Many enzymes of the major metabolic pathways are categorized into superfamilies which share common folds. Current models postulate these superfamilies are the result of gene duplications coupled with mutations that result in the acquisition of new functions. Some of these new functions are considered advantageous and selected for, while others may simply be tolerated. The latter can result in metabolites being produced at low rates that are of no known use by the cell, and can become toxic when accumulated. Concurrent with the evolution of this tolerable or potentially detrimental metabolism, organisms are selected to evolve a means of correcting or “proofreading” these non-canonical metabolites to counterbalance their detrimental effects. Metabolite proofreading is a process of intermediary metabolism analogous to DNA proof reading that acts on these abnormal metabolites to prevent their accumulation and toxic effects.
Here we structurally characterize ethylmalonyl-CoA decarboxylase (EMCD), a member of the family of enoyl-CoA hydratases within the crotonase superfamily of proteins, which is coded by the ECHDC1 (enoyl-CoA hydratase domain containing 1) gene. EMCD has been shown to have a metabolic proofreading property, acting on the metabolic byproduct ethylmalonyl-CoA to prevent its accumulation which could result in oxidative damage. We use the complimentary methods of in situ crystallography, small angle X-ray scattering, and single crystal X-ray crystallography to structurally characterize EMCD, followed by homology analysis in order to propose a mechanism of action. This represents the first structure of a crotonase superfamily member thought to function as a metabolite proof reading enzyme.
|Advisor:||Snell, Edward H.|
|Commitee:||Blessing, Robert H., Gulick, Andrew M., Umland, Timothy C.|
|School:||State University of New York at Buffalo|
|School Location:||United States -- New York|
|Source:||MAI 55/01M(E), Masters Abstracts International|
|Keywords:||Crystallography, Ethylmalonyl-CoA decarboxylase, Metabolite proofreading|
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