Desmosines, formation

For purposes of this manuscript, we wish to concentrate only on the steps leading to the formation of desmosines, amino acids found predominantly in elastin. With respect to their formation, the following suggests their spontaneous formation from peptidyl lysine and the oxidation product, peptidyl allysine. Narayanan et al. (28,29) have shown that when purified lysyl oxidase and non-crosslined elastin, specifically tropoelastin, are incubated together, the desmosines are formed. Desmosine formation, however, only occurs at temperatures that favor fibrillar arrangements of tropoelastin. Subsequently, it is felt that the maturation of non-crosslinked elastin into cross-linked elastin appears to involve only two major steps, namely insolublization through the formation of fibrils and fixation of the fibrils by crosslinking. 

Two types of crosslinking domains exist in tropoelastin those rich in alanine (KA) and those rich in proline (KP). Within the KA domains, lysine residues are typically found in clusters of two or three amino acids, separated by two or three alanine residues. These regions are proposed to be Q-helical with 3.6 residues per turn of helix, which has the effect of positioning two lysine sidechains on the same side of the helix, although there is no direct structural evidence (Brown-Augsburger et al., 1995 Sandberg et al, 1971), and facilitating the formation of desmosine crosslinks. Desmosine crosslinks are formed by the condensation of two allysine... 

To form the desmosines, three peptidyl allysine molecules and a molecule of peptidyl lysine must condense. The steps in condensation probably involve the formation of 1,2-dihydropyridines and 1,4-dihydropyridines as shown in Figure 4 (19-24,46,48). Several kinds of chemical evidence (46,48) suggest that the hydropyridines are easily oxidized under normal oxygen tension to corresponding pyridinium ions, such as the desmosines (isodesmosine or desmosine). The exact pathway by which the desmosines are formed, however, is still not clear. 

Figure 4. A general scheme for the formation of desmosine from lysine. The figure was adapted from W. R. Gray (19). Reactions within the box are considered to be reversible. Steps that result in the formation of lysinonorleucine, merodes-rnosine or desmosine are considered irreversible. Two separate pathways by which desmosine may be formed are indicated by the solid or broken lines.

Formation of desmosine and isodesmosine covalent cross-links in elastin. Three allysine residues (Ra, R3, and R4) and one lysyl residue (R ) condense to give a desmosine cross-link. The allysine residues ( -aldehydes) are derived from the oxidative deamination of lysyl residues. The isodesmosine cross-link is formed similarly, except that it contains a substitution at position 2 rather than at position 4, along with substitutions at 1,3, and 5 on the pyridinium ring. 

Figure I. Elastin cross-links formation. Lysine is converted into allysine via lysyl oxidase, which leads to the formation of lysinonor leucine and allysine aldol (blue). The spontaneous condensation between lysine and allysine will generate tetra-substituted desmosine and isodemosine cross-link structures (red). 

Narayanan, A. S., Page, R. C., Kuzan, F., and Cooper, C. G., 1978, Elastin cross-linking in vitro. Studies on factors influencing the formation of desmosines by lysyl oxidase action on tropoelastin, Biochem. J. 173 857-862. 

Partridge and co-workers (1964, 1966) proposed that the structural integrity of elastin results from the formation of cross-linking substances called desmosine and isodesmosine. This group also obtained experimental evidence which indicated that the cross-linking substances desmosine and isodesmosine in elastin are formed by the condensation of lysine residues in elastin precursors. Thus, the results of Starcher et al. (1964) could be explained by assuming that the increased lysine content of elastin from copper-deficient chick aorta resulted from a decreased conversion of lysine to desmosine. This assumption was confirmed by the experiments of Miller et al. (1965), who demonstrated that the desmosine content of copper-deficient tissue decreases as the lysine content increases. 

F. Formation of crosslinks in elastin forming desmosine and isodesmosine (Davis and... 

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