{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T00:09:20Z","timestamp":1776470960221,"version":"3.51.2"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"14","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2006,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Motivation: The local and global aspects of metabolic network analyses allow us to identify enzymes or reactions that are crucial for the survival of the organism(s), therefore directing us towards the discovery of potential drug targets.<\/jats:p>\n                  <jats:p>Results: We demonstrate a new method (\u2018load points\u2019) to rank the enzymes\/metabolites in the metabolic network and propose a model to determine and rank the biochemical lethality in metabolic networks (enzymes\/metabolites) through \u2018choke points\u2019. Based on an extended form of the graph theory model of metabolic networks, metabolite structural information was used to calculate the k-shortest paths between metabolites (the presence of more than one competing path between substrate and product). On the basis of these paths and connectivity information, load points were calculated and used to empirically rank the importance of metabolites\/enzymes in the metabolic network. The load point analysis emphasizes the role that the biochemical structure of a metabolite, rather than its connectivity (hubs), plays in the conversion pathway.<\/jats:p>\n                  <jats:p>In order to identify potential drug targets (based on the biochemical lethality of metabolic networks), the concept of choke points and load points was used to find enzymes (edges) which uniquely consume or produce a particular metabolite (nodes). A non-pathogenic bacterial strain Bacillus subtilis 168 (lactic acid producing bacteria) and a related pathogenic bacterial strain Bacillus anthracis Sterne (avirulent but toxigenic strain, producing the toxin Anthrax) were selected as model organisms. The choke point strategy was implemented on the pathogen bacterial network of B.anthracis Sterne. Potential drug targets are proposed based on the analysis of the top 10 choke points in the bacterial network. A comparative study between the reported top 10 bacterial choke points and the human metabolic network was performed. Further biological inferences were made on results obtained by performing a homology search against the human genome.<\/jats:p>\n                  <jats:p>Availability: The load and choke point modules are introduced in the Pathway Hunter Tool (PHT), the basic version of which is available on<\/jats:p>\n                  <jats:p>Contact: \u00a0d.schomburg@uni-koeln.de<\/jats:p>\n                  <jats:p>Supplementary information: Supplementary data are available on Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btl181","type":"journal-article","created":{"date-parts":[[2006,5,8]],"date-time":"2006-05-08T21:39:44Z","timestamp":1147124384000},"page":"1767-1774","source":"Crossref","is-referenced-by-count":88,"title":["Observing local and global properties of metabolic pathways: \u2018load points\u2019 and \u2018choke points\u2019 in the metabolic networks"],"prefix":"10.1093","volume":"22","author":[{"given":"Syed Asad","family":"Rahman","sequence":"first","affiliation":[{"name":"Cologne University Bioinformatics Center, CUBIC 1 \u00a0 1 \u00a0 \u00a0 Z\u00fclpicher Strasse 47, 50674 Koeln, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dietmar","family":"Schomburg","sequence":"additional","affiliation":[{"name":"Cologne University Bioinformatics Center, CUBIC 1 \u00a0 1 \u00a0 \u00a0 Z\u00fclpicher Strasse 47, 50674 Koeln, Germany"},{"name":"Institute for Biochemistry 2 \u00a0 2 \u00a0 \u00a0 Z\u00fclpicher Strasse 47, 50674 Koeln, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2006,5,8]]},"reference":[{"key":"2023012408523655800_b1","doi-asserted-by":"crossref","first-page":"3389","DOI":"10.1093\/nar\/25.17.3389","article-title":"Gapped BLAST and PSI-BLAST: a new generation of protein database search programs","volume":"25","author":"Altschul","year":"1997","journal-title":"Nucleic Acids Res."},{"key":"2023012408523655800_b2","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1073\/pnas.0306458101","article-title":"The metabolic world of Escherichia coli is not small","volume":"101","author":"Arita","year":"2004","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012408523655800_b3","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nrg1272","article-title":"Network biology: understanding the cell's functional organization","volume":"5","author":"Barabasi","year":"2004","journal-title":"Nat. Rev. Genet."},{"key":"2023012408523655800_b4","doi-asserted-by":"crossref","first-page":"19103","DOI":"10.1073\/pnas.0505231102","article-title":"The global transcriptional regulatory network for metabolism in Escherichia coli exhibits few dominant functional states","volume":"102","author":"Barrett","year":"2005","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012408523655800_b5","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1038\/78659","article-title":"Import of host delta-aminolevulinate dehydratase into the malarial parasite: identification of a new drug target","volume":"6","author":"Bonday","year":"2000","journal-title":"Nat. Med."