|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|
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In spite of the major structural differences between collagens and elastin, both proteins contain lysine or hydroxylysine-derived covalent cross-links, the formation of which is catalyzed by the family of lysyl oxidase enzymes. The locations of these cross-links depend on the amino acid sequence and quaternary structural arrangements, but may also be quite flexible (Siegel 1974, Kagan et al. 1984, Nagan & Kagan 1994, for reviews, see Kielty et al. 1993 and Smith-Mungo & Kagan 1998). Lysyl oxidases oxidatively deaminate certain lysine and hydroxylysine residues in collagens and lysine residues in elastin to form the corresponding α-aminoadipic-δ-semialdehydes, usually referred to by their trivial names as allysine and hydroxyallysine (Figure 1) (Pinnell & Martin 1968, Kagan 1986, Reiser et al. 1992, Kielty et al. 1993, Kagan 1994, Bateman et al. 1996, Cleary & Gibson 1996).
Figure 1. Lysyl oxidase oxidatively deaminates a peptidyl lysine to generate a peptidyl α-aminoadipic-δ-semialdehyde (allysine), which spontaneously reacts with corresponding aldehydes to form various di-, tri-, or tetrafunctional cross-links (Kagan 1986).
In collagens, the lysine and hydroxylysine-derived cross-links are essential in providing the tensile strength and mechanical stability of the collagen fibrils and other supramolecular assemblies (Light & Bailey 1980, Bateman et al. 1996, Bailey 2001). Two related cross-linking pathways can be distinguished for collagens because the oxidations are restricted to two specific lysine and hydroxylysine residues, one in each of the N- and C-terminal telopeptide sequence (see Figure 2A) (Eyre et al. 1984, Kagan 1986, 1994, Reiser et al. 1992, Kielty et al. 1993). The lysine aldehyde pathway occurs primarily in the adult skin, cornea, and sclera (Eyre 1987), whereas the hydroxylysine aldehyde pathway occurs primarily in the bone, cartilage, ligament, tendons, embryonic skin, and most major internal connective tissues of the body (Kielty et al. 1993). Oxidative deamination is followed by spontaneous condensation reactions that result in various bi-, tri-, and tetrafunctional cross-links (Figure 2A). Lysine- and hydroxylysine-derived aldehydes can react with corresponding aldehydes on adjacent polypeptide chains forming aldol condensation products, or with unmodified lysine and hydroxylysine residues, forming bifunctional cross-links, such as lysinonorleucine and hydroxylysinonorleucine. The aldol condensation products can also react with a histidine residue to form aldol histidine, which may further react with an additional lysine residue to form the tetrafunctional cross-link histidinohydroxymerodesmosine (Reiser et al. 1992). In the hydroxylysine pathway, the bifunctional cross-links spontaneously undergo an Amadori rearrangement, resulting in ketoimine cross-links, which then mature further into trifunctional 3-hydroxypyridinium and lysyl pyridinium cross-links (Reiser et al. 1992, Bailey et al. 1998, Byers 2001).
Figure 2. Reactions of lysine and hydroxylysine in the biosynthesis of the cross-links in collagens (A) and elastin (B). After oxidative deamination to form reactive aldehydes, subsequent condensation reactions result in various bi-, tri-, and tetrafunctional cross-links. To simplify, intermediates in the reactions are not shown.
The most important feature of elastin, crucial for its proper functioning in elastic fibers, is the high degree of cross-linking of the individual polypeptide chains (Kielty et al. 1993). Approxymately 30 of the 40 lysine residues per 1000 amino acids present in tropoelastin, the precursor of elastin, are oxidated to aldehydes (Eyre et al. 1984, Kagan 1986, 1994, Reiser et al. 1992, Rosenbloom 1993, Rosenbloom et al. 1993). Tropoelastin differs from collagens in that it has no hydroxylysine or histidine residues, and therefore only lysine-derived cross-links are found in mature elastin (Rosenbloom 1993). In addition, certain condensation products, such as desmosines and isodesmosines, are specific for elastin and are not found in collagens (Reiser et al. 1992, Kielty et al. 1993, Rosenbloom 1993). The cross-links in elastin are otherwise formed in a similar manner as those in collagens (see Figure 2B). Two allysines can form an aldol condensation product, and one allysine can form lysinonorleucine with an unmodified lysine residue. Aldol condensation of the product with an unmodified lysine residue results in the trifunctional merodesmosine. Further condensation of a dehydrated aldol condensation product with dehydrolysinonorleucine, or reaction of merodesmosine with allysine results in the tetrafunctional desmosine and isodesmosine cross-links (Reiser et al 1992, Rosenbloom 1993).