Structural basis for the bi-functionality of human oxaloacetate decarboxylase FAHD1

We present crystallographic data of human FAHD1 that provide new insights into the structure of the catalytic center at high resolution, featuring a flexible ‘lid’-like helical region which folds into a helical structure upon binding of the ODx inhibitor oxalate. The oxalate-driven structural transition results in the generation of a potential catalytic triad consisting of E33, H30 and an associated water molecule. In silico docking studies indicate that the substrate is further stabilized by a complex hydrogen-bond network, involving amino acids Q109 and K123, identified herein as potential key residues for FAHD1 catalytic activity. Mutation of amino acids H30, E33 and K123 each had discernible influence on the ApH and/or ODx activity of FAHD1, suggesting distinct catalytic mechanisms for both activities. The structural analysis presented here provides a defined structural map of the active site of FAHD1 and contributes to a better understanding of the FAH superfamily of enzymes.

Source: Biochemical Journal - November 20, 2018 Category: Biochemistry Authors: Weiss, A. K. H., Naschberger, A., Loeffler, J. R., Gstach, H., Bowler, M. W., Holzknecht, M., Cappuccio, E., Pittl, A., Etemad, S., Dunzendorfer-Matt, T., Scheffzek, K., Liedl, K. R., Jansen-Dürr, P. Tags: Research Articles Source Type: research