},{"key":"2023012408523655800_b6","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/nature02456","article-title":"Integrating high-throughput and computational data elucidates bacterial networks","volume":"429","author":"Covert","year":"2004","journal-title":"Nature"},{"key":"2023012408523655800_b7","doi-asserted-by":"crossref","first-page":"W326","DOI":"10.1093\/nar\/gki437","article-title":"Metabolic PathFinding: inferring relevant pathways in biochemical networks","volume":"33","author":"Croes","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"2023012408523655800_b8","first-page":"2765","article-title":"Use of the choke point in the prediction of flow limitation in elastic tubes","volume":"39","author":"Dawson","year":"1980","journal-title":"Fed. Proc."},{"key":"2023012408523655800_b9","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/nbt1075","article-title":"Chemogenomic profiling on a genome-wide scale using reverse-engineered gene networks","volume":"23","author":"di Bernardo","year":"2005","journal-title":"Nat. Biotechnol."},{"key":"2023012408523655800_b10","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1023\/A:1013713905833","article-title":"Metabolomics\u2014the link between genotypes and phenotypes","volume":"48","author":"Fiehn","year":"2002","journal-title":"Plant Mol. Biol."},{"key":"2023012408523655800_b11","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1038\/81137","article-title":"Metabolite profiling for plant functional genomics","volume":"18","author":"Fiehn","year":"2000","journal-title":"Nat. Biotechnol."},{"key":"2023012408523655800_b12","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1073\/pnas.0307490100","article-title":"Chemogenomic profiling: identifying the functional interactions of small molecules in yeast","volume":"101","author":"Giaever","year":"2004","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012408523655800_b13","doi-asserted-by":"crossref","first-page":"7821","DOI":"10.1073\/pnas.122653799","article-title":"Community structure in social and biological networks","volume":"99","author":"Girvan","year":"2002","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012408523655800_b14","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1093\/nar\/30.1.402","article-title":"LIGAND: database of chemical compounds and reactions in biological pathways","volume":"30","author":"Goto","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"2023012408523655800_b15","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/S1359-6446(05)03369-6","article-title":"Global properties of biological networks","volume":"10","author":"Grigorov","year":"2005","journal-title":"Drug Discov. Today"},{"key":"2023012408523655800_b16","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1038\/nature03288","article-title":"Functional cartography of complex metabolic networks","volume":"433","author":"Guimera","year":"2005","journal-title":"Nature"},{"key":"2023012408523655800_b17","doi-asserted-by":"crossref","first-page":"C47","DOI":"10.1038\/35011540","article-title":"From molecular to modular cell biology","volume":"402","author":"Hartwell","year":"1999","journal-title":"Nature"},{"key":"2023012408523655800_b18","doi-asserted-by":"crossref","first-page":"11853","DOI":"10.1021\/ja036030u","article-title":"Development of a chemical structure comparison method for integrated analysis of chemical and genomic information in the metabolic pathways","volume":"125","author":"Hattori","year":"2003","journal-title":"J. Am. Chem. Soc."},{"key":"2023012408523655800_b19","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1002\/cbic.200400128","article-title":"Computational design of reduced metabolic networks","volume":"5","author":"Holzhutter","year":"2004","journal-title":"Chembiochem."},{"key":"2023012408523655800_b20","doi-asserted-by":"crossref","first-page":"2050","DOI":"10.1093\/bioinformatics\/bth199","article-title":"Constructing an enzyme-centric view of metabolism","volume":"20","author":"Horne","year":"2004","journal-title":"Bioinformatics"},{"key":"2023012408523655800_b21","doi-asserted-by":"crossref","first-page":"4039","DOI":"10.2174\/1381612043382440","article-title":"Action of anti-HIV drugs and resistance: reverse transcriptase inhibitors and protease inhibitors","volume":"10","author":"Imamichi","year":"2004","journal-title":"Curr. Pharm. Des."},{"key":"2023012408523655800_b22","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/35036627","article-title":"The large-scale organization of metabolic networks","volume":"407","author":"Jeong","year":"2000","journal-title":"Nature"},{"key":"2023012408523655800_b23","doi-asserted-by":"crossref","first-page":"D277","DOI":"10.1093\/nar\/gkh063","article-title":"The KEGG resource for deciphering the genome","volume":"32","author":"Kanehisa","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"2023012408523655800_b24","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1093\/bioinformatics\/btg395","article-title":"Minimal cut sets in biochemical reaction networks","volume":"20","author":"Klamt","year":"2004","journal-title":"Bioinformatics"},{"key":"2023012408523655800_b25","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/36786","article-title":"The complete genome sequence of the gram-positive bacterium Bacillus subtilis","volume":"390","author":"Kunst","year":"1997","journal-title":"Nature"},{"key":"2023012408523655800_b26","first-page":"82","article-title":"A novel graph-based similarity measure for 2D chemical structures","volume":"15","author":"Le","year":"2004","journal-title":"Genome Inform. Ser. Workshop Genome Inform."