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PubMed2006

Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma.

Understanding tumor metabolism is important for the development of anticancer therapies. Immunohistochemical evaluation of colorectal adenocarcinomas showed that cancer cells share common enzyme/transporter activities suggestive of an anaerobic metabolism [high lactate dehydrogenase 5 (LDH5)/hypoxia-inducible factor alphas (HIFalphas)] with high ability for glucose absorption and lactate extrusion [high glucose transporter 1 (GLUT1)/monocarboxylate transporter (MCT1)]. The tumor-associated fibroblasts expressed proteins involved in lactate absorption (high MCT1/MCT2), lactate oxidation (high LDH1 and low HIFalphas/LDH5), and reduced glucose absorption (low GLUT1). The expression profile of the tumor-associated endothelium indicated aerobic metabolism (high LDH1 and low HIFalphas/LDH5), high glucose absorption (high GLUT1), and resistance to lactate intake (lack of MCT1). It is suggested that the newly formed stroma and vasculature express complementary metabolic pathways, buffering and recycling products of anaerobic metabolism to sustain cancer cell survival. Tumors survive and grow because they are capable of organizing the regional fibroblasts and endothelial cells into a harmoniously collaborating metabolic domain.

Adenocarcinoma↗
PubMed2004

In vivo approaches and rationale for quantifying kinetics and imaging brain lipid metabolic pathways.

Developing a kinetic strategy to examine rates of lipid metabolic pathways can help to elucidate the roles that lipids play in tissue function and structure in health and disease. This review summarizes such a strategy, and shows how it has been applied to quantify different kinetic aspects of brain lipid metabolism in animals and humans. Methods involve injecting intravenously a radioactive or heavy isotope labeled substrate that will be incorporated into a lipid metabolic pathway, and using chemical analytical and/or imaging procedures (e.g., quantitative autoradiography or positron emission tomography) to determine tracer distribution in brain regions and their lipid compartments as a function of time. From the measurements, fluxes, turnover rates, half-lives and ATP consumption rates can be calculated, and incorporation rates can be imaged. Experimental changes in these kinetic parameters can help to identify changes in the expression of regulatory enzymes, and thus aid in drug targeting. Cases that are discussed are arachidonic acid turnover and imaging of neuroreceptor-initiated phospholipase A2 activation, ether phospholipid biosynthesis, and kinetics of the phosphatidylinositol cycle.

Adenosine Triphosphate↗
PubMed2002

PathFinder: reconstruction and dynamic visualization of metabolic pathways.

MOTIVATION: Beyond methods for a gene-wise annotation and analysis of sequenced genomes new automated methods for functional analysis on a higher level are needed. The identification of realized metabolic pathways provides valuable information on gene expression and regulation. Detection of incomplete pathways helps to improve a constantly evolving genome annotation or discover alternative biochemical pathways. To utilize automated genome analysis on the level of metabolic pathways new methods for the dynamic representation and visualization of pathways are needed. RESULTS: PathFinder is a tool for the dynamic visualization of metabolic pathways based on annotation data. Pathways are represented as directed acyclic graphs, graph layout algorithms accomplish the dynamic drawing and visualization of the metabolic maps. A more detailed analysis of the input data on the level of biochemical pathways helps to identify genes and detect improper parts of annotations. As an Relational Database Management System (RDBMS) based internet application PathFinder reads a list of EC-numbers or a given annotation in EMBL- or Genbank-format and dynamically generates pathway graphs.

Bacillus subtilis↗
PubMed1993

Preliminary studies about novel strategies to reverse chemoresistance to adriamycin regarding glutathione metabolism, peroxisomal and extraperoxisomal hydroperoxide and valproic acid metabolic pathways.

The present work was aimed at defining novel strategies to reverse chemoresistance to anticancer drugs, especially by interfering with cellular glutathione metabolism, peroxisomal and/or extraperoxisomal hydroperoxide metabolic pathways. Preliminary results are presented about molecules we demonstrated to be capable of interfering with hydrogen peroxide metabolism in cells. Prior to describing these molecules, a short overview of glutathione and free radical metabolic pathways is presented as well as a rapid presentation of the characteristics of chemo-sensitivity and -resistance towards the anticancer drug adriamycin, with special emphasis on hydrogen peroxide metabolism. The strategies currently developed to reverse chemoresistance are further presented in subsequent sections, our own strategy to achieve inhibition of hydrogen peroxide breakdown and stimulation of peroxisomal hydrogen peroxide production is illustrated on the basis of molecular modelling studies and biochemical investigations on extraperoxisomal and peroxisomal metabolic pathways. Preliminary studies on cultured cells have been initiated. The perspective for future studies is presented as well as other possible models of chemoresistance as target for the design of hydrogen peroxide metabolism-interfering pharmacomolecules.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Metabolic pathway analysis of yeast strengthens the bridge between transcriptomics and metabolic networks.

