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In Alzheimer's disease and spongiform encephalopathies proteins transform from their native states into fibrils. We find that several amyloid-forming proteins harbor an ␣-helix in a polypeptide segment that should form a ␤-strand according to secondary structure predictions. In 1324 nonredundant protein structures, 37 ␤-strands with >7 residues were predicted in segments where the experimentally determined structures show helices. These discordances include the prion protein

SummaryShort-chain dehydrogenases/reductases (SDR) constitute one of the largest enzyme superfamilies with presently over 46 000 members. In phylogenetic comparisons, members of this superfamily Correspondence to: Bengt Persson and Udo Oppermann, bpn@ifm.liu.se, udo.oppermann@sgc.ox.ac.uk. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. show early divergence where the majority have only low pair-wise sequence identity, although sharing common structural properties. The SDR enzymes are present in virtually all genomes investigated, and in humans over 70 SDR genes have been identified. In humans, these enzymes are involved in the metabolism of a large variety of compounds, including steroid hormones, prostaglandins, retinoids, lipids and xenobiotics. It is now clear that SDRs represent one of the oldest protein families and contribute to essential functions and interactions of all forms of life. As this field continues to grow rapidly, a systematic nomenclature is essential for future annotation and reference purposes. A functional subdivision of the SDR superfamily into at least 200 SDR families based upon hidden Markov models forms a suitable foundation for such a nomenclature system, which we present in this paper using human SDRs as examples. NIH Public Access

Short-chain dehydrogenases/reductases (SDRs) are enzymes of great functional diversity. Even at sequence identities of typically only 15-30%, specific sequence motifs are detectable, reflecting common folding patterns. We have developed a functional assignment scheme based on these motifs and we find five families. Two of these families were known previously and are called ÔclassicalÕ and ÔextendedÕ families, but they are now distinguished at a further level based on coenzyme specificities. This analysis gives seven subfamilies of classical SDRs and three subfamilies of extended SDRs. We find that NADP(H) is the preferred coenzyme among most classical SDRs, while NAD(H) is that preferred among most extended SDRs. Three families are novel entities, denoted ÔintermediateÕ, ÔdivergentÕ and ÔcomplexÕ, encompassing short-chain alcohol dehydrogenases, enoyl reductases and multifunctional enzymes, respectively. The assignment scheme was applied to the genomes of human, mouse, Drosophila melanogaster, Caenorhabditis elegans, Arabidopsis thaliana and Saccharomyces cerevisiae. In the animal genomes, the extended SDRs amount to around one quarter or less of the total number of SDRs, while in the A. thaliana and S. cerevisiae genomes, the extended members constitute about 40% of the SDR forms. The numbers of NAD(H)-dependent and NADP(H)-dependent SDRs are similar in human, mouse and plant, while the proportions of NAD(H)-dependent enzymes are much lower in fruit fly, worm and yeast. We show that, in spite of the great diversity of the SDR superfamily, the primary structure alone can be used for functional assignments and for predictions of coenzyme preference.Keywords: short-chain dehydrogenases/reductases; genome; coenzyme; sequence patterns; bioinformatics.Short-chain dehydrogenases/reductases (SDRs) are enzymes of 250 residue subunits catalysing NAD(P)(H)-dependent oxidation/reduction reactions. The concept of SDRs was established in 1981 [1], at a time when the only members known were a prokaryotic ribitol dehydrogenase and an insect alcohol dehydrogenase. Since then, the SDR family has grown enormously, both in the number of known members and the diversity of their functions. Already some years ago, over 1000 forms were ascribed to the SDR superfamily [2], and currently at least 3000 members, including species variants, are known with a substrate spectrum ranging from alcohols, sugars, steroids and aromatic compounds to xenobiotics. The N-terminal region binds the coenzymes NAD(H) or NADP(H), while the C-terminal region constitutes the substrate binding part. Although the residue identity is as low as 15-30%, the 3D folds are quite similar, except for the C-terminal regions. The SDRs have been divided into two large families, ÔclassicalÕ and ÔextendedÕ, with different Gly-motifs in the coenzyme-binding regions, and different chain lengths; around 250 residues in classical SDRs and 350 in extended SDRs [3]. Few residues are completely conserved, but several sequence motifs are distinguishable within the families.It is d...

