Lysyl oxidase roles

Copper is a component of many enzymes including amine oxidase, lysyl oxidase, ferroxidase, cytochrome oxidase, dopamine P-hydroxylase, superoxide dismutase and tyrosinase. This latter enzyme is present in melanocytes and is important in formation of melanin controlling the colour of skin, hair and eyes. Deficiency of tyrosinase in skin leads to albinism. Cu " ion plays an important role in collagen formation. 

The storage role of (Cu,Zn)-SOD in seeds e.g. seems plausible, when the Cu-carrier function of ceruloplasmin is considered The lipophilic anti-inflammatory and anti-ulcer Cu-chelates could also raise the Cu concentration in certain tissues and thus enhance their lysyl oxidase activity. But especially Cu(acetylsalicylate)2 inhibited protine,2-oxoglutarate dioxygenase (EC 1.14.11.2) and lysine,2-oxoglutarate dioxygenase (EC 1.14.1.4), which are also important enzymes in the processing of collagen... 

Lysine tyrosylquinone (LTQ). Another copper amine oxidase, lysyl oxidase, which oxidizes side chains of lysine in collagen and elastin (Eq. 8-8) contains a cofactor that has been identified as having a lysyl group of a different segment of the protein in place of the - OH in the 2 position of topaquinone.465 Lysyl oxidase plays an essential role in the crosslinking of collagen and elastin. 

Copper is an essential component of numerous key metalloenzymes which are critical in melanin formation, myelin formation and crosslinking of collagen and elastin. Copper plays a vital role in hemopoiesis, maintenance of vascular and skeletal integrity, and structure and function of the nervous system. Thus a deficiency of copper can lead to a variety of adverse effects such as increased fragility in bones, aneurysm formation in arteries and a loss of lysyl oxidase activity in cartilage.54 57 Articles on copper also appear in Siget1, volumes 3 and 5, all of volumes 12 and 13, and volume 14,... 

Tropoelastin molecules are crosslinked in the extracellular space through the action of the copper-dependent amine oxidase, lysyl oxidase. Specific members of the lysyl oxidase-like family of enzymes are implicated in this process (Liu etal, 2004 Noblesse etal, 2004), although their direct roles are yet to be demonstrated enzymatically. Lysyl oxidase catalyzes the oxidative deamination of e-amino groups on lysine residues (Kagan and Sullivan, 1982) within tropoelastin to form the o-aminoadipic-6-semialdehyde, allysine (Kagan and Cai, 1995). The oxidation of lysine residues by lysyl oxidase is the only known posttranslational modification of tropoelastin. Allysine is the reactive precursor to a variety of inter- and intramolecular crosslinks found in elastin. These crosslinks are formed by nonenzymatic, spontaneous condensation of allysine with another allysine or unmodified lysyl residues. Crosslinking is essential for the structural integrity and function of elastin. Various crosslink types include the bifunctional crosslinks allysine-aldol and lysinonorleucine, the trifunctional crosslink merodes-mosine, and the tetrafunctional crosslinks desmosine and isodesmosine (Umeda etal, 2001). 

Jensen, S. A., Vrhovski, B., and Weiss, A. S. (2000). Domain 26 of tropoelastin plays a dominant role in association by coacervation./. Biol. Chem. 275, 28449-28454. Kagan, H. M., and Sullivan, K. A. (1982). Lysyl oxidase Preparation and role in elastin biosynthesis. Methods Enzymol. 82, 637-650. 

Figure 2. Synthesis of mature elastin fibers. Some evidence suggests the possibility for proforms to elastin that appear as the first products of translation. These products are cleaved to tropoelastin (27), which appears to combine with microfibrillar protein. Although post-translational events important to the synthesis of the microfibrillar protein have not been defined, it is clear that it is a major component on which is organized or assembled the profibrillar forms of elastin. Cross-linking is catalyzed by lysyl oxidase, a copper-requiring protein (30). Recent information on the elastin proteinase(s) involved in tropoelastolysis would suggest that proteolysis may also play a role in elastin fiber...

Recently it has been demonstrated by Rayton and Harris (30) that the role of copper, in addition to its presumed role as a cofactor, is related to the induction of lysyl oxidase. Cycloheximide, but not actinomycin D, completely inhibits the incorporation of 64cuII into lysyl oxidase. They suggest that the mechanism may be similar to the induction of ferritin by iron. 

With such an ill-defined substrate, and the requirement of a partial purification of lysyl oxidase before assay (46,47), the examination of the enzyme s role in maturation or pathological processes has been less than quantitative. However, the availability of the purified enzyme has allowed several investigators... 

Anderson C, Bartlett SJ, Gansner JM, Wilson D, He L, Gitlin JD, Kelsh RN, Dowden J. Chemical genetics suggests a critical role for lysyl oxidase in zebrafish notochord morphogenesis. Mol. Biosyst. 2007 3 51-59. 

Copper plays an important role in the constituents of many enzymes of the mammalian organism as well as in plants and anthropods. Several classes of oxidizing enzymes for copper have been described, including the cytochrome oxidases which are the terminal oxidases in the mitochondrial electron transport system, a key reaction in energy metabolism (34), and the amine oxidases (35) of which there are a number that contain copper (36,37,38), Lysyl oxidase (39) is probably the most important since it plays a major role in elastin and collagen synthesis... 

Kagan HM, Sullivan KA (1982) Lysyl oxidase preparation and role in elastin biosynthesis. Methods Enzymol 82 Pt A 637-650... 

Copper-zinc superoxide dismutase (CuZn-SOD) inhibits cell-mediated oxidation of LDL, but transgenic mice overexpressing CuZn-SOD might have increased atherosclerotic lesion area (388). The role of copper in atherosclerosis is difficult to predict and the studies are conflicting copper is an intrinsic constituent of SOD and ceruloplasmin and a component of Lysyl oxidase (the enzyme involved in collagen synthesis, a major component of ECM). Also, copper ions catalyze oxidative modification of LDL in vitro and possibly in vivo (reviewed in ref. 389). 

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