Central carbon metabolism of the yeast Saccharomyces cerevisiae was analyzed using metabolic pathway analysis tools. Elementary flux modes for three substrates (glucose, galactose, and ethanol) were determined using the catabolic reactions occurring in yeast. Resultant elementary modes were used for gene deletion phenotype analysis and for the analysis of robustness of the central metabolism and network functionality. Control-effective fluxes, determined by calculating the efficiency of each mode, were used for the prediction of transcript ratios of metabolic genes in different growth media (glucose-ethanol and galactose-ethanol). A high correlation was obtained between the theoretical and experimental expression levels of 38 genes when ethanol and glucose media were considered. Such analysis was shown to be a bridge between transcriptomics and fluxomics. Control-effective flux distribution was found to be promising in in silico predictions by incorporating functionality and regulation into the metabolic network structure.

Biomass↗
PubMed2006

Progress in in silico functional genomics: the malaria Metabolic Pathways database.

Genomic, transcriptomic and proteomic data can be turned into biologically meaningful information if they are synthesized into processes. Such amalgamation has been done for the most virulent malaria parasite Plasmodium falciparum in the Metabolic Pathways database. The dialectics of construction of metabolic pathways and other biological processes using this database is presented here. Additional features, such as links to other databases and the incorporation of transcriptomic clocks, are elucidated. Comparison of Metabolic Pathways to other similar databases is analyzed.

Animals↗
PubMed2001

Activation of cardiac afferents by arachidonic acid: relative contributions of metabolic pathways.

Arachidonic acid (AA) is metabolized via cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P-450 (CP450) pathways to a variety of bioactive products. The sensitivity of cardiac afferent endings to AA and its metabolites, especially those derived from LOX and CP450 pathways, is currently unclear. We examined AA-induced activation of cardiac vagal chemosensitive afferents in non- and postischemic hearts in rats and evaluated the relative contributions of the three metabolic pathways to the effects. Epicardial application of AA activated the cardiac afferents dose dependently in both nonischemic and postischemic hearts, with afferent responses greater in the latter condition. In nonischemic hearts, the afferent response to AA was abolished only after simultaneous administration of indomethacin and 17-octadecynoic acid (COX and CP450 inhibitors, respectively). Nordihydroguaiaretic acid (a LOX inhibitor) had no effect on the afferent response to AA. In postischemic hearts, abolition of the afferent response to AA required simultaneous blockade of all three pathways. None of the AA metabolic inhibitors affected resting activity of cardiac afferents in nonischemic hearts, but each suppressed afferent activity during ischemia-reperfusion. Most COX metabolites, CP450 metabolites, and 5-LOX metabolites tested were capable of activating cardiac afferents. The 12-LOX metabolites and 15-LOX metabolites had no effect on afferent activity. These data indicate that in the nonischemic heart, basal AA metabolism does not contribute to resting afferent activity, but AA is capable of activating cardiac afferents via COX and CP450 but not LOX pathways. During ischemia-reperfusion, all three metabolic pathways contribute to activation of cardiac vagal afferents with an enhanced responsiveness to AA. Our results suggest that induction of the 5-LOX pathway contributes to the enhanced sensitivity of cardiac vagal afferents to AA in the ischemic condition.

Animals↗
PubMed1998

Nitrosative stress: metabolic pathway involving the flavohemoglobin.

Nitric oxide (NO) biology has focused on the tightly regulated enzymatic mechanism that transforms L-arginine into a family of molecules, which serve both signaling and defense functions. However, very little is known of the pathways that metabolize these molecules or turn off the signals. The paradigm is well exemplified in bacteria where S-nitrosothiols (SNO)-compounds identified with antimicrobial activities of NO synthase-elicit responses that mediate bacterial resistance by unknown mechanisms. Here we show that Escherichia coli possess both constitutive and inducible elements for SNO metabolism. Constitutive enzyme(s) cleave SNO to NO whereas bacterial hemoglobin, a widely distributed flavohemoglobin of poorly understood function, is central to the inducible response. Remarkably, the protein has evolved a novel heme-detoxification mechanism for NO. Specifically, the heme serves a dioxygenase function that produces mainly nitrate. These studies thus provide new insights into SNO and NO metabolism and identify enzymes with reactions that were thought to occur only by chemical means. Our results also emphasize that the reactions of SNO and NO with hemoglobins are evolutionary conserved, but have been adapted for cell-specific function.

