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Conformational Ensembles from Experimental Data
and Computer Simulations
Poster Abstracts
53
20-POS
Board 20
Insight into Oxygen Diffusion in Oxygenases
Carmen Domene
,
Kings College London, London, United Kingdom.
The 2-oxoglutarate (2OG) dependent oxygenases are a superfamily of non-haem iron dependent
oxygenases, most of which use the Krebs cycle intermediate, 2-oxoglutarate (2OG), as a
cosubstrate. We are interested in understanding these enzymes for their ability to catalyse
synthetically difficult or ‘impossible’ reactions (e.g. the stereoselective hydroxylation of
unactivated carbon-hydrogen bonds), for their diverse physiological roles, and for their links to
disease. These enzymes have important roles in oxygen sensing, collagen biosynthesis, fatty acid
metabolism and in the epigenetic regulation of gene expression.
There are estimated to be 60-80 human 2OG oxygenases. Defining functions for all human '2OG
oxygenases' at biochemical, cellular, and physiological level is crucial. Given the mechanistic
and structural conservation amongst 2OG oxygenases, we are attempting to define the molecular
features that are responsible for their reaction with O
2
. As part of this, a combined computational
and experimental approach has been followed. Crystal structures have been obtained, small-
molecule inhibitors of 2OG oxygenases have been identified, and computational mechanistic
studies using equilibrium and non-equilibrium computer simulations have been carried out. An
overview of this project will be given in this presentation.