An Algorithm for Efficient Identification of Branched Metabolic Pathways

This article presents a new graph-based algorithm for identifying branched metabolic pathways in multi-genome scale metabolic data. The term branched is used to refer to metabolic pathways between compounds that consist of multiple pathways that interact biochemically. A branched pathway may produce a target compound through a combination of linear pathways that split compounds into smaller ones, work in parallel with many compounds, and join compounds into larger ones. While branched metabolic pathways predominate in metabolic networks, most previous work has focused on identifying linear metabolic pathways. The ability to automatically identify branched pathways is important in applications that require a deeper understanding of metabolism, such as metabolic engineering and drug target identification. The algorithm presented in this article utilizes explicit atom tracking to identify linear metabolic pathways and then merges them together into branched metabolic pathways. We provide results on several well-characterized metabolic pathways that demonstrate that the new merging approach can efficiently find biologically relevant branched metabolic pathways.

[1]  Jay D. Keasling,et al.  Engineering the lycopene synthetic pathway in E. coli by comparison of the carotenoid genes of Pantoea agglomerans and Pantoea ananatis , 2007, Applied Microbiology and Biotechnology.

[2]  J. Nielsen,et al.  Mathematical modelling of metabolism. , 2000, Current opinion in biotechnology.

[3]  Mark Stitt,et al.  Pyrimidine and purine biosynthesis and degradation in plants. , 2006, Annual review of plant biology.

[4]  Lydia E. Kavraki,et al.  Finding metabolic pathways using atom tracking , 2010, Bioinform..

[5]  J A Washington,et al.  Erythromycin: a microbial and clinical perspective after 30 years of clinical use (1). , 1985, Mayo Clinic proceedings.

[6]  P. Turnbaugh,et al.  An Invitation to the Marriage of Metagenomics and Metabolomics , 2008, Cell.

[7]  Masaaki Kotera,et al.  RPAIR : a reactant-pair database representing chemical changes in enzymatic reactions , 2004 .

[8]  R. Potenz,et al.  Organization of a cluster of erythromycin genes in Saccharopolyspora erythraea , 1990, Journal of bacteriology.

[9]  Christoph Kaleta,et al.  Response to comment on 'Can sugars be produced from fatty acids? A test case for pathway analysis tools' , 2009, Bioinform..

[10]  Zhihao Hu,et al.  Process and Metabolic Strategies for Improved Production of Escherichia coli-Derived 6-Deoxyerythronolide B , 2002, Applied and Environmental Microbiology.

[11]  Kiyoko F. Aoki-Kinoshita,et al.  From genomics to chemical genomics: new developments in KEGG , 2005, Nucleic Acids Res..

[12]  Ka-Yiu San,et al.  Enhanced Lycopene Productivity by Manipulation of Carbon Flow to Isopentenyl Diphosphate in Escherichia coli , 2005, Biotechnology progress.

[13]  J. Nielsen,et al.  The role of metabolic engineering in the production of secondary metabolites. , 1998, Current opinion in microbiology.

[14]  Kim Sneppen,et al.  Pathway identification by network pruning in the metabolic network of Escherichia coli , 2009, Bioinform..

[15]  Oliver Kohlbacher,et al.  Using Atom Mapping Rules for an Improved Detection of Relevant Routes in Weighted Metabolic Networks , 2008, J. Comput. Biol..

[16]  J. van Helden,et al.  Metabolic pathfinding using RPAIR annotation. , 2009, Journal of molecular biology.

[17]  Suzanne M. Paley,et al.  The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases , 2015, Nucleic Acids Res..

[18]  J. Bailey,et al.  Toward a science of metabolic engineering , 1991, Science.

[19]  Oliver Kohlbacher,et al.  MetaRoute: fast search for relevant metabolic routes for interactive network navigation and visualization , 2008, Bioinform..

[20]  Adam M. Feist,et al.  Reconstruction of biochemical networks in microorganisms , 2009, Nature Reviews Microbiology.

[21]  Costas D Maranas,et al.  Microbial 1-butanol production: Identification of non-native production routes and in silico engineering interventions. , 2010, Biotechnology journal.

[22]  John A. Washington,et al.  Erythromycin: A Microbial and Clinical Perspective After 30 Years of Clinical Use (First of Two Parts)* , 1985 .

[23]  W. Marsden I and J , 2012 .

