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- W2765460003 abstract "Author(s): Collazo, Lara Patricia | Advisor(s): Klinman, Judith P | Abstract: Enzymes are complex systems that contain a variety of pockets, clefts, and channels throughout the protein matrix. These gaps and tunnels represent potential transport pathways for gases, ions, and other small molecules, and can play a critical role in tuning enzyme function. In this work, the functional role of gas migration pathways was examined in soybean lipoxygenase 1 (SLO-1), a prototypical lipoxygenase that catalyzes the regio- and stereospecific peroxidation of linoleic acid to 13S hydroperoxyoctadecadienoic acid (13S HPOD). Two computational techniques--implicit ligand sampling and CAVER--were employed to evaluate pathways for oxygen migration in the enzyme. Both approaches converged on a single channel deemed most competent for oxygen delivery. Interestingly, this channel is consistent with a cavity originally detected in the crystal structure of SLO-1 and previously proposed as a pathway for oxygen. Site-directed mutagenesis was used to assess the impact of introducing bulk at the channel's bottleneck residues. Introducing tryptophan into the pathway at positions 553 and 496 resulted in increased Michaelis constants for oxygen and disrupted reaction regio- and stereospecificity, supporting a functional role for the tunnel in oxygen trafficking. Intriguingly, mutations at Ile553 and Leu496 appear to influence oxygen migration in distinct ways. Introducing tryptophan at 553 dramatically reduces O2 access to the active site, as evidenced by a markedly increased KM(O2)--744 uM O2 compared to 38 uM O2 for wild-type--together with an increase in the proportion of 13R, 9S, and 9R HPOD isomers generated. Introducing bulk at 496, by contrast, appears to ungate an alternate pathway for O2 access, as evidenced by an increased proportion of 9S and 9R HPOD isomers generated. The divergent behavior of the Ile553Trp and Leu496Trp mutants provides striking evidence for the plasticity of oxygen pathways, which can be manipulated via single site mutations. Taken together, our computational and mutagenesis studies point to a single delivery channel that shuttles oxygen to the active site of SLO-1 and tunes the regio- and stereospecificity of oxygen insertion into linoleic acid. Our results speak to the vital role that the protein matrix plays in regulating catalysis and lay the framework for future protein engineering efforts in oxygen-dependent enzymes." @default.
- W2765460003 created "2017-11-10" @default.
- W2765460003 creator A5047848604 @default.
- W2765460003 date "2013-01-01" @default.
- W2765460003 modified "2023-09-27" @default.
- W2765460003 title "Investigating Gas Migration in Enzymes: Dioxygen Channels inside of Soybean Lipoxygenase 1" @default.
- W2765460003 hasPublicationYear "2013" @default.
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