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Structural Basis for Promoting and Preventing Decarboxylation in Glutaryl-Coenzyme A Dehydrogenases

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Demmer,  Ulrike
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Warkentin,  Eberhard
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Ermler,  Ulrich       
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Citation

Wischgoll, S., Demmer, U., Warkentin, E., Günther, R., Boll, M., & Ermler, U. (2010). Structural Basis for Promoting and Preventing Decarboxylation in Glutaryl-Coenzyme A Dehydrogenases. Biochemistry, 49(25), 5350-5357. doi:10.1021/bi100317m.


Cite as: https://hdl.handle.net/11858/00-001M-0000-0024-D71C-B
Abstract
Glutaryl-coenzyme A dehydrogenases (GDHs) involved in amino acid degradation were thought to catalyze both the dehydrogenation and decarboxylation of glutaryl-coenzyme A to crotonyl-coenzyme A and CO2. Recently, a structurally related but nondecarboxylating, glutaconyl-coenzyme A-forming GDH was characterized in the obligately anaerobic bacteria Desulfococcusmultivorans (GDHDes) which conserves the free energy of decarboxylation by a Na+-pumping glutaconyl-coenzyme A decarboxylase. To understand the distinct catalytic behavior of the two GDH types on an atomic basis, we determined the crystal structure of GDHDes with and without glutaconyl-coenzyme A bound at 2.05 and 2.1Å resolution, respectively. The decarboxylating and nondecarboxylating capabilities are provided by complex structural changes around the glutaconyl carboxylate group, the key factor being a Tyr -> Val exchange strictly conserved between the two GDH types. As a result, the interaction between the glutaconyl carboxylate and the guanidinium group of a conserved arginine is stronger in GDHDes (short and planar bidentate hydrogen bond) than in the decarboxylating human GDH (longer and monodentate hydrogen bond), which is corroborated by molecular dynamics studies. The identified structural changes prevent decarboxylation (i) by strengthening the C4-C5 bond of glutaconylcoenzyme A, (ii) by reducing the leaving group potential of CO2, and (iii) by increasing the distance between the C4 atom (negatively charged in the dienolate transition state) and the adjacent glutamic acid.