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PubMed1981

Metabolism studies of 3,3',4,4'-tetrachloroazobenzene. I. In vitro metabolic pathways with rat liver microsomes.

The metabolism of 3,3',4,4'-tetrachloroazobenzene (TCAB), an important environmental and occupational toxicant, by rat liver microsomes has been examined in a NADPH-generating system. The metabolic pathways were delineated by the combined use of high pressure liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). The rate of [14C]TCAB metabolism using induced microsomes was found to be 381 +/- 59 pmol/min/mg microsomal protein. Approximately 13% of the radioactivity from the [14C]TCAB substrate was covalently bound to the macromolecular pellet at the end of a 2-h incubation period. In addition, three distinct TCAB metabolites were isolated from the organic extracts and subsequently identified. Experiments with carbon monoxide, 2-diethylaminoethyl 2,2-diphenylvalerate hydrochloride (SKF 525-A), and control (uninduced) microsomes indicated the participation of the cytochrome P-450-dependent monooxygenases. The biological significance of both oxidative and reductive metabolic pathways were discussed. It was suggested that the generation of a reactive arene oxide intermediate mediated by oxidative enzymes may be crucial for some of the TCAB toxic effects observed in rodent tissues.

Animals↗

PubMed2005

Reconstruction of phylogenetic relationships from metabolic pathways based on the enzyme hierarchy and the gene ontology.

There has been much interest in the structural comparison and alignment of metabolic pathways. Several techniques have been conceived to assess the similarity of metabolic pathways of different organisms. In this paper, we show that the combination of a new heuristic algorithm for the comparison of metabolic pathways together with any of three enzyme similarity measures (hierarchical, information content, and gene ontology) can be used to derive a metabolic pathway similarity measure that is suitable for reconstructing phylogenetic relationships from metabolic pathways. Experimental results on the Glycolysis pathway of 73 organisms representing the three domains of life show that our method outperforms previous techniques.

Enzymes↗

PubMed2003

MetaFluxNet, a program package for metabolic pathway construction and analysis, and its use in large-scale metabolic flux analysis of Escherichia coli.

We have developed MetaFluxNet which is a stand-alone program package for the management of metabolic reaction information and quantitative metabolic flux analysis. It allows users to interpret and examine metabolic behavior in response to genetic and/or environmental modifications. As a result, quantitative in silico simulations of metabolic pathways can be carried out to understand the metabolic status and to design the metabolic engineering strategies. The main features of the program include a well-developed model construction environment, user-friendly interface for metabolic flux analysis (MFA), comparative MFA of strains having different genotypes under various environmental conditions, and automated pathway layout creation. The usefulness and functionality of the program are demonstrated by applying to metabolic pathways in E. coli. First, a large-scale in silico E. coli model is constructed using MetaFluxNet, and then the effects of carbon sources on intracellular flux distributions and succinic acid production were investigated on the basis of the uptake and secretion rates of the relevant metabolites. The results indicated that among three carbon sources available, the most reduced substrate is sorbitol which yields efficient succinic acid production. The software can be downloaded from http://mbel.kaist.ac.kr/.

Computer Simulation↗

PubMed1989

Evidence of a new metabolic pathway of 5-fluorouracil in Escherichia coli from in vivo 19F-NMR spectroscopy.

Two distinct metabolic pathways of 5-fluorouracil are proposed in Escherichia coli. The first metabolic pathway is a reductive degradation with the formation of dihydrofluorouracil as the first metabolite. The second metabolic pathway is shown to be a hydroxylating degradation, possibly with the formation of 5-hydro-6-hydroxy-5-fluorouracil as the first metabolite. The metabolites of both pathways undergo subsequent hydrolytic degradation with fluoride ion as the common final product. The chemical structures of these metabolites were partially identified by 19F-NMR. The results show a close resemblance between these two metabolic pathways with in vivo pyrimidine biodegradation. The reductive degradation has been proposed by several laboratories, whereas the hydroxy degradation has not been reported before. Both the reductive and hydroxy pathways are demonstrated in this report, to be independent reactions.

