- General characteristics of metalloproteinases
- -Metaloproteinases exopeptidases
- -Metaloproteinases endopeptidases
- Matrix Metalloproteinases (MMP)
- Collagenases (MMP-1, MMP-8, MMP-13, MMP-18)
- Gelatinases (MMP-2, MMP-9)
- Stromalysins (MMP-3, MMP-10, MMP-11)
- Matrilisins (MMP-7, MMP-26).
- Membrane associated metalloproteases (MT-MMP)
- Other matrix metalloproteinases
- -ADAM Proteins
- Other functions and alterations
- Protein modification
- Health effects
- Associated pathologies
- Therapeutic uses
The metalloproteinases or metalloproteases are enzymes that degrade proteins and that require the presence of a metal atom to have activity. The executive arm of all the activities carried out by a cell are enzymes.
Although many proteins have a structural role, a large number, if not most, have some catalytic activity. A group of these enzymes are responsible for degrading other proteins.
Collectively these enzymes are called proteinases or proteases. The group of proteases that require a metal atom to be active are called metalloproteinases.
Proteases, in general, fulfill an important and numerous group of tasks in a cell. The most global task of all is to allow the turnover of proteins present in a cell.
That is, eliminate old proteins, and allow their replacement by new proteins. New proteins are synthesized de novo on ribosomes during the translation process.
The most important role of metalloproteinases, in particular, is to regulate the behavior of the cell. This is achieved by this particular group of proteases by controlling the presence and time of presence of transcriptional regulators, response mediators, receptors, structural membrane proteins and internal organelles, etc.
Depending on their mode of degradation, proteases, including metalloproteinases, are classified into endoproteases (metalloendoproteases) or exoproteases (metalloexoproteases).
The former degrade proteins from one end of the protein (ie, amino or carboxyl). Endoproteases, on the other hand, cut inside the protein with a certain specificity.
General characteristics of metalloproteinases
Metalloproteinases are perhaps the most diverse group of proteases of the six that exist. Proteases are classified according to their catalytic mechanism. These groups are the cysteine, serine, threonine, aspartic acid, glutamic acid, and metalloproteinases proteases.
All metalloproteinases require a metal atom to perform their catalytic cleavage. The metals present in metalloproteinases mainly include zinc, but other metalloproteinases use cobalt.
In order to carry out its function, the metal atom must be coordinately complexed to the protein. This is done through four points of contact.
Three of them use one of the charged amino acids histidine, lysine, arginine, glutamate, or aspartate. The fourth coordination point is made by a water molecule.
The International Union of Biochemistry and Molecular Biology has established a classification system for enzymes. In this system, enzymes are identified by the letters EC and a coding system of four numbers.
The first number identifies enzymes according to their mechanism of action, and divides them into six large classes. The second number separates them according to the substrate on which they act. The other two numbers perform even more specific divisions.
Since metalloproteinases catalyze hydrolysis reactions, they are identified with the number EC4, according to this classification system. Additionally, they belong to subclass 4, which houses all hydrolases that act on peptide bonds.
Metalloproteinases, like the rest of the proteinases, can be classified according to the place of the polypeptide chain that attacks.
They act on the peptide bonds of the terminal amino acids of the polypeptide chain. All the metalloproteinases that have two catalytic metal ions and some with a single metal ion are included here.
They act on any peptide bond within the polypeptide chain, resulting in two lower molecular weight polypeptide molecules.
Many of the metalloproteinases with a single catalytic metal ion act in this way. This includes matrix metalloproteinases and ADAM proteins.
Matrix Metalloproteinases (MMP)
They are enzymes capable of acting catalytically on some components of the extracellular matrix. The extracellular matrix is the set of all the substances and materials that are part of a tissue and that are found on the outside of cells.
They are a large group of enzymes present in physiological processes, and participate in morphological and functional alterations of many tissues.
In skeletal muscles, for example, they play a very important role in the formation, remodeling and regeneration of muscle tissue. They also act on the various types of collagens present in the extracellular matrix.
Collagenases (MMP-1, MMP-8, MMP-13, MMP-18)
Hydrolytic enzymes that act on type I, II and III collagen found between cells. Product of the catabolism of these substances denatured collagen or gelatin is obtained.
