Author:
Huang Hua,Pandya Chetanya,Liu Chunliang,Al-Obaidi Nawar F.,Wang Min,Zheng Li,Toews Keating Sarah,Aono Miyuki,Love James D.,Evans Brandon,Seidel Ronald D.,Hillerich Brandan S.,Garforth Scott J.,Almo Steven C.,Mariano Patrick S.,Dunaway-Mariano Debra,Allen Karen N.,Farelli Jeremiah D.
Abstract
Large-scale activity profiling of enzyme superfamilies provides information about cellular functions as well as the intrinsic binding capabilities of conserved folds. Herein, the functional space of the ubiquitous haloalkanoate dehalogenase superfamily (HADSF) was revealed by screening a customized substrate library against >200 enzymes from representative prokaryotic species, enabling inferred annotation of ∼35% of the HADSF. An extremely high level of substrate ambiguity was revealed, with the majority of HADSF enzymes using more than five substrates. Substrate profiling allowed assignment of function to previously unannotated enzymes with known structure, uncovered potential new pathways, and identified iso-functional orthologs from evolutionarily distant taxonomic groups. Intriguingly, the HADSF subfamily having the least structural elaboration of the Rossmann fold catalytic domain was the most specific, consistent with the concept that domain insertions drive the evolution of new functions and that the broad specificity observed in HADSF may be a relic of this process.
Funder
HHS | National Institutes of Health
HHS | NIH | National Institute of Biomedical Imaging and Bioengineering
Publisher
Proceedings of the National Academy of Sciences
Cited by
113 articles.
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