Biomedical subjects

Minoru Kanehisa

Publications and source records attributed to Minoru Kanehisa.

At least 37 records · Page 2Linked to original sources

PubMed2005

Positive regulation of sugar catabolic pathways in the cyanobacterium Synechocystis sp. PCC 6803 by the group 2 sigma factor sigE.

The sigE gene of Synechocystis sp. PCC 6803 encodes a group 2 sigma factor for RNA polymerase and has been proposed to function in transcriptional regulation of nitrogen metabolism. By using microarray and Northern analyses, we demonstrated that the abundance of transcripts derived from genes important for glycolysis, the oxidative pentose phosphate pathway, and glycogen catabolism is reduced in a sigE mutant of Synechocystis maintained under the normal growth condition. Furthermore, the activities of the two key enzymes of the oxidative pentose phosphate pathway, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, encoded by the zwf and gnd genes were also reduced in the sigE mutant. The dark enhancements in both enzyme activity and transcript abundance apparent in the wild type were eliminated by the mutation. In addition, the sigE mutant showed a reduced rate of glucose uptake and an increased intracellular level of glycogen. Moreover, it was unable to proliferate under the light-activated heterotrophic growth conditions. These results indicate that SigE functions in the transcriptional activation of sugar catabolic pathways in Synechocystis sp. PCC 6803.

Bacterial Proteins↗

PubMed2005

Supervised enzyme network inference from the integration of genomic data and chemical information.

MOTIVATION: The metabolic network is an important biological network which relates enzyme proteins and chemical compounds. A large number of metabolic pathways remain unknown nowadays, and many enzymes are missing even in known metabolic pathways. There is, therefore, an incentive to develop methods to reconstruct the unknown parts of the metabolic network and to identify genes coding for missing enzymes. RESULTS: This paper presents new methods to infer enzyme networks from the integration of multiple genomic data and chemical information, in the framework of supervised graph inference. The originality of the methods is the introduction of chemical compatibility as a constraint for refining the network predicted by the network inference engine. The chemical compatibility between two enzymes is obtained automatically from the information encoded by their Enzyme Commission (EC) numbers. The proposed methods are tested and compared on their ability to infer the enzyme network of the yeast Saccharomyces cerevisiae from four datasets for enzymes with assigned EC numbers: gene expression data, protein localization data, phylogenetic profiles and chemical compatibility information. It is shown that the prediction accuracy of the network reconstruction consistently improves owing to the introduction of chemical constraints, the use of a supervised approach and the weighted integration of multiple datasets. Finally, we conduct a comprehensive prediction of a global enzyme network consisting of all enzyme candidate proteins of the yeast to obtain new biological findings. AVAILABILITY: Softwares are available upon request.

Algorithms↗

PubMed2005

Global analysis of circadian expression in the cyanobacterium Synechocystis sp. strain PCC 6803.

Cyanobacteria are the only bacterial species found to have a circadian clock. We used DNA microarrays to examine circadian expression patterns in the cyanobacterium Synechocystis sp. strain PCC 6803. Our analysis identified 54 (2%) and 237 (9%) genes that exhibited circadian rhythms under stringent and relaxed filtering conditions, respectively. The expression of most cycling genes peaked around the time of transition from subjective day to night, suggesting that the main role of the circadian clock in Synechocystis is to adjust the physiological state of the cell to the upcoming night environment. There were several chromosomal regions where neighboring genes were expressed with similar circadian patterns. The physiological functions of the cycling genes were diverse and included a wide variety of metabolic pathways, membrane transport, and signal transduction. Genes involved in respiration and poly(3-hydroxyalkanoate) synthesis showed coordinated circadian expression, suggesting that the regulation is important for the supply of energy and carbon source in the night. Genes involved in transcription and translation also followed circadian cycling patterns. These genes may be important for output of the rhythmic information generated by the circadian clock. Our findings provided critical insights into the importance of the circadian clock on cellular physiology and the mechanism of clock-controlled gene regulation.

3-Hydroxybutyric Acid↗

PubMed2005

Utilizing evolutionary information and gene expression data for estimating gene networks with bayesian network models.

