Metal-dependent inhibition and substrate promiscuity in metallo-deacylases

Inhibitors of Histone Deacetylases enzymes (HDACs) are attractive anticancer compounds because HDACs are directly involved in post translational modifications of proteins, for example, the acetylation of histone lysine residues alters interactions with the DNA backbone. Several classes of HDACs are known to be hydrolytic metalloenzyme that can exhibit a wide range of catalytic activities when substituted with different transition metal ions, indeed different metal ions in metalloenzymes can affect enzyme function by maintaining the structure of the active site, but providing alternative coordination interactions for substrate, transitions states and intermediates. We are exploring the behavior of metalloisomorfs of bacterial N-succinyl-l,l-diaminopimelic acid desuccinylase (dapE), a model metallohydrolase with similarities to HDACs. A deeper understanding of the substrate binding-mode on the metal catalytic active site and a closer look to the coordination chemistry of different metals, would allow us to design new possible substrates and inhibitors of dapE and therefore have an insights into the molecular interactions of metal-targeting compounds with zinc dependent metalloenzymes that may assist the design of drug compounds and potentially provide new strategies to overcome drug-resistance