Specificity Effects of Amino Acid Substitutions in Promiscuous Hydrolases: Context-Dependence of Catalytic Residue Contributions to Local Fitness Landscapes in Nearby Sequence Space

Christopher D. Bayer, Bert van Loo, Florian Hollfelder*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)
5 Downloads (Pure)

Abstract

Catalytic promiscuity can facilitate evolution of enzyme functions—a multifunctional catalyst may act as a springboard for efficient functional adaptation. We test the effect of single mutations on multiple activities in two groups of promiscuous AP superfamily members to probe this hypothesis. We quantify the effect of site-saturating mutagenesis of an analogous, nucleophile-flanking residue in two superfamily members: an arylsulfatase (AS) and a phosphonate monoester hydrolase (PMH). Statistical analysis suggests that no one physicochemical characteristic alone explains the mutational effects. Instead, these effects appear to be dominated by their structural context. Likewise, the effect of changing the catalytic nucleophile itself is not reaction-type-specific. Mapping of “fitness landscapes” of four activities onto the possible variation of a chosen sequence position revealed tremendous potential for respecialization of AP superfamily members through single-point mutations, highlighting catalytic promiscuity as a powerful predictor of adaptive potential.

Original languageEnglish
Pages (from-to)1001-1015
Number of pages15
JournalChemBioChem
Volume18
Issue number11
Early online date2 May 2017
DOIs
Publication statusPublished - 6 Jun 2017
Externally publishedYes

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