Macromolecular basis for homocystein-induced changes in proteoglycan structure in growth and arteriosclerosis.
Cell culture monolayers deficient in cystathionine synthetase bound more inorganic sulfate than normal cell monolayers during growth to confluence; this was correlated with the production of granular proteoglycan by the abnormal cells and fibrillar proteoglycan by normal cells. Homocysteine was demonstrated to be an active precursor of esterified sulfate, confirming our previous finding of this sulfation pathway in liver. The cell cultures deficient in cystathionine synthetase were found to assume an abnormal cellular distribution on the surface of the culture dish, resembling the distribution assumed by neoplastic cells with loss of contact inhibition; the degree of abnormality of the cellular distribution was correlated with the amount of granular proteoglycan produced by the cells and the amount of inorganic sulfate binding by the cell monolayers. Pyridoxine was found to increase the growth rate of cell cultures from a patient with pyridoxineresponsive homocystinuria and to increase the production of fibrillar proteoglycan by the cells; no effect of pyridoxine was observed in the cell cultures from a patient who failed to respond to pyridoxine therapy. The findings suggest that the change in macromolecular conformation of cellular proteoglycans from fibrillar to granular is due to increased sulfation of the carbohydrate envelope of the molecule. The significance of the findings is related to the pathogenesis of homocystinuria, the phenomenon of contact inhibition, the action of growth hormone and initiation of arteriosclerotic plaques.
D001161:Arteriosclerosis / Q000201:enzymology / Q000209:etiology / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D003260:Contact Inhibition; D003594:Cytoplasmic Granules; D013006:Growth Hormone / Q000494:pharmacology; D006710:Homocysteine / Q000378:metabolism*; D006712:Homocystinuria / Q000201:enzymology / Q000209:etiology / Q000378:metabolism; D006801:Humans; D012695:L-Serine Dehydratase / Q000378:metabolism*; D046911:Macromolecular Substances; D011134:Polysaccharides / Q000378:metabolism*; D011736:Pyridoxine / Q000494:pharmacology; D013431:Sulfates / Q000378:metabolism
D046911:Macromolecular Substances; D011134:Polysaccharides; D013431:Sulfates; D006710:Homocysteine; D013006:Growth Hormone; D012695:L-Serine Dehydratase; D011736:Pyridoxine