Hydroxyproline collagen structure

Vitamin C is essential for the formation of collagen, the principal structural protein in skin, bone, tendons, and ligaments, being a cofactor in the hydroxylation of the amino acids proline to 4-hydroxyproline, and of lysine to 5-hydroxylysine. These hydroxyamino acids account for up to 25% of the collagen structure. Vitamin C is also associated with some other hydroxylation reactions, e.g. the hydroxylation of tyrosine to dopa (dihydroxyphenylalanine) in the pathway to catecholamines (see Box 15.3). Deficiency leads to scurvy, a condition characterized by muscular pain, skin lesions, fragile blood vessels, bleeding gums, and tooth loss. Vitamin C also has valuable antioxidant properties (see Box 9.2), and these are exploited commercially in the food industries. 

Ramachandran, G. N., Bansal, M., and Bhatnagar, R. S. (1973). A hypothesis on the role of hydroxyproline in stabilizing collagen structure. Biochim. Biophys. Acta 322,166-171. 

The role of carbohydrates in collagen structure is still controversial. The hydroxyproline residues in collagen are required for stabilization of the triple helix by hydrogen bond formation. In the absence of vitamin C (scurvy), the melting temperature of collagen can drop from 42°C to 24°C, because of the loss of interstrand hydrogen bond formation from the lack of hydroxyproline residues. 

Early in our studies it was expected that the post-translational modification of proline hydroxylation, so important to proper collagen structure and function, would raise the value of the temperature, T, for the onset of the inverse temperature transition for models of elastin. Accordingly, hydroxyproline (Hyp) was incorporated by chemical synthesis into the basic repeating sequence to give the protein-based polymers poly[fvs,i(Val-Pro-Gly-Val-Gly), fHyp( al-Hyp-Gly-Val-Gly)], where f sl -i- fnyp = 1 and values of fnyp were 0, 0.01, and 0.1. The effect of prolyl hydroxylation is shown in Figure 7.49. Replacement of proline by hydroxyproline markedly raises the temperature for hydrophobic association. Prolyl hydroxylation moves the movable cusp of... 

For the regular 61y-X-Y part of the collagen structures I now propose an assemblage of 3-stacks, similar to that represented in Figure 1 (but with left-handed helices, requiring an interchange of the C-H and C-R bond locations in the projection). Certain modifications of the structure at and near proline and hydroxyproline residues are also necessary. 

The amino acids proline and hydroxyproline exert a stabilizing influence on the triple helix as described in detail in Sect. 4.5. By examining the CB peptides of collagen, a structural stability which is directly proportional to the itnino acid content may thus be found. It has, however, not been possible to synthesize model peptides displaying structural stability comparable to that of the native peptides having corresponding amino acid contents. 

Fig. 4. Helical structure of collagen, typical amino acid sequence within a collagen strand, and exchangeable versus non-exchangeable hydrogen atoms in an individual leucine molecule (Gly - glycine. Pro - Proline, Leu - leucine. Hyp - hydroxyproline.

The many (possibly more than 30) types of collagens found in human connective tissues have substantially the same chemical structure consisting mainly of glycine with smaller amounts of proline and some lysine and alanine. In addition, there are two unusual amino acids, hydroxyproline and hydroxylysine, neither of which has a corresponding base-triplet or codon within the genetic code. There is therefore, extensive post-translational modification of the protein by hydroxylation and also by glycosylation reactions. 

Although the exact amino acid sequence differs between the various collagens, the primary structure usually conforms to a repeating tripeptide Gly-X-Y where X and Y are, proline, lysine, or hydroxyproline, hydroxylysine respectively. A single unit of collagen is a triple helix composed of three a chains. This conformation differs from the common a helix found in proteins in two important ways ... 

So what does this magical molecule do Actually, it does two things, one rather more crystalline clear than the other. The crystal clear thing that ascorbic acid does is act as coenzyme for an enzyme known as prolyl hydroxylase. This enzyme catalyzes the conversion of the amino acid proline to hydroxyproline, a major, if exotic, amino acid in the structural protein collagen ... 

Collagen synthesized in the absence of ascorbic acid (i.e. without hydroxyproline) cannot form its usual stable structure. Collagen is a major component of the structural and connective tissues of the body bone, cartilage, tendons, ligaments, teeth, and skin. Small wonder that things sort of fall apart in the absence of adequate ascorbic acid to support the activity of prolyl hydroxylase. 

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