Escherichia coli↗

PubMed1991

Glucose metabolic pathways in the anaerobic rumen fungus Neocallimastix frontalis EB188.

Primary pathways for glucose metabolism were established in the anaerobic rumen fungus Neocallimastix frontalis EB188. This highly capable cellulolytic organism demonstrated a strict anaerobic integration of metabolic pathways. Glycolysis in N. frontalis EB188 was coupled to malate dehydrogenase, 'malic' enzyme and specified hydrogenosome reactions. Pyruvate, as in most life forms, was a pivotal compound. The major fermentation products of N. frontalis EB188 were acetate, ethanol and lactate, with the concomitant generation of H2. On the basis of its unique characteristics and streamlined fermentation pathways, it was concluded that N. frontalis EB188 should be an important contributor to programs generating energy and selected chemicals from currently intractable biomass.

Acetates↗

PubMed1997

Examination of metabolic pathways and identification of human liver cytochrome P450 isozymes responsible for the metabolism of barnidipine, a calcium channel blocker.

1. In a human liver microsomal system, barnidipine was converted into three primary metabolites, an N-debenzylated product (M-1), a hydrolyzed product of the benzyl-pyrrolidine ester (M-3) and an oxidized product of the dihydropyridine ring (M-8). 2. Involvement of CYP3A in the three primary metabolic pathways was revealed by the following studies: (a) inhibition of CYP3A, (b) a correlation study using 10 individual human liver microsomes and (c) cDNA-expression studies. The secondary metabolites, M-2 and M-4 (pyridine forms of M-1 and M-3), were most likely generated from M-8 but were unlikely from M-1 or M-3. Involvement of CYP3A in the secondary pathways of metabolism is also suggested. 3. The possibility of interactions between barnidipine and coadministered drugs was examined in vitro. The formation rate of the primary metabolites was little affected by warfarin, theophylline, phenytoin, diclofenac and amitriptyline at concentrations of 200 microM, but was inhibited by glibenclamide, simvastatin and cyclosporin A. IC50 for the latter drugs was estimated to be > 200, 200 and 20 microM respectively, which was roughly > 200, 6000 and 50 times higher than their respective therapeutic plasma levels, suggesting that interactions with cyclosporin A, a CYP3A inhibitor, are of possible clinical relevance.

Calcium Channel Blockers↗

PubMed1995

Metabolism of 6-trans-isomers of leukotriene B4 in cultured hepatoma cells and in human polymorphonuclear leukocytes. Identification of a delta 6-reductase metabolic pathway.

The intermediate metabolic events which degrade hydroxy polyunsaturated fatty acids is largely unknown. Such molecules are common products of lipid peroxidation and lipoxygenase catalyzed oxidation of arachidonic acid. Metabolism of two 5,12-dihydroxyeicosatetraenoic acids, 6-trans-LTB4 (leukotriene B4), and 6-trans-12-epi-LTB4 was studied in HepG2 cells (a human-derived hepatoma cell line). Extensive metabolism was observed with a major metabolite identified as 4-hydroxy-6-dodecenoic acid for both epimers. Incubation of 6-trans-LTB4 epimers at shorter times revealed the formation of intermediate metabolites, including 6-hydroxy-4,8-tetradecadienoic acid and 8-hydroxy-4,6,10-hexadecatrienoic acid suggesting beta-oxidation as the major pathway leading to the formation of the common terminal metabolite. Two additional metabolites were structurally elucidated as 5-oxo-6,7-dihydro-LTB4 and 6,7-dihydro-LTB4 which have not been previously described. Formation of 5-oxo-6,7-dihydro-LTB4 and 6,7-dihydro-LTB4 were also observed during metabolism of 6-trans-12-epi-LTB4 in human polymorphonuclear leukocytes. Of particular interest is the metabolism of these compounds by beta-oxidation from the carboxyl terminus, a process which is not observed with leukotriene B4 or leukotriene C4. Identification of these metabolites suggested the operation of the 5-hydroxyeicosanoid dehydrogenase pathway followed by a delta 6-reductase metabolic pathway which has not been previously described. This pathway of beta-oxidation may limit the activity of various 5,12-diHETEs including nonenzymatic hydrolysis products of LTA4 and also the recently described B4-isoleukotrienes.