[24]  F Keller,et al.  Allocation of raffinose family oligosaccharides to transport and storage pools in Ajuga reptans: the roles of two distinct galactinol synthases. , 2000, The Plant journal : for cell and molecular biology.

[25]  Masanori Arita In silico atomic tracing by substrate-product relationships in Escherichia coli intermediary metabolism. , 2003, Genome research.

[26]  S. Wodak,et al.  Inferring meaningful pathways in weighted metabolic networks. , 2006, Journal of molecular biology.

[27]  C. Steinbeck,et al.  Recent developments of the chemistry development kit (CDK) - an open-source java library for chemo- and bioinformatics. , 2006, Current pharmaceutical design.

[28]  Gregory Stephanopoulos,et al.  Construction of lycopene-overproducing E. coli strains by combining systematic and combinatorial gene knockout targets , 2005, Nature Biotechnology.

[29]  Jens Nielsen,et al.  Metabolic engineering of -lactam production , 2003 .

[30]  Chaitan Khosla,et al.  Structure and mechanism of the 6-deoxyerythronolide B synthase. , 2007, Annual review of biochemistry.

[31]  Yoshihiro Yamanishi,et al.  KEGG for linking genomes to life and the environment , 2007, Nucleic Acids Res..

[32]  Thomas Peterbauer,et al.  Biochemistry and physiology of raffinose family oligosaccharides and galactosyl cyclitols in seeds , 2001, Seed Science Research.

[33]  Frédéric Boyer,et al.  Ab initio reconstruction of metabolic pathways , 2003, ECCB.

[34]  Y. Zhuang,et al.  Genetic Modulation of the Overexpression of Tailoring Genes eryK and eryG Leading to the Improvement of Erythromycin A Purity and Production in Saccharopolyspora erythraea Fermentation , 2008, Applied and Environmental Microbiology.

[35]  J A Washington,et al.  Erythromycin: a microbial and clinical perspective after 30 years of clinical use (2). , 1985, Mayo Clinic proceedings.

[36]  Y. Zhang,et al.  Structural biology of the purine biosynthetic pathway , 2008, Cellular and Molecular Life Sciences.

[37]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[38]  C R Hutchinson,et al.  Sequencing and mutagenesis of genes from the erythromycin biosynthetic gene cluster of Saccharopolyspora erythraea that are involved in L-mycarose and D-desosamine production. , 1997, Microbiology.

[39]  A W Murray,et al.  The biological significance of purine salvage. , 1971, Annual review of biochemistry.

[40]  I. Brikun,et al.  Engineering of the methylmalonyl-CoA metabolite node of Saccharopolyspora erythraea for increased erythromycin production. , 2007, Metabolic engineering.

[41]  Yves Deville,et al.  An overview of data models for the analysis of biochemical pathways , 2003, Briefings Bioinform..

[42]  D. Fell,et al.  The small world inside large metabolic networks , 2000, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[43]  Sarbani Pal A Journey Across the Sequential Development of Macrolides and Ketolides Related to Erythromycin , 2006 .

[44]  Kenneth J. Kauffman,et al.  Advances in flux balance analysis. , 2003, Current opinion in biotechnology.

[45]  Jotun Hein,et al.  Rahnuma: hypergraph-based tool for metabolic pathway prediction and network comparison , 2009, Bioinform..

[46]  Francisco J. Planes,et al.  A critical examination of stoichiometric and path-finding approaches to metabolic pathways , 2008, Briefings Bioinform..

[47]  Masanori Arita The metabolic world of Escherichia coli is not small. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[48]  S. Rao,et al.  PathMiner: predicting metabolic pathways by heuristic search , 2003, Bioinform..

[49]  Arnold L. Demain,et al.  The β-lactam antibiotics: past, present, and future , 2004, Antonie van Leeuwenhoek.

[50]  Robert H. White,et al.  Purine biosynthesis in the domain Archaea without folates or modified folates , 1997, Journal of bacteriology.

[51]  G. Sandmann,et al.  Carotenoid biosynthesis and biotechnological application. , 2001, Archives of biochemistry and biophysics.

[52]  Juho Rousu,et al.  BMC Systems Biology BioMed Central Methodology article , 2009 .

[53]  Lydia E. Kavraki,et al.  Identifying Branched Metabolic Pathways by Merging Linear Metabolic Pathways , 2011, RECOMB.

[54]  Rainer Schrader,et al.  Metabolic pathway analysis web service (Pathway Hunter Tool at CUBIC) , 2005, Bioinform..