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A Positively Selected Residue Influences Enzyme Functionalities
Author(s) -
Ivarsson Ylva,
Norrgård Malena A.,
Tars Kaspars,
Mannervik Bengt
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a474-a
Subject(s) - tripeptide , residue (chemistry) , enzyme , steric effects , glutathione , saturated mutagenesis , electrophile , biochemistry , gene , mutagenesis , chemistry , stereochemistry , amino acid , mutation , mutant , catalysis
Glutathione transferases (GSTs) are a family of multifunctional enzymes that utilize the tripeptide glutathione (GSH) to detoxify a wide range of electrophiles. The GSTs are grouped into different classes based on protein sequecne similarities, but although members of a class have high sequcence identities they often display different substrate specificities. In the Mu GSTs there is evidence that a limited number of positively selected residues drive the evolution towards novel enzyme functions1. Residue 210 is one of these residues. In the present study we show by saturation‐mutagenesis of residue 210 in human GST M2‐2 how point mutations can differentially change the the enzyme’s substrate‐activity profile with alternative substrates. This demonstrates how the residue may have played a role as a functional switch in the evolution of the Mu class genes, since a duplicated gene can quite easily recruit a novel function,. Crystal structures clarify that removal of steric hindrance of a methyl group enables activity with epoxides, while other activites are maintained in the variant enzymes. The work in the authors’ laboratory was supported by the Swedish Research Council. Y.I. and M. A. were recipients of stipends from the Sven and Lilly Lawski Foundation.