Biological Evolution↗
PubMedDate not supplied

N-depyridination and N-dedimethylaminoethylation of tripelennamine and pyrilamine in the rat. New metabolic pathways.

N-(2-Dimethylaminoethyl)benzylamine and 2-benzylaminopyridine were identified as two new urinary metabolites of tripelennamine in the rat by GC/MS. 2-(4-Methoxybenzylamino)-pyridine and N-(dimethylaminoethyl)-4-hydroxybenzylamine were identified as new urinary metabolites of pyrilamine by GC/MS. Thus, in addition to N- and O-demethylation, hydroxylation, and glucuronidation, N-debenzylation, N-depyridination and N-dedimethylaminoethylation were shown to be novel pathways for metabolism of tripelennamine and pyrilamine. The mechanism for N-depyridination and N-dealkylation is discussed.

Aminopyridines↗
PubMed1993

Petri net representations in metabolic pathways.

The present methods for representing metabolic pathways are limited in their ability to handle complex systems, incorporate new information, and to provide for drawing qualitative conclusions from the structure of pathways. The theory of Petri nets is introduced as a tool for computer-implementable representation of pathways. Petri nets have the potential to overcome the present limitations, and through a multitude of properties, enable the preliminary qualitative analysis of pathways.

Computer Simulation↗
PubMed2004

Extraction of phylogenetic network modules from prokayrote metabolic pathways.

In the post-genomic era, it is important to analyze interaction networks that include genes, proteins, enzymes and compounds such as a metabolic pathway. Every organism has such networks individually. However, several parts of them are conserved in different organisms. The purpose of this analysis is to extract sub-networks composed of these common elements through the phylogenetic analysis. We extracted network modules from metabolic pathways using phylogenetic profile and cluster analysis. The enzymes of these modules are related by evolutionary and functional correlation. Our results give a valuable insight into the evolution of metabolic pathways.

Bacteria↗
PubMed2006

Meta-All: a system for managing metabolic pathway information.

BACKGROUND: Many attempts are being made to understand biological subjects at a systems level. A major resource for these approaches are biological databases, storing manifold information about DNA, RNA and protein sequences including their functional and structural motifs, molecular markers, mRNA expression levels, metabolite concentrations, protein-protein interactions, phenotypic traits or taxonomic relationships. The use of these databases is often hampered by the fact that they are designed for special application areas and thus lack universality. Databases on metabolic pathways, which provide an increasingly important foundation for many analyses of biochemical processes at a systems level, are no exception from the rule. Data stored in central databases such as KEGG, BRENDA or SABIO-RK is often limited to read-only access. If experimentalists want to store their own data, possibly still under investigation, there are two possibilities. They can either develop their own information system for managing that own data, which is very time-consuming and costly, or they can try to store their data in existing systems, which is often restricted. Hence, an out-of-the-box information system for managing metabolic pathway data is needed. RESULTS: We have designed META-ALL, an information system that allows the management of metabolic pathways, including reaction kinetics, detailed locations, environmental factors and taxonomic information. Data can be stored together with quality tags and in different parallel versions. META-ALL uses Oracle DBMS and Oracle Application Express. We provide the META-ALL information system for download and use. In this paper, we describe the database structure and give information about the tools for submitting and accessing the data. As a first application of META-ALL, we show how the information contained in a detailed kinetic model can be stored and accessed. CONCLUSION: META-ALL is a system for managing information about metabolic pathways. It facilitates the handling of pathway-related data and is designed to help biochemists and molecular biologists in their daily research. It is available on the Web at http://bic-gh.de/meta-all and can be downloaded free of charge and installed locally.

Database Management Systems↗
PubMed2005

Automation of gene assignments to metabolic pathways using high-throughput expression data.

