PROXIMAL: a method for Prediction of Xenobiotic Metabolism

Abstract

BackgroundContamination of the environment with bioactive chemicals has emerged as a potential public health risk. These substances that may cause distress or disease in humans can be found in air, water and food supplies. An open question is whether these chemicals transform into potentially more active or toxic derivatives via xenobiotic metabolizing enzymes expressed in the body. We present a new prediction tool, which we call PROXIMAL (Prediction of Xenobiotic Metabolism) for identifying possible transformation products of xenobiotic chemicals in the liver. Using reaction data from DrugBank and KEGG, PROXIMAL builds look-up tables that catalog the sites and types of structural modifications performed by Phase I and Phase II enzymes. Given a compound of interest, PROXIMAL searches for substructures that match the sites cataloged in the look-up tables, applies the corresponding modifications to generate a panel of possible transformation products, and ranks the products based on the activity and abundance of the enzymes involved.ResultsPROXIMAL generates transformations that are specific for the chemical of interest by analyzing the chemical’s substructures. We evaluate the accuracy of PROXIMAL’s predictions through case studies on two environmental chemicals with suspected endocrine disrupting activity, bisphenol A (BPA) and 4-chlorobiphenyl (PCB3). Comparisons with published reports confirm 5 out of 7 and 17 out of 26 of the predicted derivatives for BPA and PCB3, respectively. We also compare biotransformation predictions generated by PROXIMAL with those generated by METEOR and Metaprint2D-react, two other prediction tools.ConclusionsPROXIMAL can predict transformations of chemicals that contain substructures recognizable by human liver enzymes. It also has the ability to rank the predicted metabolites based on the activity and abundance of enzymes involved in xenobiotic transformation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-015-0241-4) contains supplementary material, which is available to authorized users.

Towards creating an extended metabolic model (EMM) for E. coli using enzyme promiscuity prediction and metabolomics data

“…Further, the workflow provides balanced reactions to document such enzymatic activities. We utilized PROXIMAL [35], which first identifies patterns of structural transformations associated with enzymes in the biological sample and then applies these transformations to known sample metabolites to predict putative metabolic products. Using PROXIMAL in this way allows attributing putative metabolic products to specific enzymatic activity and deriving balanced biochemical reactions that capture the promiscuous activity.…”

“…Each reaction is assumed to be reversible unless indicated otherwise. EMMA utilizes PROXIMAL [35], a method for creating biotransformation operators from KEGG reactions IDs using RDM (Reaction Center, Difference Region, and Matched Region) patterns [36], and then applying the operators to given molecules. While initially developed to investigate products of Cytochrome P450 (CYP) enzymes, highly promiscuous enzymes utilized for detoxification, the PROXIMAL method is generic.…”

Biological Filtering and Substrate Promiscuity Prediction for Annotating Untargeted Metabolomics

“…Our novel annotation workflow ( Figure 1C), EMMF, applies an EMM-based filter to identify the candidate set. To create this model, we adopted a previously described method, PROXIMAL [40] (Supplementary Methods). Although originally developed to analyze the products of xenobiotic transformation reactions catalyzed by possible via cytochrome P450 (CYP) enzymes, PROXIMAL was shown to be also effective in predicting promiscuous enzyme products for Escherichia coli [41].…”

Advances in Computational Prediction of Regioselective and Isoform-Specific Drug Metabolism Catalyzed by CYP450s.

“…Yousofshahi et al recently have developed a tool for xenobiotic metabolism prediction called PROXIMAL (Prediction of Xenobiotic Metabolism). [58] This approach consists of three major steps. Molecules are treated like graphs with atoms as nodes and covalent bonds as edges.…”