Unraveling the Structure and Mechanism of the MST(ery) Enzymes

Abstract

The menaquinone, siderophore, and tryptophan (MST) enzymes transform chorismate to generate precursor molecules for the biosynthetic pathways defined in their name. Kinetic data, both steady-state and transient-state, and X-ray crystal structures indicate that these enzymes are highly conserved both in mechanism and in structure. Because these enzymes are found in pathogens but not in humans, there is considerable interest in these enzymes as drug design targets. While great progress has been made in defining enzyme structure and mechanism, inhibitor design has lagged behind. This review provides a detailed description of the evidence that begins to unravel the mystery of how the MST enzymes work, and how that information has been used in inhibitor design.

Chorismate- and isochorismate converting enzymes: versatile catalysts acting on an important metabolic node

“…§ Rather than providing an exhaustive compilation of original experiments, we aimed to prepare a general overview serving as a starting point for research into the field and as a complement to a wealth of prior subfamily-and subtopic-specific reviews. [6][7][8][9][10][11][12][13] In addition, recent advances in the field and their potential influence on the understanding of chorismate-converting enzymes in general are highlighted, followed by a brief overview of novel chorismate-derived natural products and biocatalytic applications of chorismate-converting enzymes.…”

Helices on interdomain interface couple catalysis in the ATPPase domain with allostery inPlasmodium falciparumGMP synthetase

“…A design involving intricate organization of the two domains enables allosteric activation of the GATase domain, coordination of the catalytic events and ammonia tunnelling in all GATs. The reactions catalysed by GATs are indispensable for various cellular functions, and hence, many GATs are being pursued as drug targets against cancer, infectious pathogens and towards development of herbicides [9][10][11][12][13].…”

“…From these structures, it is clear that variations in ammonia tunnelling mechanisms exist. Whereas, preformed conduits for tunnelling ammonia are seen in some, in other cases tunnel is evident upon substrate binding [7,9,20]. Examples of triad GATs in whose structures a tunnel cannot be visualized are also present [25].…”

Plants fight fungi using kiwellin proteins

“…Chorismate is a key metabolite molecule in plants, and enzymes that use it compete to co-opt the molecule into their respective biosynthetic pathways, which generate molecules that include amino acids, hormones, vitamins and plant cell-wall components 13 . Enzymes that use chorismate have similar structures and reaction mechanisms 14,15 . The ability of ZmKWL1 to inhibit Cmu1 with such specificity raises the question of whether other kiwellins in plants have evolved to specifically inhibit related enzymes, including isochorismatases.…”