title: PrenDB, a Substrate Prediction Database to Enable Biocatalytic Use of Prenyltransferases.
abstract: Prenyltransferases of the dimethylallyltryptophan synthase (DMATS) superfamily catalyze the attachment of prenyl or prenyl-like moieties to diverse acceptor compounds. These acceptor molecules are generally aromatic in nature and mostly indole or indole-like. Their catalytic transformation represents a major skeletal diversification step in the biosynthesis of secondary metabolites, including the indole alkaloids. DMATS enzymes thus contribute significantly to the biological and pharmacological diversity of small molecule metabolites. Understanding the substrate specificity of these enzymes could create opportunities for their biocatalytic use in preparing complex synthetic scaffolds. However, there has been no framework to achieve this in a rational way. Here, we report a chemoinformatic pipeline to enable prenyltransferase substrate prediction. We systematically catalogued 32 unique prenyltransferases and 167 unique substrates to create possible reaction matrices and compiled these data into a browsable database named PrenDB. We then used a newly developed algorithm based on molecular fragmentation to automatically extract reactive chemical epitopes. The analysis of the collected data sheds light on the thus far explored substrate space of DMATS enzymes. To assess the predictive performance of our virtual reaction extraction tool, 38 potential substrates were tested as prenyl acceptors in assays with three prenyltransferases, and we were able to detect turnover in >55% of the cases. The database, PrenDB (www.kolblab.org/prendb.php), enables the prediction of potential substrates for chemoenzymatic synthesis through substructure similarity and virtual chemical transformation techniques. It aims at making prenyltransferases and their highly regio- and stereoselective reactions accessible to the research community for integration in synthetic work flows.
authors.affiliation: From the Department of Pharmaceutical Chemistry, Philipps-University, Marburg, Hesse 35032, Germany.|Synmikro, LOEWE Centre for Synthetic Microbiology, Philipps-University, Marburg, Hesse 35043, Germany.
authors.forename: Jakub
authors.initials: J
authors.lastname: Gunera
authors.affiliation: the Institute of Pharmaceutical Biology and Biotechnology, Philipps-University, Marburg, Hesse 35032, Germany, and.
authors.forename: Florian
authors.initials: F
authors.lastname: Kindinger
authors.affiliation: Synmikro, LOEWE Centre for Synthetic Microbiology, Philipps-University, Marburg, Hesse 35043, Germany shuming.li@staff.uni-marburg.de.|the Institute of Pharmaceutical Biology and Biotechnology, Philipps-University, Marburg, Hesse 35032, Germany, and.
authors.forename: Shu-Ming
authors.initials: SM
authors.lastname: Li
authors.affiliation: From the Department of Pharmaceutical Chemistry, Philipps-University, Marburg, Hesse 35032, Germany, peter.kolb@uni-marburg.de.|Synmikro, LOEWE Centre for Synthetic Microbiology, Philipps-University, Marburg, Hesse 35043, Germany.
authors.forename: Peter
authors.identifier: 0000-0003-4089-614X
authors.initials: P
authors.lastname: Kolb
mesh_terms: D000465:Algorithms; D019883:Alkyl and Aryl Transferases / Q000737:chemistry* / Q000378:metabolism*; D055162:Biocatalysis; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D007211:Indoles / Q000737:chemistry / Q000378:metabolism*; D017368:Protein Prenylation; D013379:Substrate Specificity
chemical_list: D007211:Indoles; C030374:indole; D019883:Alkyl and Aryl Transferases; C032409:tryptophan dimethylallyltransferase
keywords: bioinformatics; chemoinformatics; computer modeling; enzyme catalysis; high-throughput screening (HTS); prenyltransferases; reaction database; substrate prediction; substrate specificity