Mabbitt_2016_Biochemistry_55_1408

Reference

Title : Conformational Disorganization within the Active Site of a Recently Evolved Organophosphate Hydrolase Limits Its Catalytic Efficiency - Mabbitt_2016_Biochemistry_55_1408
Author(s) : Mabbitt PD , Correy GJ , Meirelles T , Fraser NJ , Coote ML , Jackson CJ
Ref : Biochemistry , 55 :1408 , 2016
Abstract : The evolution of new enzymatic activity is rarely observed outside of the laboratory. In the agricultural pest Lucilia cuprina, a naturally occurring mutation (Gly137Asp) in alpha-esterase 7 (LcalphaE7) results in acquisition of organophosphate hydrolase activity and confers resistance to organophosphate insecticides. Here, we present an X-ray crystal structure of LcalphaE7:Gly137Asp that, along with kinetic data, suggests that Asp137 acts as a general base in the new catalytic mechanism. Unexpectedly, the conformation of Asp137 observed in the crystal structure obstructs the active site and is not catalytically productive. Molecular dynamics simulations reveal that alternative, catalytically competent conformers of Asp137 are sampled on the nanosecond time scale, although these states are less populated. Thus, although the mutation introduces the new reactive group responsible for organophosphate detoxification, the catalytic efficiency appears to be limited by conformational disorganization: the frequent sampling of low-energy nonproductive states. This result is consistent with a model of molecular evolution in which initial function-changing mutations can result in enzymes that display only a fraction of their catalytic potential due to conformational disorganization.
ESTHER : Mabbitt_2016_Biochemistry_55_1408
PubMedSearch : Mabbitt_2016_Biochemistry_55_1408
PubMedID: 26881849
Gene_locus related to this paper: luccu-E3aest7

Related information

Gene_locus related to this paper: luccu-E3aest7

Citations formats

Mabbitt PD, Correy GJ, Meirelles T, Fraser NJ, Coote ML, Jackson CJ (2016)
Conformational Disorganization within the Active Site of a Recently Evolved Organophosphate Hydrolase Limits Its Catalytic Efficiency
Biochemistry 55 :1408

Mabbitt PD, Correy GJ, Meirelles T, Fraser NJ, Coote ML, Jackson CJ (2016)
Biochemistry 55 :1408