In vertebrates, this enzyme is produced by different cells, such as fibroblasts and macrophages, as well as by epithelial cells. They can also act on other molecules of the extracellular matrix.
Gelatinases (MMP-2, MMP-9)
They help in the catabolism process of type I, II and III collagens. They also act on denatured collagen or gelatin obtained after the action of collagenases.
Stromalysins (MMP-3, MMP-10, MMP-11)
They act on type IV collagens and other molecules of the extracellular matrix associated with collagen. Its activity on gelatin is limited.
Matrilisins (MMP-7, MMP-26).
They are structurally simpler metalloproteinases than the others. They are related to tumor epithelial cells.
Membrane associated metalloproteases (MT-MMP)
These are part of the basement membranes. They participate in the proteolytic activities of other metalloproteinases in the matrix.
Neprilysin is a matrix metalloproteinase that has zinc as a catalyst ion. It is responsible for hydrolyzing the peptides at the amino-terminal hydrophobic residue.
This enzyme is found in numerous organs, including the kidney, brain, lung, vascular smooth muscle, as well as in endothelial, cardiac, blood, fat cells, and fibroblasts.
Neprilysin is essential for the metabolic degradation of vasoactive peptides. Some of these peptides act as vasodilators, but others have vasoconstrictive effects.
Neprisilin inhibition, in conjunction with angiotensin receptor inhibition, has become a very promising alternative therapy in the treatment of patients with heart failure.
Other matrix metalloproteinases
There are some metalloproteinases that do not fall into any of the above categories. Example of them we have the MMP-12; MMP-9; MMP-20; MMP-22; MMP-23 and MMP-28.
ADAMs (A Disintegrin And Metalloprotease, for its name in English) are a group of metalloproteinases, known as metalloproteases - disintegrins.
These include enzymes that cut or remove portions of proteins that are excluded from the cell by the cell membrane.
Some ADAMs, especially in humans, lack a functional protease domain. Its main functions include acting on spermatogenesis and sperm-ovum fusion. They are an important component of the venom of many snakes.
Other functions and alterations
Metalloproteinases can participate in the modification (maturation) of some proteins in post-translational processes.
This can occur concomitantly with, or subsequent to, the synthesis of the target protein or in the final site where it resides to exert its function. This is generally achieved with the cleavage of a limited number of amino acid residues from the target molecule.
In more extensive cleavage reactions, the target proteins can be completely degraded.
Any alteration in the functioning of metalloproteinases can have unwanted effects on human health. In addition, some other pathological processes involve in some way the participation of this important group of enzymes.
Matrix metalloproteinase 2, for example, plays an important role in cancer invasion, progression and metastasis, including endometrial cancer. In other cases, alteration of MME homeostasis has been linked to arthritis, inflammation, and some types of cancer.
Finally, metalloproteinases fulfill other functions in nature that are not directly related to the physiology of the individual that produces them. For some animals, for example, the production of poisons is important in their mode of survival.
In fact, the venom of many snakes contains a complex mix of bioactive compounds. Among them are several metalloproteinases that cause bleeding, tissue damage, edema, necrosis, among other effects in the victim.
It has been possible to determine that the enzymes of the MMP family participate in the development of various diseases; skin diseases, vascular dysfunctions, cirrhosis, pulmonary emphysema, cerebral ischemia, arthritis, periodontitis, and cancer metastasis, among others.
It is believed that the great variety of forms that can occur in matrix metalloproteinases may favor the alteration of various mechanisms of genetic regulation, thus leading to a change in the genetic profile.
To inhibit the development of pathologies associated with MMP, different inhibitors of metallopreinases, both natural and artificial, have been used.
Natural inhibitors have been isolated from numerous marine organisms, including fish, mollusks, algae, and bacteria. Synthetic inhibitors, for their part, generally contain a chelating group that binds and inactivates the catalytic metal ion. The results obtained with these therapies, however, have not been conclusive.
Matrix metalloproteinases have several therapeutic uses. They are used to treat burns, as well as various types of ulcers. They have also been used to remove scar tissue and to facilitate the regeneration process in organ transplants.
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