The dynamic determinants of reaction specificity in the IMPDH/GMPR family of (β/α)₈ barrel enzymes

Abstract

The inosine monophosphate dehydrogenase (IMPDH)/guanosine monophosphate reductase (GMPR) family of (β/α)₈ enzymes presents an excellent opportunity to investigate how subtle changes in enzyme structure change reaction specificity. IMPDH and GMPR bind the same ligands with similar affinities and share a common set of catalytic residues. Both enzymes catalyze a hydride transfer reaction involving a nicotinamide cofactor hydride, and both reactions proceed via the same covalent intermediate. In the case of IMPDH, this intermediate reacts with water, while in GMPR it reacts with ammonia. In both cases, the two chemical transformations are separated by a conformational change. In IMPDH, the conformational change involves a mobile protein flap while in GMPR, the cofactor moves. Thus reaction specificity is controlled by differences in dynamics, which in turn are controlled by residues outside the active site. These findings have some intriguing implications for the evolution of the IMPDH/GMPR family.

Keywords::

• Guanine nucleotide biosynthesis
• IMP dehydrogenase
• GMP reductase
• monovalent cation activation
• drug resistance
• water activation
• ammonia selectivity
• enzyme evolution

Acknowledgements

The author thanks Jeff Boucher for the alignment of IMPDH and GMPR sequences.

Declaration of interest

This work was supported by NIH grant GM054403 (LH). Molecular graphics images were produced using the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH P41 RR001081).

Editor: Michael M. Cox