Since microarray gene expression data do not contain sufficient information for estimating accurate gene networks, other biological information has been considered to improve the estimated networks. Recent studies have revealed that highly conserved proteins that exhibit similar expression patterns in different organisms, have almost the same function in each organism. Such conserved proteins are also known to play similar roles in terms of the regulation of genes. Therefore, this evolutionary information can be used to refine regulatory relationships among genes, which are estimated from gene expression data. We propose a statistical method for estimating gene networks from gene expression data by utilizing evolutionarily conserved relationships between genes. Our method simultaneously estimates two gene networks of two distinct organisms, with a Bayesian network model utilizing the evolutionary information so that gene expression data of one organism helps to estimate the gene network of the other. We show the effectiveness of the method through the analysis on Saccharomyces cerevisiae and Homo sapiens cell cycle gene expression data. Our method was successful in estimating gene networks that capture many known relationships as well as several unknown relationships which are likely to be novel. Supplementary information is available at http://bonsai.ims.u-tokyo.ac.jp/~tamada/bayesnet/.

Bayes Theorem↗

PubMed2005

Conservation of gene co-regulation between two prokaryotes: Bacillus subtilis and Escherichia coli.

We measured conservation of gene co-regulation between two distantly related prokaryotes, B. subtilis and E. coli. The co-regulation between genes was extracted from knowledge of regulation of genes stored in databases. For B. subtilis operons, we obtained the data set from ODB which we have developed and, for the regulons, we used DBTBS. For E. coli data set, we used known regulons derived from RegulonDB. We obtained a reliable data set of co-regulated genes in B. subtilis and E. coli. About 60-80 % of gene pairs conserved co-regulation relationships, so co-regulation between genes are highly conserved even between distantly related species. To measure the functional relationship between these conserved genes, we used KEGG PATHWAY and COG. When two co-regulated genes are in the same biological pathway in KEGG or share the same functional category in COG, we assume that they have the same function. As a result, we also found that many conserved co-regulated gene pairs share the same functions. These observations would help to predict gene co-regulation and protein functions.

Bacillus subtilis↗

PubMed2005

Comprehensive analysis and prediction of synthetic lethality using subcellular locations.

The lethality of a gene is a fundamental and representative measure for understanding the function of a gene and its associated bio-systems. Recently, many research groups have started focusing on the concept of synthetic lethality. The synthetic lethality between genes is defined by the combination of mutations in two genes causing cell death. Here, we confirm that synthetic lethality and cellular location have close relationships among the Saccharomyces cerevisiae genes. Furthermore, we attempt the prediction of candidate gene pairs with synthetic lethality. The prediction is based on the hierarchical aspect model (HAM) which learns from a data set of cellular location to estimate a likelihood value indicating the synthetic lethality between genes.

Cell Death↗

PubMed2005

Comparative analysis of DNA-binding proteins between thermophilic and mesophilic bacteria.

Thermophilic bacteria are one of the most attractive forms of life, and their adaptation mechanisms to elevated temperatures have been extensively studied over the years. Thermal adaptations of cell components such as proteins and RNA are well studied, but adaptations of interactions between these components must be also vital for the thermophiles. Protein-DNA interactions play crucial roles in the cell, but little is known about their thermal adaptations. In this study, we analyzed DNA-binding proteins from thermophilic bacteria. Comparison of amino acid compositions at the DNA-binding interfaces between thermophiles and their mesophilic close relatives revealed several commonalities between phylogenetically unrelated organisms. Advantages and limitations of our methods will be also discussed.

Adaptation, Physiological↗

PubMed2005

A global representation of the carbohydrate structures: a tool for the analysis of glycan.

Glycan resources have been developed of late, such as carbohydrate databases, analysis tools, and algorithms for analysis of carbohydrate features. With this background, bioinformatics approaches to carbohydrate research have recently begun using a large amount of protein and carbohydrate data. This paper introduces one of these projects that elucidates the range of carbohydrate structures. In this study, the variety of carbohydrate structures have been enumerated in a global tree structure called variation trees, using the KEGG GLYCAN database, which is a public-domain glycan resource for bioinformatics analysis. Additionally, a glycosyltransferase mapping list of glycosyltransferases and their catalyzing glycosidic linkages was constructed. From this, we present the composite structure map (CSM), which is a structural variation map integrating its variation trees and glycosyltransferase map list. CSM is able to display, for example, expression data of glycosyltransferases in a compact manner, illustrating its versatility as a new bioinformatics resource and tool capable of analyzing carbohydrate structures on a global scale. These resources are available at http://www.genome.jp/kegg/glycan/.