Carcinoma, Hepatocellular↗

PubMed2004

Computational prediction of human metabolic pathways from the complete human genome.

BACKGROUND: We present a computational pathway analysis of the human genome that assigns enzymes encoded therein to predicted metabolic pathways. Pathway assignments place genes in their larger biological context, and are a necessary first step toward quantitative modeling of metabolism. RESULTS: Our analysis assigns 2,709 human enzymes to 896 bioreactions; 622 of the enzymes are assigned roles in 135 predicted metabolic pathways. The predicted pathways closely match the known nutritional requirements of humans. This analysis identifies probable omissions in the human genome annotation in the form of 203 pathway holes (missing enzymes within the predicted pathways). We have identified putative genes to fill 25 of these holes. The predicted human metabolic map is described by a Pathway/Genome Database called HumanCyc, which is available at http://HumanCyc.org/. We describe the generation of HumanCyc, and present an analysis of the human metabolic map. For example, we compare the predicted human metabolic pathway complement to the pathways of Escherichia coli and Arabidopsis thaliana and identify 35 pathways that are shared among all three organisms. CONCLUSIONS: Our analysis elucidates a significant portion of the human metabolic map, and also indicates probable unidentified genes in the genome. HumanCyc provides a genome-based view of human nutrition that associates the essential dietary requirements of humans with a set of metabolic pathways whose existence is supported by the human genome. The database places many human genes in a pathway context, thereby facilitating analysis of gene expression, proteomics, and metabolomics datasets through a publicly available online tool called the Omics Viewer.

Arabidopsis↗

PubMed2006

Phylophenetic properties of metabolic pathway topologies as revealed by global analysis.

BACKGROUND: As phenotypic features derived from heritable characters, the topologies of metabolic pathways contain both phylogenetic and phenetic components. In the post-genomic era, it is possible to measure the "phylophenetic" contents of different pathways topologies from a global perspective. RESULTS: We reconstructed phylophenetic trees for all available metabolic pathways based on topological similarities, and compared them to the corresponding 16S rRNA-based trees. Similarity values for each pair of trees ranged from 0.044 to 0.297. Using the quartet method, single pathways trees were merged into a comprehensive tree containing information from a large part of the entire metabolic networks. This tree showed considerably higher similarity (0.386) to the corresponding 16S rRNA-based tree than any tree based on a single pathway, but was, on the other hand, sufficiently distinct to preserve unique phylogenetic information not reflected by the 16S rRNA tree. CONCLUSION: We observed that the topology of different metabolic pathways provided different phylogenetic and phenetic information, depicting the compromise between phylogenetic information and varying evolutionary pressures forming metabolic pathway topologies in different organisms. The phylogenetic information content of the comprehensive tree is substantially higher than that of any tree based on a single pathway, which also gave clues to constraints working on the topology of the global metabolic networks, information that is only partly reflected by the topologies of individual metabolic pathways.

Chromosome Mapping↗

PubMed1991

The rationalization of high enzyme concentration in metabolic pathways such as glycolysis.

