Structural insights into the catalytic reaction trigger and inhibition of d-3-hydroxybutyrate dehydrogenase

d-3-Hydroxybutyrate dehydrogenase catalyzes the reversible conversion of acetoacetate and d-3-hydroxybutyrate. These ketone bodies are both energy-storage forms of acetyl-CoA. In order to clarify the structural mechanisms of the catalytic reaction with the cognate substrate d-3-hydroxybutyrate and of the inhibition of the reaction by inhibitors, the enzyme from Alcaligenes faecalis has been analyzed by X-ray crystallography in liganded states with the substrate and with two types of inhibitor: malonate and methylmalonate. In each subunit of the tetrameric enzyme, the substrate is trapped on the nicotinamide plane of the bound NAD+. An OMIT map definitively shows that the bound ligand is d-3-hydroxybutyrate and not acetoacetate. The two carboxylate O atoms form four hydrogen bonds to four conserved amino-acid residues. The methyl group is accommodated in the nearby hydrophobic pocket so that the formation of a hydrogen bond from the OH group of the substrate to the hydroxy group of Tyr155 at the active centre is facilitated. In this geometry, the H atom attached to the C3 atom of the substrate in the sp3 configuration is positioned at a distance of 3.1 Å from the nicotinamide C4 atom in the direction normal to the plane. In addition, the donor–acceptor relationship of the hydrogen bonds suggests that the Tyr155 OH group is allowed to ionize by the two donations from the Ser142 OH group and the ribose OH group. A comparison of the protein structures with and witho...
Source: Acta Crystallographica Section F - Category: Biochemistry Authors: Tags: X-ray crystal structure d-3-hydroxybutyrate dehydrogenase substrate inhibitor catalytic reaction trigger ketone bodies acetyl-CoA research communications Source Type: research

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