BIOCHEMISTRY: A TEXTBOOK FOR MEDICAL UNIVERSITIES - E. S. Severin - 2004

CHAPTER 15. BIOCHEMISTRY OF THE EXTRACELLULAR MATRIX

II. Elastin

Elastin is the major protein of elastic fibers, which are abundant in the Extracellular matrix of Tissues such as Skin, Blood vessel walls, ligaments, and Lungs. These tissues possess remarkable mechanical properties: they can stretch to several times their initial length while maintaining high tensile strength, and return to their original state upon the release of tension. The rubber-like properties of these tissues are determined by the Composition and Structure of elastin, a glycoprotein with a molecular mass of 70 kDa.

A. Structure of Elastin

1. Amino Acid Composition and conformational features of elastin are described in Chapter 1 of the textbook.

Significance of Desmosine and Lysinonorleucine

In the extracellular space, elastin molecules form fibers and sheets in which individual peptide chains are linked by numerous rigid cross-links into a branched network. The formation of these cross-links involves Lysine residues from two, three, or four peptide chains. The resulting structures are known as desmosines (desmosine or isodesmosine). It is hypothesized that these heterocyclic compounds are formed as follows: first, 3 lysine residues are oxidized to their corresponding ε-aldehydes, which then condense with a fourth lysine residue to form a substituted pyridine ring. The oxidation of lysine residues to ε-aldehydes is catalyzed by copper-dependent lysyl oxidase, an activity that also depends on the presence of pyridoxine (see Section I, B).

Class="center">Desmosine (formed by four lysine residues)

In addition to desmosines, lysinonorleucine, formed by two lysine residues, can also participate in the formation of cross-links.

Lysinonorleucine (formed by two lysine residues)

The presence of covalent cross-links between peptide chains with a disordered, random conformation allows the entire network of elastin fibers to stretch and recoil in various directions, imparting elasticity to the respective tissues (Fig. 15-12).

Fig. 15-12. Elastin molecules are linked by covalent cross-links into an extensive network.

It should be noted that elastin is synthesized as a soluble monomer called tropoelastin. Following cross-linking, elastin acquires its final extracellular form, which is characterized by insolubility, high stability, and a very low turnover rate.

Disorders of Elastin Structure and Their Consequences

When desmosine formation is reduced or absent, cross-links are insufficient or fail to form altogether. As a result, elastic tissues exhibit a lower tensile strength and develop abnormalities such as thinning, laxity, and excessive extensibility, effectively losing their rubber-like properties. Clinically, such defects may manifest as cardiovascular alterations (aneurysms and aortic ruptures, Heart valve defects), frequent Pneumonia, and pulmonary emphysema.

Causes of Elastin Structural Defects

✵ decreased lysyl oxidase activity caused by copper or pyridoxine deficiency;

✵ lysyl oxidase deficiency in hereditary disorders;

✵ Menkes disease, characterized by impaired copper absorption.

B. Catabolism of Elastin

Digestion of Elastin

Native dietary elastin is not hydrolyzed by Trypsin and Chymotrypsin, but is slowly cleaved by Pepsin at pH 2.0. Pancreatic Elastase hydrolyzes elastin following a distinct lag phase. It is an endopeptidase that preferentially cleaves peptide bonds formed by the carboxyl groups of aliphatic Amino Acids.

Degradation of Elastin

Elastin catabolism involves neutrophil elastase. This highly active protease is secreted into the extracellular space by neutrophils, where it breaks down elastin and other structural Proteins. This process is of particular importance in the lungs. Because lung tissue does not regenerate, the destruction of elastin in the alveolar walls leads to a loss of elastic properties, alveolar destruction, and The Development of pulmonary emphysema (overinflation of the lungs with air or gas generated within the tissues).

Under normal conditions, this does not occur because neutrophil elastase and other proteases are inhibited by a protein known as α₁-antitrypsin (α₁-AT). The bulk of α₁-AT is synthesized by The Liver and circulates in the blood. In the lungs, α₁-AT is synthesized by alveolar macrophages, which protects the alveoli from the action of elastase (Fig. 15-13). An α₁-AT deficiency, which can result from various Mutations in the Gene encoding this protein, increases the risk of developing pulmonary emphysema. Currently, this condition can be prevented and treated through weekly intravenous administration of α₁-AT.

Fig. 15-13. Destruction of pulmonary alveoli by neutrophil elastase.