hydroxylysine and Homocystinuria

The collagens are the major structural glycoproteins of connective tissues. A unique primary structure and a multiplicity of post-translational modification reactions are required for normal fibrillogenesis. The post-translational modifications include hydroxylation of prolyl and lysyl residues, glycosylation, folding of the molecule into triple-helical conformation, proteolytic conversion of precursor procollagen to collagen, and oxidative deamination of certain lysyl and hydroxylysyl residues. Any defect in the normal mechanisms responsible for the synthesis and secretion of collagen molecules or the deposition of these molecules into extracellular fibers could result in abnormal fibrillogenesis; such defects could result in a connective tissue disease. Recently, defects in the regulation of the types of collagen synthesized and in the enzymes involved in the post-translational modifications have been found in heritable diseases of connective tissue. Thus far, the primary heritable disorders of collagen metabolism in man include lysyl hydroxylase deficiency in Ehlers-Danlos syndrome type VI, p-collagen peptidase deficency in Ehlers-Danlos syndrome type VII, decreased synthesis of type III collagen in Ehlers-Danlos syndrome type IV, lysyl oxidase deficency in S-linked cutis laxa and Ehlers-Danlos syndrome type V, and decreased synthesis of type I collagen in osteogenesis imperfecta.

Topics: Aortic Diseases; Bone and Bones; Brain Diseases; Collagen; Connective Tissue; Cutis Laxa; Ehlers-Danlos Syndrome; Fascia; Genetic Linkage; Homocystinuria; Humans; Hydroxylysine; Hydroxyproline; Joints; Marfan Syndrome; Microbial Collagenase; Osteogenesis Imperfecta; Protein Biosynthesis; Protein Conformation; Protein-Lysine 6-Oxidase; Sex Chromosomes; Skin Abnormalities

Topics: Aging; Animals; Colchicine; Collagen; Collagen Diseases; Ehlers-Danlos Syndrome; Glucosyltransferases; Growth; Homocystinuria; Humans; Hydroxylysine; Hydroxyproline; Marfan Syndrome; Menkes Kinky Hair Syndrome; Penicillamine; Procollagen; Procollagen-Proline Dioxygenase; Protein Biosynthesis; Protein-Lysine 6-Oxidase; Scurvy; Skin; Transcription, Genetic; Vascular Diseases

The biochemical mechanism accounting for the connective tissue abnormalities in homocystinuria was explored by examining the effects of various amino acids known to accumulate in the plasma of patients with this disease on cross-link formation in collagen. Neutral salt solutions of purified, rat skin collagen, rich in cross-link precursor aldehydes, were polymerized to native type fibrils by incubating at 37 degrees C in the presence of homocysteine, homocystine, or methionine. After the polymerization was completed, each sample was examined for the formation of covalent intermolecular cross-links, assessed indirectly by solubility tests and directly by measuring the cross-link compounds after reduction with tritiated sodium borohydride and hydrolysis. Collagen solutions containing homocysteine (0.01 M-0.1 M) failed to form insoluble fibrils. Furthermore, much less of the reducible cross-links, Delta(6,7) dehydrohydroxylysinonorleucine, Delta(6,7) dehydrohydroxylysinohydroxynorleucine, and histidino-dehydrohydroxymerodesmosine were formed in the preparations containing homocysteine as compared with the control and the samples containing methionine or homocystine. The content of the precursor aldehydes, alpha-aminoadipic-delta-semialdehyde (allysine) and the aldol condensation product, was also markedly diminished in tropocollagen incubated with homocysteine. It is concluded that homocysteine interferes with the formation of intermolecular cross-links that help stabilize the collagen macromolecular network via its reversible binding to the aldehydic functional groups. Analysis of the collagen cross-links in skin biopsy samples obtained from three patients with documented homocystinuria showed that the cross-links were significantly decreased as compared with the age-matched controls, supporting the tentative conclusions reached from the in vitro model studies. In addition, the solubility of dermal collagen in non-denaturing solvents was significantly increased in the two patients examined, reflecting a functional defect in collagen cross-linking. Although the concentration of homocysteine used in this study to demonstrate these effects in vitro is clearly higher than that which is observed in homocystinuric's plasma, the data do suggest a possible pathogenetic mechanism of connective tissue defect in homocystinuria.

Topics: Adult; Aldehydes; Amino Acids; Biopsy; Borohydrides; Child; Collagen; Dialysis; Histidine; Homocysteine; Homocystine; Homocystinuria; Humans; Hydrolysis; Hydroxylysine; Methionine; Microscopy, Electron; Norleucine; Skin; Sodium; Solubility; Temperature; Time Factors; Tritium