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Proteases are of great interest as possible drug targets, because they regulate many physiological processes including infection, cell growth and death, fertilization, inflammation, allergic reactions, bone remodeling, tumor growth and blood clotting. Bacterial proteases are critical to the toxicity of many pathogens as they commonly target host pathways that lead to the death of the host organism. Therefore, the development of novel drugs and antibiotics that target bacterial protease is of great importance. At present, there are five catalytic types of bacterial proteases that have been recognized. Four are based on the type of amino acid found at the active site (serine, threonine, cysteine, or aspartate), while the fifth type coordinates a metal ion in its active site. These metalloproteases (MPRs) are specific proteases use coordinated metal ions to attack the peptide bond to cleave proteins. The metal ion is usually zinc, cobalt, or manganese. Generally, MPRs are divided into two groups depending on how many metal ions are required in the catalytic mechanism. So far, most MPRs are one-metal-iondependent proteases, with the exception of some exopeptidases that require two catalytic metal ions for efficient cleavage. MPRs are widely used by bacteria and play various pathogenic roles in infection. For example, some bacteria use MPRs to process enterotoxin (e.g. cholera toxin) to their active state. Other bacteria use proteases as part of their toxins, which is the case for the Botulinum neurotoxins (BoNT) and Tetanus neurotoxins (TeNT) that use MPRs to directly cleave target host proteins. For these reasons, MPRs are important targets for compound screening.
Most MPRs are zinc-dependent proteases and are integral to virtually all aspects of metabolism.The consensus binding motif for zinc-containing metalloproteases is HEXXH, in which two histidine residues coordinate zinc divalent cationic binding. This zinc-binding motif has been found in the light chain of Clostridium Botulinum neurotoxins, Bacteroides fragilis enterotoxin, and Bacillus anthracis lethal factor. These light chain proteases require the presence of zinc for activity. Of specific interest to this work, Botulinum neurotoxin (BoNT) light chains cleave one of three soluble Nethylamaleimide-sensitive factor-attachment protein receptor (SNARE) proteins that are components of the neuroexocytosis machinery. Cleavage of these proteins leads to the blockade of neurotransmitter release and consequent paralysis. The light chain of Bacillus anthracis lethal toxin, known as lethal factor (LF) cleaves the mitogen-activated protein kinase-kinases (MAPKKs) at their amino-terminus. Though the toxicity of many bacterial toxins are due to the Zn metalloproteases activity, the Zn coordinating active site is highly conserved across many families of zinc metalloproteases. This makes it difficult to target the active site of toxin MPRs, as the numerous cellular Zn metalloproteases, such as matrix metalloprotease (MMPs) and metalloproteases with a disintegrin domain (ADAM) are critical for cell processes. Therefore, understanding the structure-activity relationships of these enzymes would be beneficial for the development of potential inhibitors. In addition, a further understanding of the mechanism of these enzymes will offer great opportunity for compound screening or create new and useful protease compounds that specifically target toxin MPRs.