Lysylhydroxylases represent a group of enzymes responsible for the hydroxylation of lysine residues within proteins. Thus, they mainly participate in the formation of connective tissue. Disturbances in the function of lysylhydroxylases manifest themselves in such diseases as scurvy or hereditary Ehlers-Danlos syndrome.
What are lysylhydroxylases?
Lysylhydroxylases are enzymes whose function is to catalyze the posttranslational modification of the amino acid lysine by the incorporation of a hydroxyl group into hydroxyllysine. This strengthens the connective tissue because their protein chains are given the opportunity to cross-link further via the hydroxyl groups. Human lysylhydroxylase consists of 727 amino acids, among others. Lysylhydroxylases also belong to the group of hydroxylases, i.e. enzymes that generally catalyze the incorporation of hydroxyl groups into molecules. Thus, in addition to lysylhydroxylases, prolylhydroxylases, phenylalanine hydroxylase, tyrosine hydroxylase or tryptophan hydroxylase also belong to the group of hydroxylases or oxidoreductases. Especially together with the prolyl hydroxylases, the lysyl hydroxylases play an important role in the function of connective tissue. Both enzyme groups require the coenzyme vitamin C for their function.
Function, action, and roles
The function of lysylhydroxylases is exclusively to catalyze the incorporation of hydroxyl groups into lysine residues within a protein. In this process, the amino acid hydroxylamine is formed from lysine as part of a posttranslational modification. Although hydroxylamine also occurs freely, it cannot be incorporated into the protein in this form. Post-translational modification thus means the subsequent conversion of this amino acid after the protein has been built. With the exchange of a hydrogen atom for the hydroxyl group, a functional group is incorporated at this point in the protein that can perform bridging functions. With the help of the hydroxyl group, different protein chains can crosslink with each other. Furthermore, sugar molecules can bind to this functional group. Both reactions are, among other things, very important in the formation of connective tissue. The connective tissue surrounds the organism and the internal organs. It must be firm and taut in order to be able to separate the functionally different organs from each other. This is ensured by the proteins of the connective tissue, which contain a high percentage of the amino acids lysine and proline. After their incorporation into the protein, both amino acids are subsequently partially modified for this purpose by being given a hydroxyl group. As already mentioned, in the case of proline this reaction is catalyzed by prolyl hydroxylases and in the case of lysine by lysyl hydroxylases. Thus, after protein formation, these modification reactions provide a network of protein chains that represent tight connective tissue. Without the function of both enzymes, the formation of a functional connective tissue would not be possible at all. However, both enzymes function only with the help of the coenzyme ascorbic acid, i.e. vitamin C. Therefore, in the case of structurally altered enzymes due to mutation or a deficiency of vitamin C, the build-up of connective tissue may be disturbed, leading to serious diseases.
Formation, occurrence, properties, and optimal values
The gene PLOD1 is responsible for the coding of human lysylhydroxylase. The name PLOD1 is derived from the name of the lysylhydroxylase “procollagen lysine, 2-oxoglutarate-5-dioxygenase 1.” This gene is located on chromosome 1. Since new connective tissue is constantly produced, there is also a permanent need for the production of lysylhydroxylases. Therefore, a mutation of this gene can be very consequential for the health of the organism.
Diseases and disorders
Disorders in the function of lysylhydroxylases play a particularly important role in the diseases scurvy and Ehlers-Danlos syndrome. Scurvy is known as an ancient seafarer’s disease, which is caused by a deficiency of vitamin C. Vitamin C, also known as ascorbic acid, acts as a coenzyme of lysylhydroxylases and prolylhydroxylases. When it is lacking, the amino acids lysine and proline can no longer be hydroxylated in connective tissue protein. Since there is a constant building and breaking down of connective tissue proteins, the protein chains can cross-link less and less during the period of vitamin deficiency. The connective tissue becomes flabby and can no longer fulfill its function properly.A wide range of symptoms occur, including general exhaustion, susceptibility to infections, bleeding gums, tooth loss, poor healing of wounds, severe skin problems, muscle wasting and many other health impairments. Scurvy can eventually lead to death through general heart failure or severe infections. Ancient seafarers were particularly affected because they were unable to obtain vitamin C during long voyages at sea. It has been shown that the disease heals immediately when certain foods such as sauerkraut are given. The fact that the cause of the disease was a vitamin C deficiency was not recognized until later. However, the outbreak of the seafarer’s disease scurvy was later prevented by feeding the sailors sauerkraut. Another disease, but one that can only be partially attributed to a defect in human lysylhydroxylase, is Ehlers-Danlos syndrome. Ehlers-Danlos syndrome is a collective term for various hereditary connective tissue diseases with different causes. This syndrome is characterized by severe connective tissue weakness. The skin is overstretched and the joints are hypermobile. In this case, a genetically altered lysylhydroxylase triggers Ehlers-Danlos syndrome type VI. Responsible for this is a mutated gene called PLOD1, which is located on chromosome 1. The resulting defective enzyme is no longer fully functional and can only insufficiently catalyze hydroxylation reactions on lysine. A connective tissue weakness develops with the known symptoms as well as additional involvement of the eyes and internal organs. Ehlers-Danlos syndrome type VI is autosomal recessive.