Carbohydrate Conformation↗

PubMed2005

Autoimmune diseases and peptide variations.

The immune system plays an essential role in the defense of the host against invaders. Enormous numbers of lymphocytes are recruited and immense numbers of antibodies or cytokines are secreted in various kinds of immune response. But the system also has the possibility of being the cause of tissue injury or some kind of diseases. For example, when their functions target their host, an autoimmune disease occurs. Although the pathogenesis of various autoimmune diseases has been scrutinized intensively, there is little evidence as of yet. But it has been reported that in most of the disease subjects, a broad spectrum of antibodies recognizing components of self tissue or circulating self antigens that normally should be ignored are observed. In this study, we come to the conclusion that proteins targeted by these autoreactive antibodies share the same peptides with some kind of proteins of viruses known to infect human. This result supports the fact that viral infection is a speculative cause of the disease in some subjects.

Amino Acid Motifs↗

PubMed2004

Clustering under the line graph transformation: application to reaction network.

BACKGROUND: Many real networks can be understood as two complementary networks with two kind of nodes. This is the case of metabolic networks where the first network has chemical compounds as nodes and the second one has nodes as reactions. In general, the second network may be related to the first one by a technique called line graph transformation (i.e., edges in an initial network are transformed into nodes). Recently, the main topological properties of the metabolic networks have been properly described by means of a hierarchical model. While the chemical compound network has been classified as hierarchical network, a detailed study of the chemical reaction network had not been carried out. RESULTS: We have applied the line graph transformation to a hierarchical network and the degree-dependent clustering coefficient C(k) is calculated for the transformed network. C(k) indicates the probability that two nearest neighbours of a vertex of degree k are connected to each other. While C(k) follows the scaling law C(k) approximately k(-1.1) for the initial hierarchical network, C(k) scales weakly as k0.08 for the transformed network. This theoretical prediction was compared with the experimental data of chemical reactions from the KEGG database finding a good agreement. CONCLUSIONS: The weak scaling found for the transformed network indicates that the reaction network can be identified as a degree-independent clustering network. By using this result, the hierarchical classification of the reaction network is discussed.

Algorithms↗

PubMed2004

Computational assignment of the EC numbers for genomic-scale analysis of enzymatic reactions.

The EC (Enzyme Commission) numbers represent a hierarchical classification of enzymatic reactions, but they are also commonly utilized as identifiers of enzymes or enzyme genes in the analysis of complete genomes. This duality of the EC numbers makes it possible to link the genomic repertoire of enzyme genes to the chemical repertoire of metabolic pathways, the process called metabolic reconstruction. Unfortunately, there are numerous reactions known to be present in various pathways, but they will never get EC numbers because the EC number assignment requires published articles on full characterization of enzymes. Here we report a computerized method to automatically assign the EC numbers up to the sub-subclasses, i.e., without the fourth serial number for substrate specificity, given pairs of substrates and products. The method is based on a new classification scheme of enzymatic reactions, named the RC (reaction classification) number. Each reaction in the current dataset of the EC numbers is first decomposed into reactant pairs. Each pair is then structurally aligned to identify the reaction center, the matched region, and the difference region. The RC number represents the conversion patterns of atom types in these three regions. We examined the correspondence between computationally assigned RC numbers and manually assigned EC numbers by the jackknife cross-validation test and found that the EC sub-subclasses could be assigned with the accuracy of about 90%. Furthermore, we examined the correlation with genomic information as represented by the KEGG ortholog clusters (OC) and confirmed that the RC numbers are correlated not only with elementary reaction mechanisms but also with protein families.

Computers↗

PubMed2004

A score matrix to reveal the hidden links in glycans.

MOTIVATION: Glycans are the third major class of biomolecules following DNA and proteins. They are extremely vital for the functioning of multicellular organisms. However, comparing the fast development of sequence analysis techniques, informatics work on glycans have a long way to go. Alignment algorithms for glycan tree structures are one of the foremost concerns. In addition, the statistical analysis of these algorithms in terms of biological significance needs to be addressed. RESULTS: We developed a tree-structure alignment algorithm for glycans and performed a statistical analysis of these alignment scores such that biologically interesting features could be captured into a score matrix for glycans. We generated our score matrix in a manner similar to BLOSUM, but with slight variations to accomodate our glycan data, including the incorporation of linkage information. We verified the effectiveness of our new glycan score matrix by illustrating how well the resulting score matrix entries correspond with biological knowledge. Future work for even better improvements with the use of a variety of score matrices for different subclasses of glycans due to their complexity is also discussed. CONTACT: mami@kuicr.kyoto-u.ac.jp SUPPLEMENTARY INFORMATION: The glycan score matrix can be downloaded from http://kanehisa.kuicr.kyoto-u.ac.jp/Paper/kcam/glycanMatrix0.1.txt.