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The short‐chain dehydrogenase/reductase (SDR) superfamily now has over 47 000 members, most of which are distantly related, with typically 20–30% residue identity in pairwise comparisons, making it difficult to obtain an overview of this superfamily. We have therefore developed a family classification system, based upon hidden Markov models (HMMs). To this end, we have identified 314 SDR families, encompassing about 31 900 members. In addition, about 9700 SDR forms belong to families with too few members at present to establish valid HMMs. In the human genome, we find 47 SDR families, corresponding to 82 genes. Thirteen families are present in all three domains (Eukaryota, Bacteria, and Archaea), and are hence expected to catalyze fundamental metabolic processes. The majority of these enzymes are of the ‘extended’ type, in agreement with earlier findings. About half of the SDR families are only found among bacteria, where the ‘classical’ SDR type is most prominent. The HMM‐based classification is used as a basis for a sustainable and expandable nomenclature system.

We demonstrate that in order to kill cancer cells MTH1 inhibitors must also introduce oxidized nucleotides into DNA. Furthermore, we describe TH1579 as a best-in-class MTH1 inhibitor, which we expect to be useful in order to further validate the MTH1 inhibitor concept.

BackgroundShort-chain dehydrogenases/reductases (SDRs) form one of the largest and oldest NAD(P)(H) dependent oxidoreductase families. Despite a conserved ‘Rossmann-fold’ structure, members of the SDR superfamily exhibit low sequence similarities, which constituted a bottleneck in terms of identification. Recent classification methods, relying on hidden-Markov models (HMMs), improved identification and enabled the construction of a nomenclature. However, functional annotations of plant SDRs remain scarce.ResultsWide-scale analyses were performed on ten plant genomes. The combination of hidden Markov model (HMM) based analyses and similarity searches led to the construction of an exhaustive inventory of plant SDR. With 68 to 315 members found in each analysed genome, the inventory confirmed the over-representation of SDRs in plants compared to animals, fungi and prokaryotes. The plant SDRs were first classified into three major types — ‘classical’, ‘extended’ and ‘divergent’ — but a minority (10% of the predicted SDRs) could not be classified into these general types (‘unknown’ or ‘atypical’ types). In a second step, we could categorize the vast majority of land plant SDRs into a set of 49 families. Out of these 49 families, 35 appeared early during evolution since they are commonly found through all the Green Lineage. Yet, some SDR families — tropinone reductase-like proteins (SDR65C), ‘ABA2-like’-NAD dehydrogenase (SDR110C), ‘salutaridine/menthone-reductase-like’ proteins (SDR114C), ‘dihydroflavonol 4-reductase’-like proteins (SDR108E) and ‘isoflavone-reductase-like’ (SDR460A) proteins — have undergone significant functional diversification within vascular plants since they diverged from Bryophytes. Interestingly, these diversified families are either involved in the secondary metabolism routes (terpenoids, alkaloids, phenolics) or participate in developmental processes (hormone biosynthesis or catabolism, flower development), in opposition to SDR families involved in primary metabolism which are poorly diversified.ConclusionThe application of HMMs to plant genomes enabled us to identify 49 families that encompass all Angiosperms (‘higher plants’) SDRs, each family being sufficiently conserved to enable simpler analyses based only on overall sequence similarity. The multiplicity of SDRs in plant kingdom is mainly explained by the diversification of large families involved in different secondary metabolism pathways, suggesting that the chemical diversification that accompanied the emergence of vascular plants acted as a driving force for SDR evolution.