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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 

Discriminatory influence of Glu-376-->Asp mutation in medium-chain acyl-CoA dehydrogenase on the binding of selected CoA-ligands: spectroscopic, thermodynamic, kinetic, and model building studies.

We investigated the influence of Glu-376-->Asp (E376D) mutation on the UV/visible spectral, thermodynamic, and kinetic properties for the interaction of structurally different types of CoA-ligands (viz., octenoyl-CoA, acetoacetyl-CoA, and indoleacryloyl-CoA) to human liver medium-chain acyl-CoA dehydrogenase (MCAD). Whereas the E376D mutation had minimal/negligible effect on the above properties for the binding of octenoyl-CoA to the enzyme, it had pronounced effects (albeit in opposite directions) for the binding of acetoacetyl-CoA and indoleacryloyl-CoA to the enzyme. In the case of acetoacetyl-CoA, the spectrum of the enzyme-ligand complex (in the charge-transfer region; lambdamax = 545 nm) was 1.8-fold more pronounced, and the DeltaH degrees value for the binding of acetoacetyl-CoA to the enzyme was 5.6 kcal/ mol more favorable with wild-type as compared to the E376D mutant enzyme. The kinetic data revealed that the above effects were related to an increase in the dissociation "off-rate" of acetoacetyl-CoA from the enzyme-acetoacetyl-CoA complex. In contrast, in the case of IACoA, the resultant UV/visible spectrum of the enzyme-IACoA complex (lambdamax = 416 nm) was 2.7-fold less pronounced, and the DeltaH degrees value of the enzyme-IACoA complex was 6.4 kcal/ mol less favorable with the wild-type than the E376D mutant enzyme. The latter effects were supported by the fact that the above mutation impaired the dissociation "off-rate" of IACoA from the enzyme-IACoA complex by 5.7-fold. Molecular model building studies revealed that the discriminatory influence of the E376D mutation on the spectral, thermodynamic, and kinetic properties of the enzyme-ligand complexes is due to ligand-specific changes in the spatial relationship between the FAD and CoA-ligands at the enzyme site. Arguments are presented that the "void" created by excision of a methylene group from Glu-376 (upon Glu-376-->Asp mutation) is adjusted differently upon interaction with structurally different types of CoA-ligands.[1]

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