|Lysyl oxidases: Cloning and characterization of the fourth and the fifth human lysyl oxidase isoenzymes, and the consequences of a targeted inactivation of the first described lysyl oxidase isoenzyme in mice|
Cells are the basic units of all living organisms. In multicellular organisms, cells are surrounded by several structural and functional proteins which are arranged as a large heterogenous network, the extracellular matrix. It consists of numerous compounds including insoluble fibers, microfibrils, soluble proteins, and glycoproteins. The extracellular matrix is essential for providing mechanical and physiological properties for various tissues, and it also provides attachment sites for the anchoring of cells and support for their migration in tissues.
Collagens are the most abundant proteins in the human body and they provide most of the tensile strength needed in several tissues. However, proper functioning of numerous tissues such as the skin, lungs, and vessels also requires elastic properties. This resiliency is provided mainly by elastic fibers, in which the main component is a protein called elastin. The mechanical and physiological properties of the insoluble fibers formed by the two proteins, collagens and elastin, are highly dependent on covalent cross-links, which stabilize their fibrillar structures and enhance their resistance to proteolysis. These cross-links are the final products of a reaction which is initiated by the oxidation of certain lysine and hydroxylysine residues. This reaction is accomplished by extracellular copper-dependent enzymes, lysyl oxidases.
In the present study, two of the five known human lysyl oxidase isoenzymes were identified and partially characterized at the molecular level. These new enzymes were named lysyl oxidase-like 3 protein (LOXL3) and lysyl oxidase-like 4 protein (LOXL4) based on their high degree of similarity to the already known three lysyl oxidase isoenzymes. The LOXL3 and LOXL4 gene products were shown to be secreted extracellular proteins. In addition to these new isoenzymes, mice lacking the first described lysyl oxidase isoenzyme (Lox) were generated to obtain information on the function of this isoenzyme. Lox was found to be essential for proper cardiovascular function, and depletion of its activity resulted in perinatal death in this mouse model.