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Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS): UGT case example
Citation:
LaLone, C. AND D. Blatz. Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS): UGT case example. European Food Safety Authority, Jean Lou Dorne and University of Parma Luca Dellafiora SeqAPASS Webinar, Duluth, MN, March 12, 2021. https://doi.org/10.23645/epacomptox.14166608
Impact/Purpose:
This presentation will introduce the Sequence Alignment to predict Across Species Susceptibility (SeqAPASS) tool and demonstrate the features and data interpretation relative to a case example focused on UDP-Glucuronosyltransferase.
Description:
Over the last few years, the European Food Safety Authority (EFSA) has been exploring the use of modern methodologies and New Approach Methodologies (NAMs) in human health, animal health and environmental risk assessment of chemicals. First, a scientific report on available methodologies and tools to investigate toxicokinetic (TK) and toxicodynamic (TD) processes of chemicals was published with particular attention to Mode of Action (MoA) and Adverse Outcome Pathways (AOPs). The report reviewed the use of in vitro systems to investigate TK processes, physiologically-based (PB) models (i.e. PB-Kinetic (PBK) and PB-K-dynamic (PB-KD models)), in silico models (Quantitative) Structure Activity Relationship (Q)SAR), Threshold of Toxicological Concern (TTC) and read across methods) and OMICs technologies (transcriptomics, proteomics, and metabolomics) for human hazard assessment. Recommendations for future work were formulated as the result of a broad consultation of EFSA staff, experts and key international organisations. A key priority reflected the need to develop open source databases (DB) and PB-K and PB-KD models to support the integration of exposure data (external dose) with TK processes (internal dose) and toxicity data for risk assessment of chemicals. over the last decade, millions of proteins have been sequenced in thousands of species and such information is very valuable to identify potential targets for chemicals to investigate MoA and AOPs in a risk assessment context. These protein sequences and related information can be accessed from a wide range of DB including the National Center for Biotechnology Information protein DB (NCBI) (https://www.ncbi.nlm.nih.gov/protein/), the binding DB (http://www.bindingdb.org/bind/index.jsp), the Biological General Repository for Interaction Datasets (https://thebiogrid.org/) and the enzyme database Brenda (https://www.brenda-enzymes.org/) to cite but a few. Over the last few years, the US-EPA has developed the SeqAPASS tool “Sequence Alignment to Predict Across Species Susceptibility” allowing to identify the presence of protein targets in many species and explore inter-species sensitivity in chemical toxicity. SeqAPASS through molecular modelling allows to assess inter-species extrapolation of toxicity data from test species (rats, mice, etc.) to other non-target species for which toxicity data are much more limited or not available. Examples of relevant applications include 1. assessment of conservation of protein endocrine targets (484) from suite of high-throughput screening assays across mammals, 3.comparisons of individual amino acid residues at key positions involved in protein-chemical interactions and 3. in silico site-directed mutagenesis coupled with docking simulations using computational models (Lalone et al., 2018; Doering et al., 2018; Mellor et al., 2020). Other open source software allow to predict how chemicals may bind a target protein of known 3D structure such as AutoDock (http://autodock.scripps.edu/) or Gromacs to investigate the molecular dynamics of protein folding (http://www.gromacs.org/). The type of information generated from these new tools, including binding differences across proteins targets in many taxa and inter-species differences in toxicity, provide an opportunity to further refine PBK and PB-KD models for the risk assessment community. This presentation focuses on demonstrating the utility of the SeqAPASS tool for evaluation of the phase II metabolizing enzyme UDP-Glucuronosyltransferase.
URLs/Downloads:
DOI: Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS): UGT case example