Matrix metalloproteinases (MMPs) are a protein family within the metzincin superfamily, comprising zinc-dependent endopeptidases with similar structural characteristics but with different substrate preferences. MMPs are produced and secreted from cells as inactive proenzymes depending, herein, on a structural alteration for activation [1,2,3,4,5,6]. In human tissues, there are 23 different types of MMPs expressed and they can be subdivided according to their substrate specificity, sequential similarity, and domain organization [1,2,4,7,8,9,10,11,12,13,14,15,16,17] (Table 1).

The most common structural features shared by MMPs are [1,2,4,5,7,8,10,11,12,13,14,16,18] (Figure 1) a pro-domain, a catalytic domain, a hemopexin-like domain, and a transmembrane domain for membrane-type MMPs (MT-MMPs) although some MMPS do not have all the structural features represented in the figure. The pro-domain keeps MMP inactive by a cysteine switch, which interacts with the catalytic zinc making it impossible to connect the substrate. The catalytic domain has two zinc ions, three calcium ions, and three histidine residues, which are highly conserved [1,2,3,4,5,6,7,8,9,11,12,13,14,15,16,17,18,19,20]. In the terminal zone of the catalytic domain, there is a region that forms the outer wall of the S₁’ pocket [1,14,17]. This pocket is the most variable region in MMPs and it is a determining factor for substrate specificity [1,2,6,7,11,17,18]. However, there are six pockets (P₁, P₂, P₃, P₁’, P₂’, and P₃’) and the fragments of the substrates or inhibitors are named depending on the interaction with these pockets (R₁, R₂, R₃, R₁’ or R_a, R₂’, and R₃’). The linker is proline-rich, of variable length, allowing inter-domain flexibility and enzyme stability [4,8,12,13]. The hemopexin-like domain is necessary for collagen triple helix degradation and is important for substrate specificity [3,4,7,9,19].

The MMPs can process ECM proteins and glycoproteins, membrane receptors, cytokines, hormones, chemokines, adhesion molecules, and growth factors [1,3,4,6,7,9,10,11,13,14,20,21,22,23,24,25,26]. However, the presence and the activity of MMPs have been demonstrated to be intracellular [25,26]. For example, some studies show intracellular localization of MMP-2 in cardiac myocytes and colocalization of MMP-2 with troponin I in cardiac myofilaments [23]. The MMP-2 activity has also been detected in nuclear extracts from the human heart and rat liver [23]. The MMPs are involved in many biologic processes, such as tissue repair and remodulation, cellular differentiation, embryogenesis, angiogenesis, cell mobility, morphogenesis, wound healing, inflammatory response, apoptosis, ovulation, and endometrial proliferation [1,2,4,6,8,10,11,13,16,17,18,20,27]. The deregulation of MMPs activity leads to the progression of various pathologies depending on which enzyme is involved [1,6,10,13,14,15,16,17,20,27]: cancer and metastasis, inflammatory processes, arthritis, ulcers, periodontal diseases, brain degenerative diseases, liver cirrhosis, fibrotic lung diseases, otosclerosis, atherosclerosis, multiple sclerosis, dilated cardiomyopathy, aortic aneurysm, or varicose veins.

Although therapeutic strategies for specific inhibition of MMPs have been long researched, they are difficult to develop because these enzymes are involved in a myriad of pathways [2,5]. However, this inhibition can be done at the biomolecular expression and active enzyme terms [2,5,18]. The MMPs inhibitors can be divided into endogenous inhibitors, which can be specific or non-specific, and synthetic inhibitors [1,2,4,7,10,12,13,14,16,20,28,29] (Table 2).