Algorithms↗

PubMed2004

Fast and accurate database homology search using upper bounds of local alignment scores.

MOTIVATION: It is widely recognized that homology search and ortholog clustering are very useful for analyzing biological sequences. However, recent growth of sequence database size makes homolog detection difficult, and rapid and accurate methods are required. RESULTS: We present a novel method for fast and accurate homology detection, assuming that the Smith-Waterman (SW) scores between all similar sequence pairs in a target database are computed and stored. In this method, SW alignment is computed only if the upper bound, which is derived from our novel inequality, is higher than the given threshold. In contrast to other methods such as FASTA and BLAST, this method is guaranteed to find all sequences whose scores against the query are higher than the specified threshold. Results of computational experiments suggest that the method is dozens of times faster than SSEARCH if genome sequence data of closely related species are available.

Algorithms↗

PubMed2004

The evolutionary repertoires of the eukaryotic-type ABC transporters in terms of the phylogeny of ATP-binding domains in eukaryotes and prokaryotes.

ABC (ATP-binding cassette) transporters play an important role in the communication of various substrates across cell membranes. They are ubiquitous in prokaryotes and eukaryotes, and eukaryotic types (EK-types) are distinguished from prokaryotic types (PK-types) in terms of their genes and domain organizations. The EK-types and PK-types mainly consist of exporters and importers, respectively. Prokaryotes have both the EK-types and the PK-types. The EK-types in prokaryotes are usually called "bacterial multidrug ABC transporters," but they are not well characterized in comparison with the multidrug ABC transporters in eukaryotes. Thus, an exhaustive search of the EK-types among diverse organisms and detailed sequence classification and analysis would elucidate the evolutionary history of EK-types. It would also help shed some light on the fundamental repertoires of the wide variety of substrates through which multidrug ABC transporters in eukaryotes communicate. In this work, we have identified the EK-type ABC transporters in 126 prokaryotes using the profiles of the ATP-binding domain (NBD) of the EK-type ABC transporters from 12 eukaryotes. As a result, 11 clusters were identified from 1,046 EK-types ABC transporters. In particular, two large novel clusters emerged, corresponding to the bacterial multidrug ABC transporters related to the ABCB and ABCC families in eukaryotes, respectively. In the genomic context, most of these genes are located alone or adjacent to genes from the same clusters. Additionally, to detect functional divergences in the NBDs, the Kullback-Leibler divergence was measured among these bacterial multidrug transporters. As a result, several putative functional regions were identified, some corresponding to the predicted secondary structures. We also analyzed a phylogeny of the EK-type ABC transporters in both prokaryotes and eukaryotes, which revealed that the EK-type ABC transporters in prokaryotes have certain repertoires corresponding to the conventional ABC protein groups in eukaryotes. On the basis of these findings, we propose an updated evolutionary hypothesis in which the EK-type ABC transporters in both eukaryotes and prokaryotes consisted of several kinds of ABC transporters in putative ancestor cells before the divergence of eukaryotic and prokaryotic cells.

ATP-Binding Cassette Transporters↗

PubMed2004

Application of a new probabilistic model for recognizing complex patterns in glycans.

MOTIVATION: The study of carbohydrate sugar chains, or glycans, has been one of slow progress mainly due to the difficulty in establishing standard methods for analyzing their structures and biosynthesis. Glycans are generally tree structures that are more complex than linear DNA or protein sequences, and evidence shows that patterns in glycans may be present that spread across siblings and into further regions that are not limited by the edges in the actual tree structure itself. Current models were not able to capture such patterns. RESULTS: We have applied a new probabilistic model, called probabilistic sibling-dependent tree Markov model (PSTMM), which is able to inherently capture such complex patterns of glycans. Not only is the ability to capture such patterns important in itself, but this also implies that PSTMM is capable of performing multiple tree structure alignments efficiently. We prove through experimentation on actual glycan data that this new model is extremely useful for gaining insight into the hidden, complex patterns of glycans, which are so crucial for the development and functioning of higher level organisms. Furthermore, we also show that this model can be additionally utilized as an innovative approach to multiple tree alignment, which has not been applied to glycan chains before. This extension on the usage of PSTMM may be a major step forward for not only the structural analysis of glycans, but it may consequently prove useful for discovering clues into their function.

