Panoramic view of a superfamily of phosphatases through substrate profiling

By Hua Huang, Chetanya Pandya, Chunlian Liu, Nawar Al-Obaidi, Min Wang, Li Zheng, Sarah Toews Keating, Miyuki Aono, J. Love, B. Evans and 7 more. 2015

147 citations recorded by the source corpus.

Significance Here, we examine the activity profile of the haloalkanoic acid dehalogenase (HAD) superfamily by screening a customized library against >200 enzymes from a broad sampling of the superfamily. From this dataset, we can infer the function of nearly 35% of the superfamily. Overall, the superfamily was found to show high substrate ambiguity, with 75% of the superfamily utilizing greater than five substrates. In addition, the HAD members with the least amount of structural accessorization of the Rossmann fold were found to be the most specific, suggesting that elaboration of the core domain may have led to increased substrate range of the superfamily. 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.

Subfields: Materials Chemistry, Molecular Biology

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In Materials Chemistry

1. Christine A. Orengo
2. David A. Lee

In Molecular Biology

1. David A. Lee
2. Christine A. Orengo
3. Ian Sillitoe
4. Mohammed Alquraishi

Citations in the corpus

• Gene3D: Extensive prediction of globular domains in proteins (2017, background): “Through genomic re-arrangements, domains can be inserted into other domains with important consequences for function, such as altering catalytic properties (6).”