Hydroxylysine is a nonclassical proteinogenic amino acid. It is incorporated into the corresponding protein as lysine and hydrolyzed to hydroxylysine within the polypeptide with the help of an enzyme. It represents one of the main components of collagen proteins of connective tissue.
What is hydroxylysine?
Hydroxylysine is a proteinogenic amino acid that is first incorporated into a protein as lysine. Therefore, it is a non-canonical proteinogenic amino acid. The term “canonical” means classical. So there is no separate codon for this amino acid. Hydroxylysine is mainly found in the collagen of connective tissue and in glycoproteins. There, lysine is converted into hydroxylysine by enzymatic processes. In the process, only part of the lysine is converted into hydroxylysine. The properties of the respective collagens depend on the amount of hydrolyzed lysine and proline residues. In free form, hydroxylysine can be isolated as hydrochloride. The hydrochloride of hydroxylysine is a beige powder with a melting point that ranges from 225 to 230 degrees. It is a basic amino acid, which also makes proteins containing hydroxylysine react basic. Hydroxylysine was discovered by American biochemist and co-founder of “clinical chemistry” Donald Van Slyke (1883 – 1971).
Function, action, and roles
Hydroxylysine has a great importance in the construction of connective tissue. Glycoproteins also contain hydroxylysine to form glycosidic bonds of the protein with sugar residues at the hydroxyl residue. Within collagen, it is responsible for cross-linking the individual protein molecules. Together with hydroxylproline, the hydrolyzed form of proline, it is also instrumental in building the tertiary and quaternary structures of collagen. The hydroxylation of lysine is catalyzed by the enzyme lysylhydroxylase with the participation of the cofactors iron ions and ascorbic acid (vitamin C). The distribution pattern of hydroxylated lysine residues in collagen is neither particularly rigid nor flexible. There are recurring patterns. However, there are also entire areas within the protein that do not contain hydroxylated lysine residues. While hydroxyproline is responsible for the helical structure of collagen by binding three protein chains, cross-links between the different protein molecules are formed via the hydroxyl groups of hydroxylysine. In addition, these molecular groups also serve as a binding site for a glycosidic bond with a sugar. Overall, this ensures the strength of the connective tissue. If there is a deficiency of hydroxylysine within the proteins, it cannot be remedied by additional intake of the amino acid. There is no codon for free hydroxylysine, so its incorporation into the corresponding protein is not possible. The value of dietary supplements with additions of hydroxylysine is therefore highly questionable. Therefore, the deficiency must be due to insufficient hydroxylysis of lysine.
Formation, occurrence, properties, and optimal values
Hydroxylysine is found only in the collagen of humans and animals. In addition, there are several glycoproteins that also contain hydroxylysine. These include adiponectin, among others. Adiponectin is a hormone that is produced in adipose tissue and has a significant influence on the effectiveness of insulin. Hydroxylysine has also been detected in some bacteria such as Staphylococcus aureus. The distribution of hydroxylated lysine is not uniform in collagen. There are positions where it is almost always found. In other areas, hydroxylysine is almost never found. This uneven distribution determines the structure of collagen. Within the triple helix structure of collagen, hydroxylysine is always found at the Y position of the Gly-X-Y repeating sequence. In the short regions with nonhelical structure, hydroxylysine also occurs in other positions.
Diseases and disorders
Connective tissue is absolutely dependent on the presence of hydroxylysine. Collagen can only be stable and strong if the cross-links of the protein molecules also function. A deficiency of hydroxylysine causes connective tissue weakness. If it is present only in extremely small amounts or not at all, the corresponding organism would not be viable. The connective tissue would no longer be able to perform its function as a limiting and supporting tissue for the organs. In fact, there are diseases that are due to a deficiency of hydroxylysine.Since this amino acid is initially incorporated as lysine during protein biosynthesis, it cannot be a primary deficiency. Hydroxylysine is formed from lysine within the collagen protein with the help of lysylhydroxylases. Thus, hydroxylysine deficiency can only result from a defect in this enzyme or its inadequate function. Thus, there is a group of heterogeneous congenital connective tissue deficiencies known as Ehlers-Danlos syndrome. A number of mutations can be responsible for this clinical picture. Among other things, lysylhydroxylase may be defective, so that too little lysine is hydroxylated. Ehlers-Danlos syndrome is manifested by overstretching of the skin and overmovement of the joints. Internal organs, vessels, tendons, ligaments and muscles are also affected. The prognosis depends on the severity of the defect. If the vessels are involved, an unfavorable course is to be expected. Complete failure of the lysylhydroxylase enzyme is incompatible with life and is therefore not observed. However, even with an intact enzyme, connective tissue weakness may occur under certain circumstances due to its low activity. Lysylhydroxylase requires iron ions and ascorbic acid (vitamin C) as cofactors. If, for example, vitamin C is lacking, so-called scurvy occurs. Scurvy is an acquired disease of connective tissue caused by missing hydroxyl groups on proline and lysine residues of collagen. The cause is low activity of proline hydroxylase and lysine hydroxylase due to ascorbic acid deficiency.
