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Detailed kinetics and regulation of mammalian 2-oxoglutarate dehydrogenase. BMC Biochem 2011 Sep 26;12:53



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2-s2.0-80053379940   18 Citations


BACKGROUND: Mitochondrial 2-oxoglutarate (α-ketoglutarate) dehydrogenase complex (OGDHC), a key regulatory point of tricarboxylic acid (TCA) cycle, plays vital roles in multiple pathways of energy metabolism and biosynthesis. The catalytic mechanism and allosteric regulation of this large enzyme complex are not fully understood. Here computer simulation is used to test possible catalytic mechanisms and mechanisms of allosteric regulation of the enzyme by nucleotides (ATP, ADP), pH, and metal ion cofactors (Ca(2+) and Mg(2+)).

RESULTS: A model was developed based on an ordered ter-ter enzyme kinetic mechanism combined with con-formational changes that involve rotation of one lipoic acid between three catalytic sites inside the enzyme complex. The model was parameterized using a large number of kinetic data sets on the activity of OGDHC, and validated by comparison of model predictions to independent data.

CONCLUSIONS: The developed model suggests a hybrid rapid-equilibrium ping-pong random mechanism for the kinetics of OGDHC, consistent with previously reported mechanisms, and accurately describes the experimentally observed regulatory effects of cofactors on the OGDHC activity. This analysis provides a single consistent theoretical explanation for a number of apparently contradictory results on the roles of phosphorylation potential, NAD (H) oxidation-reduction state ratio, as well as the regulatory effects of metal ions on ODGHC function.

Author List

Qi F, Pradhan RK, Dash RK, Beard DA


Ranjan K. Dash PhD Professor in the Biomedical Engineering department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Ketoglutarate Dehydrogenase Complex
Models, Biological
Protein Conformation
Reproducibility of Results
jenkins-FCD Prod-468 69a93cef3257f26b866d455c1d2b2d0f28382f14