The cellular concentration of enzymes of some major metabolic pathways, such as glycolysis, can approach millimolarity. This concentration of enzyme can catalyze in vitro rates which are 100-fold higher than maximum pathway flux. In an attempt to understand the need for such high enzyme concentration, an artificial metabolic pathway of five enzymes (apropos the central enzymes of glycolysis) has been modeled. Numerical methods were then used to determine the effect of enzyme concentration on: (1) the change in total free metabolite concentration as the pathway changes from low flux to high flux, (2) the time lag (transient time) in the rate of final product formation upon the transition from low flux to high flux. Both the changes in metabolite pool size and the transient time decreased with increased enzyme concentrations. When all enzymatic reactions were assigned Keq of unity, a concentration for each enzyme of 25 microM is sufficient to provide a transient time of 1 sec. When Keq different from unity are introduced, more enzyme is required to provide comparably short transient times. Under the latter condition, a pathway of sufficiently low transient time would require all the enzyme available in mammalian muscle. It is shown that there is little scope for further increases in either enzyme concentration or of catalytic efficiency of independent enzymes. Therefore, an alternative method of increasing efficiency is considered in which enzyme-bound metabolites can serve directly as substrates for subsequent enzymes in a metabolic pathway.

Animals↗

PubMed1999

The regeneration of reduced glutathione in rat forebrain mitochondria identifies metabolic pathways providing the NADPH required.

Metabolic pathways underlying the regeneration of reduced glutathione were investigated in acutely isolated metabolically active mitochondria from rat forebrain. The application of hydrogen peroxide to the organelles was accompanied by a transient increase in glutathione disulfide. The recovery of reduced glutathione was significantly improved in the presence of alternatively succinate, malate, citrate, isocitrate, or beta-hydroxybutyrate. Inhibition of succinate dehydrogenase by malonate abolished the beneficial effect of succinate on the reduction of glutathione disulfide but did not influence the effect of isocitrate. Fluorocitrate, an inhibitor of aconitase, blocked the effect exerted by citrate but did not inhibit the effects of malate or beta-hydroxybutyrate. Uncoupling of the respiratory chain by carbonyl cyanide m-chlorophenylhydrazone prevented the beneficial effect of beta-hydroxybutyrate but did not abolish the improved reduction of mitochondrial glutathione disulfide in the presence of malate and isocitrate. These results suggest that NADP+-dependent isocitrate dehydrogenase as well as malic enzyme and nicotinamide nucleotide transhydrogenase contribute to the regeneration of NADPH required for the reduction of glutathione disulfide in brain mitochondria.

Animals↗

PubMed2004

Phylogenetic analysis based on genome-scale metabolic pathway reaction content.

Phylogenetic classifications based on single genes such as rRNA genes do not provide a complete and accurate picture of evolution because they do not account for evolutionary leaps caused by gene transfer, duplication, deletion and functional replacement. Here, we present a whole-genome-scale phylogeny based on metabolic pathway reaction content. From the genome sequences of 42 microorganisms, we deduced the metabolic pathway reactions and used the relatedness of these contents to construct a phylogenetic tree that represents the similarity of metabolic profiles (relatedness) as well as the extent of metabolic pathway similarity (evolutionary distance). This method accounts for horizontal gene transfer and specific gene loss by comparison of whole metabolic subpathways, and allows evaluation of evolutionary relatedness and changes in metabolic pathways. Thus, a tree based on metabolic pathway content represents both the evolutionary time scale (changes in genetic content) and the evolutionary process (changes in metabolism).

Archaea↗

PubMed2001

A graph layout algorithm for drawing metabolic pathways.

MOTIVATION: A large amount of data on metabolic pathways is available in databases. The ability to visualise the complex data dynamically would be useful for building more powerful research tools to access the databases. Metabolic pathways are typically modelled as graphs in which nodes represent chemical compounds, and edges represent chemical reactions between compounds. Thus, the problem of visualising pathways can be formulated as a graph layout problem. Currently available visual interfaces to biochemical databases either use static images or cannot cope well with more complex, non-standard pathways. RESULTS: This paper presents a new algorithm for drawing pathways which uses a combination of circular, hierarchic and force-directed graph layout algorithms to compute positions of the graph elements representing main compounds and reactions. The algorithm is particularly designed for cyclic or partially cyclic pathways or for combinations of complex pathways. It has been tested on five sample pathways with promising results.

Algorithms↗

PubMed2006

Fatty acid metabolism pathway play an important role in carcinogenesis of human colorectal cancers by Microarray-Bioinformatics analysis.

