title: Combining chemoinformatics with bioinformatics: in silico prediction of bacterial flavor-forming pathways by a chemical systems biology approach "reverse pathway engineering".
abstract: The incompleteness of genome-scale metabolic models is a major bottleneck for systems biology approaches, which are based on large numbers of metabolites as identified and quantified by metabolomics. Many of the revealed secondary metabolites and/or their derivatives, such as flavor compounds, are non-essential in metabolism, and many of their synthesis pathways are unknown. In this study, we describe a novel approach, Reverse Pathway Engineering (RPE), which combines chemoinformatics and bioinformatics analyses, to predict the "missing links" between compounds of interest and their possible metabolic precursors by providing plausible chemical and/or enzymatic reactions. We demonstrate the added-value of the approach by using flavor-forming pathways in lactic acid bacteria (LAB) as an example. Established metabolic routes leading to the formation of flavor compounds from leucine were successfully replicated. Novel reactions involved in flavor formation, i.e. the conversion of alpha-hydroxy-isocaproate to 3-methylbutanoic acid and the synthesis of dimethyl sulfide, as well as the involved enzymes were successfully predicted. These new insights into the flavor-formation mechanisms in LAB can have a significant impact on improving the control of aroma formation in fermented food products. Since the input reaction databases and compounds are highly flexible, the RPE approach can be easily extended to a broad spectrum of applications, amongst others health/disease biomarker discovery as well as synthetic biology.
authors.affiliation: Department of Nutritional Sciences, FrieslandCampina, Amersfoort, The Netherlands ; Centre for Molecular and Biomolecular Informatics, Radboud University, Nijmegen, The Netherlands.
authors.forename: Mengjin
authors.initials: M
authors.lastname: Liu
authors.affiliation: Molecular Networks GmbH, Erlangen, Germany.
authors.forename: Bruno
authors.initials: B
authors.lastname: Bienfait
authors.affiliation: Molecular Networks GmbH, Erlangen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Sacher
authors.affiliation: Molecular Networks GmbH, Erlangen, Germany ; Computer-Chemie-Centrum, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Gasteiger
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud University, Nijmegen, The Netherlands.
authors.forename: Roland J
authors.initials: RJ
authors.lastname: Siezen
authors.affiliation: Department of Nutritional Sciences, FrieslandCampina, Amersfoort, The Netherlands.
authors.forename: Arjen
authors.initials: A
authors.lastname: Nauta
authors.affiliation: Department of Nutritional Sciences, FrieslandCampina, Amersfoort, The Netherlands.
authors.forename: Jan M W
authors.initials: JM
authors.lastname: Geurts
mesh_terms: D000613:Aminobutyrates / Q000378:metabolism; D001419:Bacteria / Q000201:enzymology / Q000378:metabolism*; D002208:Caproates / Q000378:metabolism; D003198:Computer Simulation; D007930:Leucine / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D008715:Methionine / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013440:Sulfides / Q000378:metabolism; D049490:Systems Biology / Q000379:methods*; D013649:Taste
chemical_list: D000613:Aminobutyrates; D002208:Caproates; D013438:Sulfhydryl Compounds; D013440:Sulfides; C005231:methylmercaptan; C019419:alpha-hydroxyisocaproic acid; D008715:Methionine; D007930:Leucine; C004784:dimethyl sulfide