Metabolism of homocysteine thiolactone in human cell cultures. Possible mechanism for pathological consequences of elevated homocysteine levels.
Editing of the non-protein amino acid homocysteine, a frequent type of error-correcting process in amino acid selection for protein synthesis by an aminoacyl-tRNA synthetase, results in formation of a cyclic thioester, homocysteine thiolactone. Here it is shown that human cells in which homocysteine metabolism is deregulated by a mutation in the cystathionine beta-synthase gene and/or by an antifolate drug, aminopterin (which prevents remethylation of homocysteine to methionine by methionine synthase), produce more homocysteine thiolactone, in addition to homocysteine, than unaffected cells. The thiolactone is incorporated into cellular and extracellular proteins, in addition to being secreted and hydrolyzed to homocysteine. Experiments with model proteins and amino acids suggest that the mechanism of incorporation involves acylation of side chain amino groups of lysine residues by the activated carboxyl group of the thiolactone. The metabolic conversion of homocysteine to homocysteine thiolactone and the reactivity of the thiolactone toward proteins may explain pathological consequences of elevated levels of homocysteine such as observed in vascular disease.
Jakubowski
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Department of Microbiology & Molecular Genetics, University of Medicine & Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07103, USA. jakubows@umdnj.edu
D000596:Amino Acids / Q000378:metabolism; D002478:Cells, Cultured; D046508:Culture Techniques; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000378:metabolism*; D006801:Humans; D011506:Proteins / Q000378:metabolism
D000596:Amino Acids; D011506:Proteins; D006710:Homocysteine; C007957:homocysteine thiolactone