The present study systematically explored metabolic pathways and altered expressions of genes speculatively participating in colorectal carcinogenesis by using a Microarray-Bioinformatic analysis methods. The results revealed that 157 genes were up-regulated and 281 genes were down-regulated in colorectal cancer (CRC). Gene Ontology (GO) and relevant bioinformatics tools indicated that the functional category to which 438 genes (12%; 438/3800) of the most frequent alteration belonged was metabolism. The analysis of 10 colorectal cancer tissue specimens demonstrated that genes involved in fatty acid metabolic pathways had high rates of overexpression. In addition, we stimulated CRL-1790 cell line with linoleic acid (a polyunsaturated fatty acid) for 12, 24, 48 and 72 h. Cell proliferation was elevated by 5, 25, 28 and 31% (P<0.05), respectively. Further analyses revealed that the genes increasingly expressed in the cell line included enoyl-Coenzyme A, hydratase/3-hydroxyacyl Coenzyme A dehydrogenase (EHHADH), enoyl Coenzyme A hydratase, short chain, 1, mitochondrial (ECHS1); glutaryl-Coenzyme A dehydrogenase (GCDH), acyl-Coenzyme A oxidase 2, branched chain (ACOX2); acyl-Coenzyme A dehydrogenase, C-2 to C-3 short chain precursor (ACADS); carnitine palmitoyltransferase 1B (CPT1B), acyl-CoA synthetase long-chain family member 5 (ACSL5), and cytochrome P450, family 4, subfamily A, and polypeptide 11 (CYP4A11) genes. This indicated that the stimulating effect of linoleic acid on cell proliferation was due to interference with the metabolic pathway of fatty acid metabolism. In conclusion, genes with altered expression levels in CRC were mainly associated with fatty acid metabolic pathways speculated to have an important role linked to carcinogenesis.

Aged↗

PubMed2006

The Path-A metabolic pathway prediction web server.

Pathway Analyst (Path-A) is a publicly available web server (http://path-a.cs.ualberta.ca) that predicts metabolic pathways. It takes a FASTA format file containing a set of query protein sequences from a single organism (a partial or complete proteome) and identifies those sequences that are likely to participate in any of its supported metabolic pathways (currently 10). Path-A uses a number of machine-learning and sequence analysis techniques (e.g. SVM, BLAST and HMM) to predict pathways. Each machine-learned classifier exploits similarity between sequences in the pathways of its model organisms and sequences in the query set. It predicts the pathways that are present in the query organism and annotates each predicted reaction and catalyst, using the appropriate sequences from the query set. Path-A also provides a browsable and searchable database of the pathways for the model organisms that are used to make its predictions. Path-A's predictor sets (using different classifier technologies) have been evaluated using standard cross-validation techniques on a dataset of 10 metabolic pathways across 13 model organisms--a total of 125 organism-specific pathways. The most accurate classifier technology obtained a mean precision of 78.3% and a mean recall of 92.6% in predicting all catalyst proteins, of all reactions, in all pathways present in the dataset. Although Path-A currently only supports metabolic pathways, the underlying prediction techniques are general enough for other types of pathways. Consequently, it is our intent to extend Path-A to predict other types of pathways, including signalling pathways.

Algorithms↗

PubMed1987

A transfer-function representation for regulatory responses of a controlled metabolic pathway.

A transfer-function representation for the response of a controlled metabolic pathway to the changes in influx and efflux rates of metabolites is formulated to describe analytically and approximately the regulatory behavior of the pathway around a steady state. The pathway model analyzed is an open and homogeneous system which consists of two consecutive enzymatic reactions catalyzed by an allosteric enzyme of Monod-Wyman-Changeux (MWC) dimeric model and a Michaelis-Menten-type enzyme, respectively, and undergoes the feedback inhibition by the end product. The rate equation for the system (a system of ordinary differential equations) is linearized about a steady state, so that the responses of the reaction rates to the changes in influx rate of the substrate and efflux rate of the end product are expressed in a form of transfer function. The formulation leads to the transfer function for the response of production rate of the end product to the change in its efflux rate to clarify the regulatory response of feedback mechanism in controlled metabolic pathways. The relationship among the chemical species in the system at steady states also supports a reasonable assumption that the regulatory mechanisms in metabolic pathways are to control the production of end product against the change in its demand from the cellular environments.

