title: Prediction of metabolic reactions based on atomic and molecular properties of small-molecule compounds.
abstract: BACKGROUND
  Our knowledge of the metabolites in cells and their reactions is far from complete as revealed by metabolomic measurements that detect many more small molecules than are documented in metabolic databases. Here, we develop an approach for predicting the reactivity of small-molecule metabolites in enzyme-catalyzed reactions that combines expert knowledge, computational chemistry and machine learning.
  
  
  RESULTS
  We classified 4843 reactions documented in the KEGG database, from all six Enzyme Commission classes (EC 1-6), into 80 reaction classes, each of which is marked by a characteristic functional group transformation. Reaction centers and surrounding local structures in substrates and products of these reactions were represented using SMARTS. We found that each of the SMARTS-defined chemical substructures is widely distributed among metabolites, but only a fraction of the functional groups in these substructures are reactive. Using atomic properties of atoms in a putative reaction center and molecular properties as features, we trained support vector machine (SVM) classifiers to discriminate between functional groups that are reactive and non-reactive. Classifier accuracy was assessed by cross-validation analysis. A typical sensitivity [TP/(TP+FN)] or specificity [TN/(TN+FP)] is ≈0.8. Our results suggest that metabolic reactivity of small-molecule compounds can be predicted with reasonable accuracy based on the presence of a potentially reactive functional group and the chemical features of its local environment.
  
  
  BACKGROUND
  The classifiers presented here can be used to predict reactions via a web site (http://cellsignaling.lanl.gov/Reactivity/). The web site is freely available.
authors.affiliation: Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA. fmu@lanl.gov
authors.forename: Fangping
authors.initials: F
authors.lastname: Mu
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Unkefer
authors.forename: Pat J
authors.initials: PJ
authors.lastname: Unkefer
authors.forename: William S
authors.initials: WS
authors.lastname: Hlavacek
mesh_terms: D001185:Artificial Intelligence; D055162:Biocatalysis; D002965:Classification / Q000379:methods; D019295:Computational Biology / Q000379:methods; D016208:Databases, Factual; D004798:Enzymes / Q000145:classification; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D055432:Metabolomics / Q000379:methods*; D015394:Molecular Structure
chemical_list: D004798:Enzymes