Aug 7, 2007

Molecular dioxygen enters the active site of 12/15-lipoxygenase via dynamic oxygen access channels

Proceedings of the National Academy of Sciences of the United States of America
Jan SaamHartmut Kühn


Cells contain numerous enzymes that use molecular oxygen for their reactions. Often, their active sites are buried deeply inside the protein, which raises the question whether there are specific access channels guiding oxygen to the site of catalysis. Choosing 12/15-lipoxygenase as a typical example for such oxygen-dependent enzymes, we determined the oxygen distribution within the protein and defined potential routes for oxygen access. For this purpose, we have applied an integrated strategy of structural modeling, molecular dynamics simulations, site-directed mutagenesis, and kinetic measurements. First, we computed the 3D free-energy distribution for oxygen, which led to identification of four oxygen channels in the protein. All channels connect the protein surface with a region of high oxygen affinity at the active site. This region is localized opposite to the nonheme iron providing a structural explanation for the reaction specificity of this lipoxygenase isoform. The catalytically most relevant path can be obstructed by L367F exchange, which leads to a strongly increased Michaelis constant for oxygen. The blocking mechanism is explained in detail by reordering the hydrogen-bonding network of water molecules. Our results ...Continue Reading

Mentioned in this Paper

Molecular Dynamics
Enzymes, antithrombotic
Mutagenesis, Site-Directed
Body Cavities
Dental Caries
Chinchilla Rabbits
Oxygen Affinity

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