Allosteric Regulation↗

PubMed2026

Untargeted metabolomics reveals differential metabolic pathways and biomarkers in the acute phase of Kawasaki disease.

INTRODUCTION: Kawasaki disease (KD) is one of the most common rheumatic diseases in children and manifests with multisystem clinical features. Using untargeted metabolomics, our study investigated alterations in small-molecule metabolites in plasma of children with acute KD. Our study aimed to identify differential metabolic pathways and potential biomarkers. METHODS: Plasma samples were collected from 30 children diagnosed with KD and 30 age-matched healthy controls (HC) at Jinhua Maternal and Child Health Hospital between January 2025 and December 2025. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to analyse plasma samples. Enriched pathways were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and differential metabolic pathways were determined using MetaboAnalyst 5.0. Differential metabolites were screened using the nonparametric Mann-Whitney U-test and receiver operating characteristic curve area (AUC). The conservative average AUC from nested cross-validation was reported as the primary performance metric. Pearson correlation analysis was conducted to evaluate correlations between metabolites and clinical parameters. RESULTS: In total, 261 differential metabolites were identified between the KD and HC groups, including 87 lipids and lipid-like molecules, 69 organic heterocyclic compounds, 38 benzenoids, 34 organic acids, 14 phenylpropanoids, and 19 other compounds. Pathway analysis of these differential metabolites revealed 30 putatively enriched metabolic pathways for exploratory analysis. Of these pathways, primary bile acid biosynthesis, arginine biosynthesis, histidine metabolism, and phenylalanine-tyrosine-tryptophan biosynthesis were nominally associated with KD. Six metabolites with exploratory discriminatory performance (AUC > 0.8) were further identified: L-tyrosine, L-tryptophan, glutamine, histidine, histamine, and taurocholic acid. A combined model incorporating these metabolites achieved an apparent AUC of 0.984 in the full dataset; nested cross-validation yielded a more conservative AUC of 0.889 (95% CI 0.798-0.968), indicating promising exploratory discriminatory performance. CONCLUSION: Untargeted metabolomics enables identification of metabolically perturbed pathways during the acute phase of KD. L-tyrosine, L-tryptophan, glutamine, histidine, histamine, and taurocholic acid may serve as candidate biomarkers for acute phase of KD.

Kawasaki disease↗

PubMed2003

Metabolic pathways of dioxin by CYP1A1: species difference between rat and human CYP1A subfamily in the metabolism of dioxins.

Metabolism of polychlorinated dibenzo-p-dioxins by CYP1A subfamily was examined by using the recombinant yeast microsomes. In substrate specificity and reaction specificity, considerable species differences between rats and humans were observed in both CYP1A1- and CYP1A2-dependent metabolism of dioxins. Among four CYPs, rat CYP1A1 showed the highest activity toward dibenzo-p-dioxin (DD) and mono-, di-, and trichloroDDs. To reveal the mechanism of dioxin metabolism, we examined rat CYP1A1-dependent metabolism of 2-chloro-dibenzo-p-dioxin. In addition to hydroxylation at an unsubstituted position, hydroxylation with migration of a chloride substituent, hydroxylation with elimination of a chloride substituent, and cleavage of an ether linkage of the dioxin ring were observed. In particular, the cleavage of an ether linkage of the dioxin ring appeared most important for the detoxication of dioxins. Based on these results, the metabolic pathways of 2-chloro-dibenzo-p-dioxin by rat CYP1A1 were proposed. The metabolic pathways contain most of the metabolites observed in vivo using experimental animals, suggesting that P450 monooxygenase systems including CYP1A1 are greatly responsible for dioxin metabolism in vivo.

Animals↗