Metabolism of homocysteine thiolactone in human cell cultures: Possible mechanism for pathological consequences of elevated homocysteine levels

Research output: Contribution to journalArticle

243 Scopus citations

Abstract

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 β- 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.

Original languageEnglish (US)
Pages (from-to)1935-1942
Number of pages8
JournalJournal of Biological Chemistry
Volume272
Issue number3
StatePublished - Feb 1 1997

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Metabolism of homocysteine thiolactone in human cell cultures: Possible mechanism for pathological consequences of elevated homocysteine levels'. Together they form a unique fingerprint.

  • Cite this