Lysyl oxidase functions

After secretion from the cell, certain lysyl residues of tropoelastin are oxidatively deaminated to aldehydes by lysyl oxidase, the same enzyme involved in this process in collagen. However, the major cross-links formed in elastin are the desmosines, which result from the condensation of three of these lysine-derived aldehydes with an unmodified lysine to form a tetrafunctional cross-hnk unique to elastin. Once cross-linked in its mature, extracellular form, elastin is highly insoluble and extremely stable and has a very low turnover rate. Elastin exhibits a variety of random coil conformations that permit the protein to stretch and subsequently recoil during the performance of its physiologic functions. 

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... 

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). 

Figure 3.4 Factors affecting foreign body reaction and potential points of intervention at the level of the myofibroblast (1) inhibit synthesis or release of TGF-P (2) block stimulation by TGF-P of its membrane receptors on the activated fibroblast (3) inhibit the Smad proteins, which transfer the TGF-P effect to the nucleus (4) inhibit transcription of procollagen mRNA (5) inhibit translation of the message to form procollagen (6) inhibit prolyl-4-hydroxylase, which creates hydroxyproline and facilitates helix formation (7) inhibit lysyl oxidase, which cross-links the collagen (8) enhance the function of MMPs, which degrade collagen, or inhibit TIMPs, which degrade MMPs.

Lysyl oxidases catalyze the oxidation of the e-amino group in the side chain of lysine residues in proteins, producing a reactive aldehyde functional group, which can form Schiff-base adducts with unmodified lysine residues or undergo aldol addition, creating covalent cross-links between polypeptide chains. " Lysyl oxidases are widespread in nature, and have been isolated from organisms ranging from yeast to man. 

The collagen molecules formed by removal of the propeptides spontaneously assemble into fibrils. At this stage, the fibrils are still immature and lack tensile strength, which is acquired by cross-linking. The initial step in cross-link formation is the oxidative deamination of a-amino groups in certain lysyl and hydroxyly-syl residues catalyzed by lysyl oxidase. The enzyme is a copper-dependent (probably cupric) protein, and the reaction requires molecular oxygen and pyridoxal phosphate for full activity. Only native collagen fibrils function as substrates. 

Type 2 copper centers are not uniform in ligand or ligand stereochemistries. One common feature is, however, that in the active enzyme, one coordination site is always free to bind oxygen. The most common ligand in type 2 copper centers is histidine. Tyrosine (often modified), methionine, and cysteine occur as well. There are three histidines and a modified tyrosine in amine oxidase and lysyl oxidase [28]. In diamine oxidase, two of the histidine residues have probably been replaced by cysteines [29]. In galactose oxidase, the copper ion is coordinated by two tyrosines, two histidines and an acetate ion [30]. Dopamine-/J-hydroxylase contains two differently coordinated copper ions per functional unit. One is coordinated by three histidines and a methionine and the other by two histidines and another, yet unknown, ligand [ 31 ]. Last but not least, the type 2 copper ion in Cu,Zn-superoxide dismutase is coordinated by four histidine residues, one of which connects the copper ion to the zinc ion, the second metal ion in the active site of the enzyme [32,33] (Fig. 6). 

Maintenance and repair of duodenal and gastric collagen and elastin connective tissue components also seems to be an important copper-dependent enzyme function in preventing or repairing duodenal or gastric ulcers. Induction or facilitation of de novo synthesis of lysyl oxidase by copper complexes [16] merits consideration to account for the observed rapid and normal replacement of connective tissue components in the surgically placed gastric ulcer model [178]. 

A number of copper requiring enzymes are located at the cell surface or are exported into the extracellular milieu. Examples of such secretory Cu-enzymes include copper requiring ferroxidases that function in iron transport (e.g. ceruloplasmin, CP), enzymes for neurotransmission (peptidyl amidating enzyme and dopamine hydroxylase), an extracellular superoxide dismutase (SOD) that functions in antioxidant defense and enzymes for formation of connective tissue (lysyl oxidase), and pigments (tyrosinase) (reviewed in ). En route to their designated location, each of these enzymes passes through a specialized compartment of the late Golgi where copper insertion takes place. 

Another type of inportant structural ECM proteins, the elastin, is rich in elastic tissues and organs, such as the cardiovascular and pulmonary system and skin, and of extreme importance for their proper function. The precursors of native elastin, the tropoelastins, are composed of alternating hydrophobic domains, enabling hydrophobic interaction, and lysine-rich domains, allowing for covalent cross-linking through the mediation of the enzyme lysyl oxidase. 

In Menkes disease, copper is not absorbed in the intestine and is not available for distribution throughout the body. Consequently, cuproenzymes such as cytochrome c oxidase, lysyl oxidase, and dopamine beta hydroxylase cannot function normally. Sufferers exhibit severe developmental delay subnormal body temperature kinky, steel-colored hair seizures and ultimately the degeneration of muscle, bone, and organs. Baby boys bom with the most severe form of Menkes disease typically do not live beyond then-third year of life. 

A few metalloenzymes are involved in AA metabolism or reqnire AA as a cofactor, including ascorbate oxidase and prolyl and lysyl hydroxylase. The structure and function of these enzymes are discussed in Section IV.C. 

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