Algorithms↗

PubMed2004

KCaM (KEGG Carbohydrate Matcher): a software tool for analyzing the structures of carbohydrate sugar chains.

KCaM (KEGG Carbohydrate Matcher) is a tool for the analysis of carbohydrate sugar chains, or glycans. It consists of a web-based graphical user interface that allows users to enter glycans easily with the mouse. The glycan structure is then transformed into our KCF (KEGG Chemical Function) file format and sent to our program which implements an efficient tree-structure alignment algorithm, similar to sequence alignment algorithms but for branched tree structures. Users can also retrieve glycan tree structures in KCF format from their local computers for visualization over the web. The tree-matching algorithm provides several options for performing different types of tree-matching procedures on glycans. These options consist of whether to incorporate gaps in a match, whether to take the linkage information into consideration and local versus global alignment. The results of this program are returned as a list of glycan structures in order of similarity based on these options. The actual alignment can be viewed graphically, and the annotation information can also be viewed easily since all this information is linked with KEGG's comprehensive suite of genomic data. Analogously to BLAST, users are thus able to compare glycan structures of interest with glycans from different glycan databases using a variety of tree-alignment options. KCaM is currently available at http://glycan.genome.ad.jp.

Algorithms↗

PubMed2004

The KEGG resource for deciphering the genome.

A grand challenge in the post-genomic era is a complete computer representation of the cell and the organism, which will enable computational prediction of higher-level complexity of cellular processes and organism behavior from genomic information. Toward this end we have been developing a knowledge-based approach for network prediction, which is to predict, given a complete set of genes in the genome, the protein interaction networks that are responsible for various cellular processes. KEGG at http://www.genome.ad.jp/kegg/ is the reference knowledge base that integrates current knowledge on molecular interaction networks such as pathways and complexes (PATHWAY database), information about genes and proteins generated by genome projects (GENES/SSDB/KO databases) and information about biochemical compounds and reactions (COMPOUND/GLYCAN/REACTION databases). These three types of database actually represent three graph objects, called the protein network, the gene universe and the chemical universe. New efforts are being made to abstract knowledge, both computationally and manually, about ortholog clusters in the KO (KEGG Orthology) database, and to collect and analyze carbohydrate structures in the GLYCAN database.

Animals↗

PubMed2004

Response to oxidative stress involves a novel peroxiredoxin gene in the unicellular cyanobacterium Synechocystis sp. PCC 6803.

Exposure to methyl viologen in the presence of light facilitates the production of superoxide that gives severe damage on photosynthetic apparatus as well as many cellular processes in cyanobacteria and plants. The effects of methyl viologen on global gene expression of a unicellular cyanobacterium Synechocystis sp. strain PCC 6803 were determined by DNA microarray. The ORFs sll1621, slr1738, slr0074, slr0075, and slr0589 were significantly induced by treatment of methyl viologen for 15 min commonly under conditions of normal and high light. One of these genes, slr1738, which encodes a ferric uptake repressor (Fur)-type transcriptional regulator, is located divergently next to another induced gene, sll1621, in the genome. We deleted slr1738, and compared the global gene expression patterns of this mutant to that of wild type under non-stressed conditions. It was found that sll1621 was derepressed to the greatest extent, while many other genes including slr0589 but not slr0074 or slr0075 were derepressed to lesser extent in the mutant. Genetic disruption of sll1621, which encodes a putative type 2 peroxiredoxin, indicates that it is essential for aerobic phototrophic growth in both liquid and solid media in high light and on solid medium even in low light. Slr1738 was prepared as a His-tagged recombinant protein and shown to specifically bind to the intergenic region between sll1621 and slr1738. The binding was enhanced by dithiothreitol and abolished by hydrogen peroxide. We concluded that the Fur homolog, Slr1738, plays a regulatory role in the induction of a potent antioxidant gene, sll1621, in response to oxidative stress.

Amino Acid Sequence↗