We analyzed sequence variation for chalcone synthase (Chs) and alcohol dehydrogenase (Adh) loci in 28 species in the genera Arabidopsis and Arabis and related taxa from tribe Arabideae. Chs was single-copy in nearly all taxa examined, while Adh duplications were found in several species. Phylogenies constructed from both loci confirmed that the closest relatives of Arabidopsis thaliana include Arabidopsis lyrata, Arabidopsis petraea, and Arabidopsis halleri (formerly in the genus Cardaminopsis). Slightly more distant are the North American n = 7 Arabis (Boechera) species. The genus Arabis is polyphyletic-some unrelated species appear within this taxonomic classification, which has little phylogenetic meaning. Fossil pollen data were used to compute a synonymous substitution rate of 1.5 x 10 substitutions per site per year for both Chs and Adh. Arabidopsis thaliana diverged from its nearest relatives about 5 MYA, and from Brassica roughly 24 MYA. Independent molecular and fossil data from several sources all provide similar estimates of evolutionary timescale in the Brassicaceae.

We have used an ∼8.7-Mb BAC contig of Arabidopsis thaliana Chromosome 4 to trace homeologous chromosome regions in 21 species of the family Brassicaceae. Homeologs of this segment could be identified in all tested species. Painting of pachytene chromosomes of Calepina, Conringia, and Sisymbrium species (2n = 14, 16), traditionally placed in tribe Brassiceae, showed one homeologous copy of the Arabidopsis contig, while the remaining taxa of the tribe (2n = 14-30) revealed three, and three Brassica species (2n = 34, 36, and 38) and Erucastrum gallicum (2n = 30) had six copies corresponding to the 8.7-Mb segment. The multiple homeologous copies corresponded structurally to the Arabidopsis segment or were rearranged by inversions and translocations within the diploidized genomes. These chromosome rearrangements accompanied by chromosome fusions/fissions led to the present-day chromosome number variation within the Brassiceae. Phylogenetic relationships based on the chloroplast 5Ј-trnL (UAA)-trnF(GAA) region and estimated divergence times based on sequence data of the chalcone synthase gene are congruent with comparative painting data and place Calepina, Conringia, and Sisymbrium outside the clade of Brassiceae species with triplicated genomes. Most likely, species containing three or six copy pairs descended from a common hexaploid ancestor with basic genomes similar to that of Arabidopsis. The presumed hexaploidization event occurred after the Arabidopsis-Brassiceae split, between 7.9 and 14.6 Mya.[The following individuals kindly provided reagents, samples, or unpublished information as indicated in the paper:The Brassiceae is one of the most morphologically distinct tribes within the Brassicaceae family (Cruciferae). The Brassiceae tribe is a monophyletic group (e.g., Warwick and Black 1997a,b; Anderson and Warwick 1999) comprising ∼240 species in 49-54 genera (Gómez-Campo 1999;Warwick et al. 2000), and includes economically important Brassica crops. Although the basic genome structure of six Brassica crop species was unraveled early (e.g., U 1935), there is a long-lasting debate on the origin and evolution of karyotypes in the genus Brassica and the tribe Brassiceae. The variation in basic chromosome numbers (x = 6-18) (Warwick et al. 2000) makes it difficult to decide whether species with higher basic chromosome numbers are genuine diploids or polyploids. In many Brassiceae genera, species with the lowest chromosome number are considered as diploid. Several hypotheses on ancestral basic numbers (x = 3-7) and karyotype evolution in the Brassiceae have been put forward (for review, see Prakash and Hinata 1980;Truco et al. 1996;Anderson and Warwick 1999;Prakash et al. 1999). However, without knowing phylogenetic relationships and the history of polyploidy of the Brassiceae, unambiguous conclusions cannot be drawn.Already early studies suggested that diploid Brassica species represent "balanced secondary polyploids" exhibiting internal chromosome homeology and genome duplications (e.g., Catcheside 1934;Röbbelen 196...

The identification of small molecules that fall within the biologically relevant subfraction of vast chemical space is of utmost importance to chemical biology and medicinal chemistry research. The prerequirement of biological relevance to be met by such molecules is fulfilled by natural product-derived compound collections. We report a structural classification of natural products (SCONP) as organizing principle for charting the known chemical space explored by nature. SCONP arranges the scaffolds of the natural products in a tree-like fashion and provides a viable analysis-and hypothesis-generating tool for the design of natural product-derived compound collections. The validity of the approach is demonstrated in the development of a previously undescribed class of selective and potent inhibitors of 11␤-hydroxysteroid dehydrogenase type 1 with activity in cells guided by SCONP and protein structure similarity clustering. 11␤-hydroxysteroid dehydrogenase type 1 is a target in the development of new therapies for the treatment of diabetes, the metabolic syndrome, and obesity.chemical biology ͉ compound libraries ͉ hydroxysteroid dehydrogenase ͉ cheminformatics T he efficient identification of small molecules that modulate protein function in vitro and in vivo is at the heart of chemical biology and medicinal chemistry research and the development of new therapies and diagnostics for disease. Key to their discovery is the identification and charting of biologically relevant space, i.e., the regions of complete chemical space that are relevant to biology (1-5). The underlying structures of evolutionary selected natural products (NPs) define structural prerequisites for binding to proteins (4, 6). Their structural scaffolds represent the biologically relevant and prevalidated fractions of chemical structure space explored by nature so far. Consequently, the probability that compound libraries designed to mimic the structures and properties of NP classes will be biologically relevant is high, and it is also to be expected that ''NP-guided compound library development'' (1, 4) will prove to be a viable guiding principle for the identification of small molecules for chemical biology and medicinal chemistry research (1-6).A systematic structure-orientated organizing principle of the known NPs combined with annotations of biological origin and pharmacological activity would chart the regions of chemical space explored by nature, provide a structural rationalization and categorization of NP diversity, and also provide guidance for the development of NP-like compound libraries.Statistical analyses of different NP databases have been performed in a few cases (7-10); however, a systematic and annotated structural categorization of NPs leading to development principles for compound library design is missing.Here, we introduce a structural classification of NPs (SCONP) as a idea-and hypothesis-generating tool to define structural relationships between different NP classes in a tree-like arrangement and for the design of NP-de...