Jump to main content
Jump to site search

Issue 21, 1995
Previous Article Next Article

3-Dimensional interactions between inositol monophosphatase and its substrates, inhibitors and metal ion cofactors

Abstract

Experiment has shown that bovine inositol monophosphatase requires the presence of two Mg2+ cations for activity, the second of which interacts either directly or indirectly with peripheral O-atoms on the substrate. Here we describe the 3-D structure of the active enzyme di-magnesium ion complex and the modelled binding modes for five known and dissimilar substrates, D-inositol 1-phosphate, L-inositol 1-phosphate, inositol 4-phosphate, 2′-adenosine monophosphate and ethane-1,2-diol 1-phosphate The expected location and functional role of the second metal ion within the protein in the presence of each of these substrates is very similar. The predicted binding modes and interactions with the metal ions and the protein are also presented for a range of known inhibitors. These structures highlight the small differences that exist between substrates and inhibitors in the mode of coordination for the first Mg2+ ion within the enzyme and the large differences that exist in the mode of binding for the second Mg2 + ion. This analysis indicates that the hydrolytic water molecule is located on the second Mg2+ ion and that hydrolysis proceeds via a non-inline, direct displacement. The so called ‘catalytic’ oxygen functionality of substrates serves as a hydrogen-bond acceptor for the hydrolytic water molecule and holds it on the second Mg2+ ion, but does not appear to bind to the metal ion directly. Some of the predictions of this refined new mechanism have been tested by experiment and the binding conformations of new potential inhibitors which may be able to block the site for the nucleophile on the second Mg2 + ion have been examined. A comparison of the proposed pseudorotation mechanism with an alternative in-line displacement mechanism is presented.

Back to tab navigation

Article type: Paper
DOI: 10.1039/P19950002709
Citation: J. Chem. Soc., Perkin Trans. 1, 1995,0, 2709-2727
  •   Request permissions

    3-Dimensional interactions between inositol monophosphatase and its substrates, inhibitors and metal ion cofactors

    J. Wilkie, A. G. Cole and D. Gani, J. Chem. Soc., Perkin Trans. 1, 1995, 0, 2709
    DOI: 10.1039/P19950002709

Search articles by author

Spotlight

Advertisements