General Medical Information

Collagen Synthesis

David J. Terris

Collagen is the most common protein in the animal world and is the principal component of human connective tissue, making up nearly 30% of the total body protein. It is an extracellular protein that is manufactured intracellularly by fibroblasts. During wound healing, the transcription of procollagen mRNA is upregulated. The mRNA is extensively modified and then translated on the ribosomes of the rough endoplasmic reticulum; the procollagen protein then passes through the Golgi apparatus into the extracellular space. In the extracellular space, the procollagen undergoes enzymatic cleavage of its nonhelical ends and then spontaneously assembles into fibers. Collagen is unique because it contains the amino acids hydroxyproline and hydroxylysine; the hydroxylation occurs after the proline and lysine are incorporated into the collagen chain. This requires specific enzymes (prolyl and lysyl hydroxylase) and several cofactors and substrates, including ascorbic acid, iron, and a-ketoglutarate. Without the hydroxylation of proline and lysine, the collagen molecule is unstable and offers little resistance to enzymatic degradation. This results in a compromise of collagen production and insufficient wound strength, as occurs in patients with vitamin C deficiency or scurvy. The fact that fresh fruit is able to prevent this disease was appreciated by the British Navy at the turn of the century; thus, British sailors earned the name “limeys,” because they were required to travel with limes and other citrus fruits when away at sea for long periods of time. Other posttranslational steps in collagen synthesis include glycosylation by the addition of galactose and glucose to hydroxylysine residues, which is catalyzed by galactosyltransferase and glucosyltransferase, respectively.

In addition to its two unique amino acids, collagen is also notable for the arrangement of three a-peptide chains in a right-handed triple helix with glycine in every third position along the peptide chain. The triple helical configuration of collagen is achieved by proper alignment and formation of disulfide bridges between the carboxy-terminal ends of the three a-peptide chains, with intramolecular hydrogen bonding between the chains to maintain the helical structure. Triple collagen is soluble in water and must be cross-linked to render it insoluble; this cross-linkage provides tensile strength. The nature and degree of cross-linking imparts the collagen with its tissue-specific characteristics. Numerous types of cross-linking are possible and occur in two broad categories: intramolecular and intermolecular. The first step in cross-linking is the conversion of peptide-bound lysine and hydroxylysine residues to aldehydes by means of the enzyme lysyl oxidase. This oxidative deamination yields the corresponding semialdehydes, allysine and hydroxyallysine. This step may be inhibited by administration of b(-aminopropionitrile, D-penicillamine, and isoniazid. These substances have been used with limited success experimentally in an effort to prevent excessive collagen formation. Intermolecular disulfide bonds are important cross-links because they may provide a rapid and efficient method of cross-linking fibers in proliferating tissues, such as healing wounds.

The inflammatory response to injury, and the proliferation of fibrosis that follows, are modulated by a number of variables, including cytokine activity. Several cytokines, transforming growth factor (TGF)-b, interleukin-1, and tumor necrosis factor-a, each contributes to an increase in the steady-state production of collagen. The role of cytokines in wound healing is addressed in greater detail below.