About Matrix Metalloproteinase / MMP:
MMPs, also known as matrix metalloproteinases or matrixins, are metalloproteinases that are part of a larger group of proteases called the metzincin superfamily. There are several other family members, including: Astacins, Serralysins & adamalysins
MMPs are zinc-dependent endopeptidases, which play a role in the degradation of ECM (extracellular matrix). MMPs are excreted by several different types of connective tissue cells and cells involved in bringing about a pre-inflammatory response. In normal physiological conditions, the expression of MMPs is very low, and this means that homeostasis can be maintained. MMP expression is regulated by growth factors, hormones and cytokines, so levels can vary. MMPs are controlled by specific inhibitors known as TIMPs.
MMPs share a common domain structure, which takes one of three forms: pro-peptide, catalytic, and hemopexin-like C.
Pro-peptide, initially, the MMPs are created as inactive zymogens, and the pro-peptide domain must be removed to activate the enzyme. This is part of the ‘cysteine switch’ that contains a cysteine residue that engages with zinc to keep the enzyme in an inactive state.
Catalytic, X-ray images suggest that catalytic domains have a spherical structure, which contain a minute groove that constitutes the active site. Within the active site, there is a Zn 2+ ion, which is connected to three histidine residues.
Hemopexin-like C, the hemopexin-like C terminal is attached to catalytic domains via a hinge, which comprises up to 75 amino acids. This domain has similar structural properties to serum protein hemopexin.
Matrix Metalloproteinase Function
MMPs have a number of important roles, which are involved in both physiological and pathological processes, including: Morphogenesis, Repair of tissue, Cirrhosis, Arthritis, Metastasis, Angiogenesis
MMP-2 and MMP-9 are particularly instrumental when discussing MMPs and metastasis. A lack of balance between MMPs and TIMPs has also been identified as a key characteristic of cardiovascular disease, partly because excess MMPs can contribute to the degradation of vital structures within the aortic wall. Dysregulation of MMPs has also been flagged in patients with arthritis, some forms of cancer, recurrent ulcers, and encephalomyelitis.
MMPs can degrade ECM proteins, including collagen, fibronectin, and laminin during the proliferation of cancer cells and metastasis. In this case, MMPs are predominantly produced by stromal and inflammatory cells, which are found around the tumour. Studies also suggest that malignant cancerous cells can employ MMPs to dissolve protective membranes to bring about invasion and metastasis.
MMP Mechanisms and interactions
Every MMP is synthesised as pre-proenzymes, known as zymogens, which require extracellular activation. MMPs can be activated by a number of different mechanisms, such as other proteases, proteinases, other active MMPs, chaotropic agents, and organomercurial compounds.
MMPs are inhibited by a group of protease inhibitors known as TIMPs (tissue inhibitor of metalloproteinases), which comprises TIMP-1, TIMP-2, TIMP-3 and TIMP-4.