BACKGROUND: Accurate assignment of genes to pathways is essential in order to understand the functional role of genes and to map the existing pathways in a given genome. Existing algorithms predict pathways by extrapolating experimental data in one organism to other organisms for which this data is not available. However, current systems classify all genes that belong to a specific EC family to all the pathways that contain the corresponding enzymatic reaction, and thus introduce ambiguity. RESULTS: Here we describe an algorithm for assignment of genes to cellular pathways that addresses this problem by selectively assigning specific genes to pathways. Our algorithm uses the set of experimentally elucidated metabolic pathways from MetaCyc, together with statistical models of enzyme families and expression data to assign genes to enzyme families and pathways by optimizing correlated co-expression, while minimizing conflicts due to shared assignments among pathways. Our algorithm also identifies alternative ("backup") genes and addresses the multi-domain nature of proteins. We apply our model to assign genes to pathways in the Yeast genome and compare the results for genes that were assigned experimentally. Our assignments are consistent with the experimentally verified assignments and reflect characteristic properties of cellular pathways. CONCLUSION: We present an algorithm for automatic assignment of genes to metabolic pathways. The algorithm utilizes expression data and reduces the ambiguity that characterizes assignments that are based only on EC numbers.

Algorithms↗
PubMed1968

The metabolism of aromatic acids by micro-organisms. Metabolic pathways in the fungi.

1. The metabolic pathways of aromatic-ring fission were examined in a range of fungal genera that utilize several compounds related to lignin. 2. Most of the genera, after growth on p-hydroxybenzoate, protocatechuate or compounds that are degraded to the latter (e.g. caffeate, ferulate or vanillate), rapidly oxidized these compounds, but not catechol. 3. Such genera possessed a protocatechuate 3,4-oxygenase and accumulated beta-carboxymuconate as the product of protocatechuate oxidation. This enzyme had a high pH optimum in most organisms; the Rhodotorula enzyme was competitively inhibited by catechol. 4. beta-Carboxymuconate was converted by all competent fungi into beta-carboxymuconolactone, which was isolated and characterized. None of the fungi produced or utilized at significant rates the corresponding bacterial intermediate gamma-carboxymuconolactone. 5. The lactonizing enzymes of Rhodotorula and Neurospora crassa had a pH optimum near 5.5 and approximate molecular weights of 19000 and 190000 respectively. 6. The fungi did not degrade the isomeric (+)-muconolactone, gamma-carboxymethylenebutanolide or beta-oxoadipate enol lactone at significant rates, and thus differ radically from bacteria, where beta-oxoadipate enol lactone is the precursor of beta-oxoadipate in all strains examined. 7. The end product of beta-carboxymuconolactone metabolism by extracts was beta-oxoadipate. 8. Evidence for a coenzyme A derivative of beta-oxoadipate was found during further metabolism of this keto acid. 9. A few anomalous fungi, after growth on p-hydroxybenzoate, had no protocatechuate 3,4-oxygenase, but possessed all the enzymes of the catechol pathway. Catechol was detected in the growth medium in one instance. 10. A strain of Penicillium sp. formed pyruvate but no beta-oxoadipate from protocatechuate, suggesting the existence also of a ;meta' type of ring cleavage among fungi.

Ascomycota↗
PubMed1974

Cyclic metabolic pathway of a butylated hydroxytoluene by rat liver microsomal fractions.

A cyclic metabolic pathway was obtained when 3,5-di-t-butyl-4-hydroxytoluene (BHT) was incubated with a rat liver microsomal preparation. The pathway is as follows: BHT --> 4-hydroperoxy-4-methyl-2,6-di-t-butylcyclohexa-2,5-dienone (BHT-OOH) --> 4-hydroxy-4-methyl-2,6-di-t-butylcyclohexa-2,5-dienone (BHT-3(0)OH) --> BHT. This metabolic pathway suggests that antioxidants such as BHT owe their high efficacy, at least in part, to their metabolic regeneration.

Animals↗
PubMed2004

Chromokinetics of metabolic pathways.

Some methods to study and intuitively understand steady-state flows in complicated metabolic pathways are discussed. For this purpose, a suitable decomposition of complex metabolic schemes into smaller subsystems is used. These independent subsystems are then interpreted as basic colors of a chromatic coloring scheme. The mixture of these basic colors allows an intuitive picture of how a steady state in a metabolic pathway can be understood. Furthermore, actions of drugs can be more easily investigated on this basis. An anaerobic variant of pyruvate metabolism in rat liver mitochondria is presented as a simple example. This experiment allows measurement of the percentage that each basic color contributes to the steady states resulting from different experimental conditions. Possible implementations of existing algorithms and rational design of new drugs are discussed. A MATHEMATICA program, based on a new algorithm for finding all basic colors of stoichiometric networks, is included.

Algorithms↗