},{"key":"2023012408523655800_b27","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1002\/bit.10854","article-title":"Dynamical and integrative cell signaling: challenges for the new biology","volume":"84","author":"Levchenko","year":"2003","journal-title":"Biotechnol Bioeng"},{"key":"2023012408523655800_b28","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1038\/nature02782","article-title":"Genomic analysis of regulatory network dynamics reveals large topological changes","volume":"431","author":"Luscombe","year":"2004","journal-title":"Nature"},{"key":"2023012408523655800_b29","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1093\/bioinformatics\/19.2.270","article-title":"Reconstruction of metabolic networks from genome data and analysis of their global structure for various organisms","volume":"19","author":"Ma","year":"2003","journal-title":"Bioinformatics"},{"key":"2023012408523655800_b30","doi-asserted-by":"crossref","first-page":"L07","DOI":"10.1529\/biophysj.104.055723","article-title":"Properties of metabolic networks: structure versus function","volume":"88","author":"Mahadevan","year":"2005","journal-title":"Biophys J"},{"key":"2023012408523655800_b31","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1126\/science.1078563","article-title":"Systems biology. Life's complexity pyramid","volume":"298","author":"Oltvai","year":"2002","journal-title":"Science"},{"key":"2023012408523655800_b32","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1038\/nature02298","article-title":"Multistability in the lactose utilization network of Escherichia coli","volume":"427","author":"Ozbudak","year":"2004","journal-title":"Nature"},{"key":"2023012408523655800_b33","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.tibs.2004.10.001","article-title":"Hierarchical thinking in network biology: the unbiased modularization of biochemical networks","volume":"29","author":"Papin","year":"2004","journal-title":"Trends Biochem Sci."},{"key":"2023012408523655800_b34","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1093\/bioinformatics\/bti116","article-title":"Metabolic pathway analysis web service (Pathway Hunter Tool at CUBIC)","volume":"21","author":"Rahman","year":"2005","journal-title":"Bioinformatics"},{"key":"2023012408523655800_b35","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1126\/science.1073374","article-title":"Hierarchical organization of modularity in metabolic networks","volume":"297","author":"Ravasz","year":"2002","journal-title":"Science"},{"key":"2023012408523655800_b36","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1126\/science.1071837","article-title":"Comparative genome sequencing for discovery of novel polymorphisms in Bacillus anthracis","volume":"296","author":"Read","year":"2002","journal-title":"Science"},{"key":"2023012408523655800_b37","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1016\/j.febslet.2005.01.029","article-title":"GC-MS libraries for the rapid identification of metabolites in complex biological samples","volume":"579","author":"Schauer","year":"2005","journal-title":"FEBS Lett."},{"key":"2023012408523655800_b38","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1021\/bp990048k","article-title":"Metabolic pathway analysis: basic concepts and scientific applications in the post-genomic era","volume":"15","author":"Schilling","year":"1999","journal-title":"Biotechnol. Prog."},{"key":"2023012408523655800_b39","doi-asserted-by":"crossref","first-page":"D431","DOI":"10.1093\/nar\/gkh081","article-title":"BRENDA, the enzyme database: updates and major new developments","volume":"32","author":"Schomburg","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"2023012408523655800_b40","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/73786","article-title":"A general definition of metabolic pathways useful for systematic organization and analysis of complex metabolic networks","volume":"18","author":"Schuster","year":"2000","journal-title":"Nat. Biotechnol."},{"key":"2023012408523655800_b41","doi-asserted-by":"crossref","first-page":"772","DOI":"10.4269\/ajtmh.1984.33.772","article-title":"In vitro antimalarial activity of tetrahydrofolate dehydrogenase inhibitors","volume":"33","author":"Sixsmith","year":"1984","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"2023012408523655800_b42","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1021\/ci025584y","article-title":"The Chemistry Development Kit (CDK): an open-source Java library for chemo- and bioinformatics","volume":"43","author":"Steinbeck","year":"2003","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"2023012408523655800_b43","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1515\/BC.2004.111","article-title":"Comprehensive analysis of metabolites in Corynebacterium glutamicum by gas chromatography\/mass spectrometry","volume":"385","author":"Strelkov","year":"2004","journal-title":"Biol. Chem."},{"key":"2023012408523655800_b44","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1101\/gr.2050304","article-title":"Computational analysis of Plasmodium falciparum metabolism: organizing genomic information to facilitate drug discovery","volume":"14","author":"Yeh","year":"2004","journal-title":"Genome Res."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/22\/14\/1767\/48839029\/bioinformatics_22_14_1767.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/22\/14\/1767\/48839029\/bioinformatics_22_14_1767.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T04:30:04Z","timestamp":1674534604000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/22\/14\/1767\/227488"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,5,8]]},"references-count":44,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2006,7,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btl181","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1046245.496177","asserted-by":"object"}]},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2006,7,15]]},"published":{"date-parts":[[2006,5,8]]}}}