have one or more traditional three-letter gene names that are intended to reflect some property of interest, e.g. RAD1 to identify the first gene identified from a mutant screen for radiation sensitivity. Yeast biologists have concluded that clarity in the literature is more important than their egos and nowadays they commonly agree on a single, rational primary gene name maintained in a central registry. These names are certainly duller than those for Drosophila – yeast never had ether-a-gogo but for over a
12 GROWING YEAST FOR FUN AND PROFIT Figure 2.2 A graphical view of a 20-kilobase region of yeast chromosome II, showing 11 open reading frames (ORFs) encoding proteins. The NCBI Reference Sequence project (RefSeq) clones from human and mouse that show significant homology at the protein level are overlaid on their yeast homologs. The view was generated using the browser created by the Generic Model Organism Database Project (www.gmod.org) following customization by Dr N. Siemers decade it did have WHI1 (whiskey1, named in a pub in Scotland) until the title’s overturn by the more prosaic name CLN3 (cyclin3). The number of recognized genes in yeast hovers just above 6000, remaining in flux due to continued research on which of these are spurious and what additions should be made (see Kumar et al., 2002c). Figure 2.2 provides a visual snapshot of a region of the yeast genome and illustrates the significant homology between some of the proteins coded therein and proteins from the mouse and human genomes. Unfortunately, no quantitative cross-comparison between yeast and human genomes has been published since ‘completion’ of the human genome sequence. An analysis performed in 1997 found that about one-third of yeast proteins had significant homology to a mammalian GenBank sequence (Botstein et al., 1997); by 1997 the results from Bassett et al. (1996) had been updated to suggest the existence of yeast homologs for 34% of the 84 disease-related human genes that were positionally cloned at the time. In 1998 a very stringent comparison between yeast and the newly finished Caenorhabditis elegans genome (Chervitz et al., 1998) predicted that about 40% of yeast proteins were orthologous to about 20% of those encoded in worm. Many of the remaining 80% of worm proteins contained domains also present in yeast, but their arrangement within proteins was not identical. Because 80% of C. elegans proteins apparently lack a close relative in yeast, it might seem that there is a low probability of a given gene from a multicellular organism having a yeast homolog that can be studied productively. However, these numbers are skewed by the ‘bulking out’ of the C. elegans proteome by gene duplication events that lead to huge multigene families such as that for the nuclear hormone receptors. Within core metabolic and structural functions there is virtually complete conservation across eukaryotes. A recent comparison between the predicted proteins of the S. pombe and S. cerevisiae
Page 1 and 2: Model Organisms in Drug Discovery M
Page 3 and 4: Copyright u 2003 John Wiley & Sons
Page 5 and 6: Contents List of contributors .....
Page 7 and 8: CONTENTS ix 7 Genetics and Genomics
Page 9 and 10: List of Contributors Hector Beltran
Page 11 and 12: LIST OF CONTRIBUTORS xiii Stefan Sc
Page 13 and 14: 1 Introduction to Model Systems in
Page 15 and 16: Organism INTEGRATING MODEL ORGANISM
Page 17 and 18: INTEGRATING MODEL ORGANISM RESEARCH
Page 19 and 20: INTEGRATING MODEL ORGANISM RESEARCH
Page 21: 10 GROWING YEAST FOR FUN AND PROFIT
Page 25 and 26: 14 GROWING YEAST FOR FUN AND PROFIT
Page 51 and 52: 3 Caenorhabditis elegans Functional
Page 53 and 54: THE DRUG DISCOVERY PROCESS 43 thoug
Page 55 and 56: multivulva phenotype of Ras gain-of
Page 57 and 58: disease. These molecular targets ar
Page 59 and 60: FROM DISEASE TO TARGET 49 Figure 3.
Page 61 and 62: FROM DISEASE TO TARGET 51 Figure 3.
Page 63 and 64: signaling pathway. The third catego
Page 65 and 66: FROM DISEASE TO TARGET 55 resistant
Page 67 and 68: phenomenon was first observed in C.
Page 69 and 70: profiles. The C. elegans gene expre
Page 71 and 72: emerging technologies. Forward gene
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The compound library LEAD DISCOVERY
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LEAD DISCOVERY 65 previous section,
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LEAD DISCOVERY 67 Figure 3.5 Distri
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Compound learning set for assay val
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10 000-15 000 human drug targets ar
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transporter itself. The SSRIs that
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REFERENCES 75 de Montigny, C., Blie
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REFERENCES 77 Lewis, J. A., Wu, C.
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REFERENCES 79 Tissenbaum, H. A. and
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82 DROSOPHILA AS A TOOL FOR DRUG DI
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100 DROSOPHILA AS A TOOL FOR DRUG D
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5 Drosophila - a Model System for T
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EVOLUTIONARY CONSERVATION OF DISEAS
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TARGET IDENTIFICATION/TARGET VALIDA
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CHEMICAL GENETICS 143 acid identity
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3. A hit identifies a biologically
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about their function in a multicell
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REFERENCES 149 Han, Z. S., Enslen,
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REFERENCES 151 Rintelen, F., Stocke
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6 Mechanism of Action in Model Orga
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INTRODUCTION TO COMPOUND DEVELOPMEN
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MODEL ORGANISMS ARRIVE ON THE SCENE
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ELUCIDATING THE MECHANISM OF COMPOU
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ELUCIDATING THE MECHANISM OF COMPOU
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A CASE STUDY FOR ALZHEIMER’S DISE
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NEW CHEMICAL GENETIC STRATEGIES 171
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A CASE STUDY FOR INNATE IMMUNITY 17
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GLOBAL GENE EXPRESSION STUDIES IN M
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As described above, the extensive i
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REFERENCES 179 Austin, J. and Kimbl
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REFERENCES 181 Hughes, T. R., Marto
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REFERENCES 183 Sin, N., Meng, L., W
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186 GENETICS AND GENOMICS IN THE ZE
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8 Lipid Metabolism and Signaling in
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FISH AS A MODEL ORGANISM 205 genes
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LIPID METABOLISM SCREEN 207 transpo
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LIPID METABOLISM SCREEN 209 Figure
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the embryo media containing radioac
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ZEBRAFISH AS A MODEL SYSTEM 213 Fig
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ZEBRAFISH AS A MODEL SYSTEM 215 Reg
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aspirin, which has potent inhibitor
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REFERENCES 219 Chau, I. and Cunning
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REFERENCES 221 Patrono, C., Patrign
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224 CHEMICAL MUTAGENESIS IN THE MOU
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252 SATURATION SCREENING OF DRUGGAB
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280 INDEX bupropion 92 busulfan 143
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282 INDEX Dscam 171 dual-energy X-r
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284 INDEX L-685,818 16 lead discove
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286 INDEX protein function 19-22 pr
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288 INDEX yeast (continued) functio
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